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Jones CE, Blouin S, Raimann A, Mindler G, Contento BM, Besio R, Kranzl A, Kraler B, Hartmann MA, Forlino A, Fratzl-Zelman N. Mineralised bone properties in a child with recessive osteogenesis imperfecta type XIV and in a conditional Tmem38b knockout murine model (Runx2-Cre; Tmem38b fl/fl). Bone 2025; 193:117421. [PMID: 39904399 DOI: 10.1016/j.bone.2025.117421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/20/2025] [Accepted: 01/30/2025] [Indexed: 02/06/2025]
Abstract
INTRODUCTION OI type XIV is caused by variants in the TMEM38B gene, encoding for the ubiquitously expressed endoplasmic reticulum trimeric intracellular cation channel type B (TRIC-B), causing disruptions in calcium homeostasis and collagen synthesis. Patients with OI type XIV present with a highly variable clinical phenotype, ranging from asymptomatic to severe. We present here data from a 6 year clinical follow-up of two affected siblings and bone tissue characterisation obtained during corrective surgery from one of the patients, as well as tibiae from a novel Tmem38b conditional knockout murine model (Runx2-Cre; Tmem38bfl/fl). METHODS Clinical examinations of the patients include bone mineral density (BMD) measurements using dual-energy x-ray absorptiometry (DXA) scanning and gait analyses. Quantitative backscattered electron imaging (qBEI) was used to investigate bone mineralisation density distribution (BMDD) and osteocyte lacunae properties, and confocal laser scanning microscopy was used to quantify the osteocyte lacuno-canalicular network (OLCN) in both human and murine specimens. RESULTS Both patients (P1, P2) presented with muscular hypotension, fatigue, progression of lower limb deformities, and fractures. BMDD of the osteonal bone region of the tibia and fibula specimens obtained from P1 revealed no significant shift towards higher mineral content as seen in "classical" OI. Osteocyte lacunae porosity was elevated and analyses of the OLCN revealed a reduction in canalicular density and lacunar degree. Runx2-Cre; Tmem38bfl/fl mice exhibited a very severe skeletal phenotype, with 10/12 of the tibiae showing evidence of fractures, bone deformations, or calluses. In contrast to the patient samples, both the cortex and metaphysis of mutant mice demonstrated a significant increase in the average mineral content (CaMean) and the peak of the distribution (CaPeak), as well as in osteocyte lacunae porosity (P < 0.0001), whereas canalicular density (P < 0.0001), and lacunar degree (P = 0.0004) were decreased. CONCLUSION While Runx2-Cre; Tmem38bfl/fl mice exhibit hypermineralisation of the bone matrix, this is not apparent in bone specimens obtained from the OI type XIV patient. However, both human and murine bone tissue with absence of TRIC-B demonstrate the same abnormalities of the osteocyte lacunae porosity and osteocyte lacuno-canalicular network, indicating disruption to the OLCN which is likely a general hallmark of OI bone.
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Affiliation(s)
- Chloe E Jones
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria
| | - Stéphane Blouin
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria; Vienna Bone and Growth Centre, Vienna, Austria
| | - Adalbert Raimann
- Vienna Bone and Growth Centre, Vienna, Austria; Department of Paediatrics and Adolescent Medicine, Division of Paediatric Pulmonology, Allergology and Endocrinology, Medical University of Vienna, Vienna, Austria
| | - Gabriel Mindler
- Vienna Bone and Growth Centre, Vienna, Austria; Department of Paediatric Orthopaedics, Orthopaedic Hospital Speising, Vienna, Austria
| | - Barbara M Contento
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Andreas Kranzl
- Vienna Bone and Growth Centre, Vienna, Austria; Laboratory for Gait and Movement Analysis, Orthopaedic Hospital Speising, Vienna, Austria
| | - Benjamin Kraler
- Vienna Bone and Growth Centre, Vienna, Austria; Department of Paediatric Orthopaedics, Orthopaedic Hospital Speising, Vienna, Austria
| | - Markus A Hartmann
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria; Vienna Bone and Growth Centre, Vienna, Austria
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria; Vienna Bone and Growth Centre, Vienna, Austria.
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Barnes AM, Mitra A, Knue MM, Derkyi A, Dang Do A, Dale RK, Marini JC. CRTAP-Null Osteoblasts Have Increased Proliferation, Protein Secretion, and Skeletal Morphogenesis Gene Expression with Downregulation of Cellular Adhesion. Cells 2025; 14:518. [PMID: 40214472 PMCID: PMC11988066 DOI: 10.3390/cells14070518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/24/2025] [Accepted: 03/26/2025] [Indexed: 04/14/2025] Open
Abstract
Type VII osteogenesis imperfecta (OI), caused by recessive CRTAP mutations, is predominantly lethal in the first year of life. Due to its early lethality, little is known about bone dysplasia mechanism. RNA-seq analysis of differentiated osteoblasts of siblings with a non-lethal homozygous CRTAP-null variant showed an enrichment of gene ontology terms involved in DNA replication and cell cycle compared to control. BrdU incorporation confirmed a ≈2-fold increase in proliferation in non-lethal proband osteoblasts in comparison to control cells. In addition, the expression of cyclin dependent kinase inhibitor 2A (CDKN2A), encoding a protein involved in cell cycle inhibition, was significantly reduced (>50%) in CRTAP-null osteoblasts, while cyclin B1 (CCNB1), encoding a promoter of the cell cycle, was enhanced. Ossification and bone and cartilage development gene ontology pathways were enriched among upregulated genes throughout osteoblast differentiation, as was protein secretion. Ingenuity pathway analysis indicated an upregulation of BMP2 signaling, supported by increase in both BMP2 and MSX2, an early BMP2-responsive gene, by qPCR. Throughout differentiation, CRTAP-null osteoblasts showed a decrease in transcripts related to cell adhesion and extracellular matrix organization pathways. We propose that increased proliferation and osteogenesis of type VII OI osteoblasts may be stimulated through upregulation of BMP2 signaling, altering bone homeostasis, and leading to weaker bones.
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Affiliation(s)
- Aileen M. Barnes
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA
| | - Apratim Mitra
- Bioinformatics & Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA
| | - Marianne M. Knue
- Office of the Clinical Director, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA; (M.M.K.)
| | - Alberta Derkyi
- Office of the Clinical Director, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA; (M.M.K.)
| | - An Dang Do
- Office of the Clinical Director, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA; (M.M.K.)
| | - Ryan K. Dale
- Bioinformatics & Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA
| | - Joan C. Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA
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Chaugule S, Constantinou CK, John AA, Micha D, Eekhoff M, Gravallese E, Gao G, Shim JH. Comprehensive Review of Osteogenesis Imperfecta: Current Treatments and Future Innovations. Hum Gene Ther 2025; 36:597-617. [PMID: 39932815 PMCID: PMC11971546 DOI: 10.1089/hum.2024.191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 01/08/2025] [Indexed: 02/13/2025] Open
Abstract
Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility due to reduced bone quality, often accompanied by low bone mass, recurrent fractures, hearing loss, skeletal abnormalities, and short stature. Pathogenic variants in over 20 genes lead to clinical and genetic variability in OI, resulting in diverse symptoms and severity. Current management involves a multidisciplinary approach, including antiresorptive medications, physiotherapy, occupational therapy, and orthopedic surgery, which provide symptomatic relief but no cure. Advancements in gene therapy technologies and stem cell therapies offer promising prospects for long-lasting or permanent solutions. This review provides a comprehensive overview of OI's classification, pathogenesis, and current treatment options. It also explores emerging biotechnologies for stem cells and gene-targeted therapies in OI. The potential of these innovative therapies and their clinical implementation challenges are evaluated, focusing on their imminent success in treating bone disorders.
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Affiliation(s)
- Sachin Chaugule
- Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | | | - Aijaz Ahmad John
- Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Dimitra Micha
- Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam; Amsterdam Rare Bone Disease center, Amsterdam Bone Center, Amsterdam Movement Sciences, Amsterdam Reproduction and Development, Amsterdam, The Netherlands
| | - Marelise Eekhoff
- Department of Internal Medicine, Section Endocrinology & Metabolism, Amsterdam UMC, Vrije Universiteit Amsterdam; Amsterdam Rare Bone Disease center, Amsterdam Bone Center, Amsterdam Movement Sciences, Amsterdam Reproduction and Development Amsterdam, Amsterdam, Netherlands
| | - Ellen Gravallese
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Viral Vector Core, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Jae-Hyuck Shim
- Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
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Fanis P, Morrou M, Tomazou M, Alghol HAM, Spyrou GM, Neocleous V, Phylactou LA. Identification of puberty related miRNAs in the hypothalamus of female mice. Mol Cell Endocrinol 2025; 598:112468. [PMID: 39842623 DOI: 10.1016/j.mce.2025.112468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 01/03/2025] [Accepted: 01/20/2025] [Indexed: 01/24/2025]
Abstract
BACKGROUND AND AIMS Puberty is a crucial developmental stage marked by the transition from childhood to adulthood, organized by complex hormonal signaling within the neuroendocrine system. The hypothalamus, a central region in this system, regulates pubertal functions through the hypothalamic-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH) neurons, essential in puberty control, release GnRH in a pulsatile manner, initiating the production of sex hormones. Major influence in pubertal timing has been attributed to genetic predisposition, environmental factors, and nutritional status. MicroRNAs (miRNAs), small non-coding RNA molecules, have emerged as key regulators in various cellular processes by either repressing genes or activating them by inhibiting their repressors. The present study aims to investigate the involvement of miRNAs in the control of puberty. METHODS Small RNA sequencing was used to identify and compare the total population of miRNAs in the hypothalamus of female mice before, during and after puberty. Bioinformatic analysis was applied to analyse the expression profile of miRNAs with altered levels followed by pathway enrichment analysis. RESULTS Expression levels of several miRNAs were found up- or down-regulated from pre-pubertal to pubertal stage. Furthermore, monitoring the levels of these miRNAs at the post-pubertal stage revealed four expression patterns, in which pathway analysis displayed the associations of these miRNAs with developmental processes, cell cycle regulation, metabolic biosynthesis and epigenetic regulation. CONCLUSION The findings of the present study improve our understanding of the molecular pathways underlying puberty and stress the significance of miRNAs in fine-tuning gene expression within the hypothalamus during this critical developmental stage.
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Affiliation(s)
- Pavlos Fanis
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Maria Morrou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Marios Tomazou
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Hend Abdulgadr M Alghol
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - George M Spyrou
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Vassos Neocleous
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Leonidas A Phylactou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
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Jovanovic M, Marini JC. Update on the Genetics of Osteogenesis Imperfecta. Calcif Tissue Int 2024; 115:891-914. [PMID: 39127989 PMCID: PMC11607015 DOI: 10.1007/s00223-024-01266-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024]
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal dysplasia characterized by bone fragility and deformity, growth deficiency, and other secondary connective tissue defects. OI is now understood as a collagen-related disorder caused by defects of genes whose protein products interact with collagen for folding, post-translational modification, processing and trafficking, affecting bone mineralization and osteoblast differentiation. This review provides the latest updates on genetics of OI, including new developments in both dominant and rare OI forms, as well as the signaling pathways involved in OI pathophysiology. There is a special emphasis on discoveries of recessive mutations in TENT5A, MESD, KDELR2 and CCDC134 whose causality of OI types XIX, XX, XXI and XXI, respectively, is now established and expends the complexity of mechanisms underlying OI to overlap LRP5/6 and MAPK/ERK pathways. We also review in detail new discoveries connecting the known OI types to each other, which may underlie an eventual understanding of a final common pathway in OI cellular and bone biology.
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Affiliation(s)
- Milena Jovanovic
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
- Section on Adolescent Bone and Body Composition, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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Sobaihi M, Habiballah AK, Habib AM. TMEM38B Gene Mutation Associated With Osteogenesis Imperfecta. Cureus 2024; 16:e69021. [PMID: 39385871 PMCID: PMC11463972 DOI: 10.7759/cureus.69021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2024] [Indexed: 10/12/2024] Open
Abstract
Osteogenesis imperfecta is a genetic disorder characterized by decreased bone density, bone deformities, and fractures. It results from mutations in different genes, including all steps of collagen 1 synthesis and modifications. In addition, the gene is involved in the homeostasis of intracellular calcium. TMEM38B is a gene involved in the formation of a cation channel responsible for calcium entry intracellularly. Mutations in this gene are associated with osteogenesis imperfecta. However, this mutation has not been frequently discussed in the literature. In our study, we report a case of TMEM38B-associated autosomal recessive osteogenesis imperfecta in a child of a consanguineous family presented with a history of multiple prenatal and postnatal fractures. No other associated complications are present in our case.
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Affiliation(s)
- Mrouge Sobaihi
- Department of Pediatric, King Faisal Specialist Hospital and Research Centre, Jeddah, SAU
| | - Abdullah K Habiballah
- Department of Pediatric, King Faisal Specialist Hospital and Research Centre, Jeddah, SAU
| | - Abdulrahman M Habib
- Department of Pediatric, King Faisal Specialist Hospital and Research Centre, Jeddah, SAU
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7
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Koshevaya YS, Turkunova ME, Vechkasova AO, Serebryakova EA, Donnikov MY, Papanov SI, Chernov AN, Kolbasin LN, Kovalenko LV, Glotov AS, Glotov OS. Exome Sequencing for the Diagnostics of Osteogenesis Imperfecta in Six Russian Patients. Curr Issues Mol Biol 2024; 46:4106-4118. [PMID: 38785520 PMCID: PMC11119099 DOI: 10.3390/cimb46050252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/26/2024] [Accepted: 04/27/2024] [Indexed: 05/25/2024] Open
Abstract
Osteogenesis imperfecta (OI) is a group of inherited disorders of connective tissue that cause significant deformities and fragility in bones. Most cases of OI are associated with pathogenic variants in collagen type I genes and are characterized by pronounced polymorphisms in clinical manifestations and the absence of clear phenotype-genotype correlation. The objective of this study was to conduct a comprehensive molecular-genetic and clinical analysis to verify the diagnosis of OI in six Russian patients with genetic variants in the COL1A1 and COL1A2 genes. Clinical and laboratory data were obtained from six OI patients who were observed at the Medical Genetics Center in Saint Petersburg from 2016 to 2023. Next-generation sequencing on MGISEQ G400 (MGI, China) was used for DNA analysis. The GATK bioinformatic software (version 4.5.0.0) was used for variant calling and hard filtering. Genetic variants were verified by the direct automatic sequencing of PCR products using the ABI 3500X sequencer. We identified six genetic variants, as follows pathogenic c.3505G>A (p. Gly1169Ser), c.769G>A (p.Gly257Arg), VUS c.4123G>A (p.Ala1375Thr), and c.4114A>T (p.Asn1372Tyr) in COL1A1; and likely pathogenic c.2035G>A (p.Gly679Ser) and c.739-2A>T in COL1A2. In addition, clinical cases are presented due to the presence of the c.4114A>T variant in the COL1A2 gene. Molecular genetics is essential for determining different OI types due to the high similarity across various types of the disease and the failure of unambiguous diagnosis based on clinical manifestations alone. Considering the variable approaches to OI classification, an integrated strategy is required for optimal patient management.
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Affiliation(s)
- Yulia S. Koshevaya
- Saint-Petersburg State Medical Diagnostic Center (Genetic Medical Center), 194044 Saint Petersburg, Russia; (Y.S.K.); (M.E.T.); (A.O.V.); (E.A.S.)
| | - Mariia E. Turkunova
- Saint-Petersburg State Medical Diagnostic Center (Genetic Medical Center), 194044 Saint Petersburg, Russia; (Y.S.K.); (M.E.T.); (A.O.V.); (E.A.S.)
- Federal State Budget Institution of Higher Education “North-Western State Medical University named after I.I Mechnikov”, Ministry of Public Health of the Russian Federation, 191015 Saint Petersburg, Russia
| | - Anastasia O. Vechkasova
- Saint-Petersburg State Medical Diagnostic Center (Genetic Medical Center), 194044 Saint Petersburg, Russia; (Y.S.K.); (M.E.T.); (A.O.V.); (E.A.S.)
| | - Elena A. Serebryakova
- Saint-Petersburg State Medical Diagnostic Center (Genetic Medical Center), 194044 Saint Petersburg, Russia; (Y.S.K.); (M.E.T.); (A.O.V.); (E.A.S.)
| | - Maxim Yu. Donnikov
- Department of Children’s Diseases, Medical Institute of Surgut State University, 628400 Surgut, Russia; (M.Y.D.); (L.N.K.); (L.V.K.)
| | - Svyatoslav I. Papanov
- Surgut Disctrict Clinical Center of Maternity and Childhood Health Care, 628400 Surgut, Russia;
| | - Alexander N. Chernov
- Department of General Pathology and Pathological Physiology, Institute of Experimental Medicine, 197376 Saint Petersburg, Russia
- Department of Genomic Medicine, D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint Petersburg, Russia;
| | - Lev N. Kolbasin
- Department of Children’s Diseases, Medical Institute of Surgut State University, 628400 Surgut, Russia; (M.Y.D.); (L.N.K.); (L.V.K.)
- Surgut Disctrict Clinical Center of Maternity and Childhood Health Care, 628400 Surgut, Russia;
| | - Lyudmila V. Kovalenko
- Department of Children’s Diseases, Medical Institute of Surgut State University, 628400 Surgut, Russia; (M.Y.D.); (L.N.K.); (L.V.K.)
| | - Andrey S. Glotov
- Department of Genomic Medicine, D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint Petersburg, Russia;
| | - Oleg S. Glotov
- Department of Genomic Medicine, D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint Petersburg, Russia;
- Department of Experimental Medical Virology, Molecular Genetics and Biobanking of Virological and Molecular Genetic Methods of Diagnostics of Children’s Scientific and Clinical Center for Infectious Diseases of the Federal Medical and Biological Agency, 197022 Saint Petersburg, Russia
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Sun Y, Li L, Wang J, Liu H, Wang H. Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches. ACS Pharmacol Transl Sci 2024; 7:72-96. [PMID: 38230285 PMCID: PMC10789133 DOI: 10.1021/acsptsci.3c00324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 01/18/2024]
Abstract
Osteogenesis imperfecta (OI) is an uncommon genetic disorder characterized by shortness of stature, hearing loss, poor bone mass, recurrent fractures, and skeletal abnormalities. Pathogenic variations have been found in over 20 distinct genes that are involved in the pathophysiology of OI, contributing to the disorder's clinical and genetic variability. Although medications, surgical procedures, and other interventions can partially alleviate certain symptoms, there is still no known cure for OI. In this Review, we provide a comprehensive overview of genetic pathogenesis, existing treatment modalities, and new developments in biotechnologies such as gene editing, stem cell reprogramming, functional differentiation, and transplantation for potential future OI therapy.
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Affiliation(s)
- Yu Sun
- PET
Center, Chongqing University Three Gorges
Hospital, Chongqing 404000, China
| | - Lin Li
- PET
Center, Chongqing University Three Gorges
Hospital, Chongqing 404000, China
| | - Jiajun Wang
- Medical
School of Hubei Minzu University, Enshi 445000, China
| | - Huiting Liu
- PET
Center, Chongqing University Three Gorges
Hospital, Chongqing 404000, China
| | - Hu Wang
- Department
of Neurology, Johns Hopkins University School
of Medicine, Baltimore, Maryland 21205, United States
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Ichimura A, Miyazaki Y, Nagatomo H, Kawabe T, Nakajima N, Kim GE, Tomizawa M, Okamoto N, Komazaki S, Kakizawa S, Nishi M, Takeshima H. Atypical cell death and insufficient matrix organization in long-bone growth plates from Tric-b-knockout mice. Cell Death Dis 2023; 14:848. [PMID: 38123563 PMCID: PMC10733378 DOI: 10.1038/s41419-023-06285-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 10/27/2023] [Accepted: 11/07/2023] [Indexed: 12/23/2023]
Abstract
TRIC-A and TRIC-B proteins form homotrimeric cation-permeable channels in the endoplasmic reticulum (ER) and nuclear membranes and are thought to contribute to counterionic flux coupled with store Ca2+ release in various cell types. Serious mutations in the TRIC-B (also referred to as TMEM38B) locus cause autosomal recessive osteogenesis imperfecta (OI), which is characterized by insufficient bone mineralization. We have reported that Tric-b-knockout mice can be used as an OI model; Tric-b deficiency deranges ER Ca2+ handling and thus reduces extracellular matrix (ECM) synthesis in osteoblasts, leading to poor mineralization. Here we report irregular cell death and insufficient ECM in long-bone growth plates from Tric-b-knockout embryos. In the knockout growth plate chondrocytes, excess pro-collagen fibers were occasionally accumulated in severely dilated ER elements. Of the major ER stress pathways, activated PERK/eIF2α (PKR-like ER kinase/ eukaryotic initiation factor 2α) signaling seemed to inordinately alter gene expression to induce apoptosis-related proteins including CHOP (CCAAT/enhancer binding protein homologous protein) and caspase 12 in the knockout chondrocytes. Ca2+ imaging detected aberrant Ca2+ handling in the knockout chondrocytes; ER Ca2+ release was impaired, while cytoplasmic Ca2+ level was elevated. Our observations suggest that Tric-b deficiency directs growth plate chondrocytes to pro-apoptotic states by compromising cellular Ca2+-handling and exacerbating ER stress response, leading to impaired ECM synthesis and accidental cell death.
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Affiliation(s)
- Atsuhiko Ichimura
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Yuu Miyazaki
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Hiroki Nagatomo
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Takaaki Kawabe
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Nobuhisa Nakajima
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Ga Eun Kim
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Masato Tomizawa
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Naoki Okamoto
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | | | - Sho Kakizawa
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Miyuki Nishi
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Hiroshi Takeshima
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan.
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10
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Gochuico BR, Hossain M, Talvacchio SK, Zuo MXG, Barton M, Dang Do AN, Marini JC. Pulmonary function and structure abnormalities in children and young adults with osteogenesis imperfecta point to intrinsic and extrinsic lung abnormalities. J Med Genet 2023; 60:1067-1075. [PMID: 37197785 PMCID: PMC11151334 DOI: 10.1136/jmg-2022-109009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 04/24/2023] [Indexed: 05/19/2023]
Abstract
PURPOSE Pulmonary disease is the major cause of morbidity and mortality in osteogenesis imperfecta (OI). We investigated the contribution of intrinsic lung factors to impaired pulmonary function in children and young adults with OI types III, IV, VI. METHODS Patients with type III (n=8), IV (n=21), VI (n=5), VII (n=2) or XIV (n=1) OI (mean age 23.6 years) prospectively underwent pulmonary function tests (PFTs) and thoracic CT and radiographs. RESULTS PFT results were similar using arm span or ulnar length as height surrogates. PFTs were significantly lower in type III than type IV or VI OI. All patients with type III and half of type IV OI had lung restriction; 90% of patients with OI had reduced gas exchange. Patients with COL1A1 variants had significantly lower forced expiratory flow (FEF)25%-75% compared with those with COL1A2 variants. PFTs correlated negatively with Cobb angle or age. CT scans revealed small airways bronchial thickening (100%, 86%, 100%), atelectasis (88%, 43%, 40%), reticulations (50%, 29%, 20%), ground glass opacities (75%, 5%, 0%), pleural thickening (63%, 48%, 20%) or emphysema (13%, 19%, 20%) in type III, IV or VI OI, respectively. CONCLUSION Both lung intrinsic and extrinsic skeletal abnormalities contribute to OI pulmonary dysfunction. Most young adult patients have restrictive disease and abnormal gas exchange; impairment is greater in type III than type IV OI. Decreased FEF25%-75% and thickening of small bronchi walls indicate a critical role for small airways. Lung parenchymal abnormalities (atelectasis, reticulations) and pleural thickening were also detected. Clinical interventions to mitigate these impairments are warranted. TRIAL REGISTRATION NUMBER NCT03575221.
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Affiliation(s)
- Bernadette R Gochuico
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Mahin Hossain
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
- Undergraduate Scholarship Program, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA
| | - Sara K Talvacchio
- Office of the Clinical Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
| | - Mei Xing G Zuo
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Mark Barton
- Pulmonary Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - An Ngoc Dang Do
- Office of the Clinical Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
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11
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Kodama Y, Meiri S, Asada T, Matsuyama M, Makino S, Iwai M, Yamaguchi M, Moritake H. Novel splice site variant of TMEM38B in osteogenesis imperfecta type XIV. Hum Genome Var 2023; 10:25. [PMID: 37696855 PMCID: PMC10495319 DOI: 10.1038/s41439-023-00252-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/15/2023] [Accepted: 08/19/2023] [Indexed: 09/13/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by brittle bones. In this case report, we describe a patient who suffered from OI type XIV with a novel splice site variant in the TMEM38B gene. Further research is needed to better understand the relationship between the phenotype of OI type XIV and this variant.
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Affiliation(s)
- Yoshihiko Kodama
- Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
| | - Satoru Meiri
- Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Tomoko Asada
- Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Misayo Matsuyama
- Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Shinya Makino
- Division of Clinical Genetics, University of Miyazaki, Miyazaki, Japan
| | - Minayo Iwai
- Division of Clinical Genetics, University of Miyazaki, Miyazaki, Japan
| | | | - Hiroshi Moritake
- Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
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12
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Aida N, Saito A, Azuma T. Current Status of Next-Generation Sequencing in Bone Genetic Diseases. Int J Mol Sci 2023; 24:13802. [PMID: 37762102 PMCID: PMC10530486 DOI: 10.3390/ijms241813802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
The development of next-generation sequencing (NGS) has dramatically increased the speed and volume of genetic analysis. Furthermore, the range of applications of NGS is rapidly expanding to include genome, epigenome (such as DNA methylation), metagenome, and transcriptome analyses (such as RNA sequencing and single-cell RNA sequencing). NGS enables genetic research by offering various sequencing methods as well as combinations of methods. Bone tissue is the most important unit supporting the body and is a reservoir of calcium and phosphate ions, which are important for physical activity. Many genetic diseases affect bone tissues, possibly because metabolic mechanisms in bone tissue are complex. For instance, the presence of specialized immune cells called osteoclasts in the bone tissue, which absorb bone tissue and interact with osteoblasts in complex ways to support normal vital functions. Moreover, the many cell types in bones exhibit cell-specific proteins for their respective activities. Mutations in the genes encoding these proteins cause a variety of genetic disorders. The relationship between age-related bone tissue fragility (also called frailty) and genetic factors has recently attracted attention. Herein, we discuss the use of genomic, epigenomic, transcriptomic, and metagenomic analyses in bone genetic disorders.
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Affiliation(s)
- Natsuko Aida
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kandamisaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan; (A.S.); (T.A.)
| | - Akiko Saito
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kandamisaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan; (A.S.); (T.A.)
| | - Toshifumi Azuma
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kandamisaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan; (A.S.); (T.A.)
- Oral Health Science Center, Tokyo Dental College, 2-9-18 Kandamisaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan
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13
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Jovanovic M, Mitra A, Besio R, Contento BM, Wong KW, Derkyi A, To M, Forlino A, Dale RK, Marini JC. Absence of TRIC-B from type XIV Osteogenesis Imperfecta osteoblasts alters cell adhesion and mitochondrial function - A multi-omics study. Matrix Biol 2023; 121:127-148. [PMID: 37348683 PMCID: PMC10634967 DOI: 10.1016/j.matbio.2023.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/06/2023] [Accepted: 06/16/2023] [Indexed: 06/24/2023]
Abstract
Osteogenesis Imperfecta (OI) is a heritable collagen-related bone dysplasia characterized by bone fractures, growth deficiency and skeletal deformity. Type XIV OI is a recessive OI form caused by null mutations in TMEM38B, which encodes the ER membrane intracellular cation channel TRIC-B. Previously, we showed that absence of TMEM38B alters calcium flux in the ER of OI patient osteoblasts and fibroblasts, which further disrupts collagen synthesis and secretion. How the absence of TMEM38B affects osteoblast function is still poorly understood. Here we further investigated the role of TMEM38B in human osteoblast differentiation and mineralization. TMEM38B-null osteoblasts showed altered expression of osteoblast marker genes and decreased mineralization. RNA-Seq analysis revealed that cell-cell adhesion was one of the most downregulated pathways in TMEM38B-null osteoblasts, with further validation by real-time PCR and Western blot. Gap and tight junction proteins were also decreased by TRIC-B absence, both in patient osteoblasts and in calvarial osteoblasts of Tmem38b-null mice. Disrupted cell adhesion decreased mutant cell proliferation and cell cycle progression. An important novel finding was that TMEM38B-null osteoblasts had elongated mitochondria with altered fusion and fission markers, MFN2 and DRP1. In addition, TMEM38B-null osteoblasts exhibited a significant increase in superoxide production in mitochondria, further supporting mitochondrial dysfunction. Together these results emphasize the novel role of TMEM38B/TRIC-B in osteoblast differentiation, affecting cell-cell adhesion processes, gap and tight junction, proliferation, cell cycle, and mitochondrial function.
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Affiliation(s)
- Milena Jovanovic
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Apratim Mitra
- Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | | | - Ka Wai Wong
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital (HKU-SZH), Shenzhen, China; Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Alberta Derkyi
- Office of the Clinical Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Michael To
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital (HKU-SZH), Shenzhen, China; Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Ryan K Dale
- Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States.
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14
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Udupa P, Shrikondawar AN, Nayak SS, Shah H, Ranjan A, Girisha KM, Bhavani GS, Ghosh DK. Deep intronic mutation in CRTAP results in unstable isoforms of the protein to induce type I collagen aggregation in a lethal type of osteogenesis imperfecta type VII. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166741. [PMID: 37146916 PMCID: PMC7616376 DOI: 10.1016/j.bbadis.2023.166741] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/24/2023] [Accepted: 04/27/2023] [Indexed: 05/07/2023]
Abstract
Genetic mutations are involved in Mendelian disorders. Unbuffered intronic mutations in gene variants can generate aberrant splice sites in mutant transcripts, resulting in mutant isoforms of proteins with modulated expression, stability, and function in diseased cells. Here, we identify a deep intronic variant, c.794_1403A>G, in CRTAP by genome sequencing of a male fetus with osteogenesis imperfecta (OI) type VII. The mutation introduces cryptic splice sites in intron-3 of CRTAP, resulting in two mature mutant transcripts with cryptic exons. While transcript-1 translates to a truncated isoform (277 amino acids) with thirteen C-terminal non-wild-type amino acids, transcript-2 translates to a wild-type protein sequence, except that this isoform contains an in-frame fusion of non-wild-type twenty-five amino acids in a tetratricopeptide repeat sequence. Both mutant isoforms of CRTAP are unstable due to the presence of a unique 'GWxxI' degron, which finally leads to loss of proline hydroxylation and aggregation of type I collagen. Although type I collagen aggregates undergo autophagy, the overall proteotoxicity resulted in death of the proband cells by senescence. In summary, we present a genetic disease pathomechanism by linking a novel deep intronic mutation in CRTAP to unstable mutant isoforms of the protein in lethal OI type VII.
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Affiliation(s)
- Prajna Udupa
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Akshaykumar Nanaji Shrikondawar
- Computational and Functional Genomics Group, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, Telangana, India
| | - Shalini S Nayak
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Hitesh Shah
- Department of Pediatric Orthopedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Akash Ranjan
- Computational and Functional Genomics Group, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, Telangana, India
| | - Katta M Girisha
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India; Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman
| | - Gandham SriLakshmi Bhavani
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
| | - Debasish Kumar Ghosh
- Enteric Disease Division, Department of Microbiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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15
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Besio R, Contento BM, Garibaldi N, Filibian M, Sonntag S, Shmerling D, Tonelli F, Biggiogera M, Brini M, Salmaso A, Jovanovic M, Marini JC, Rossi A, Forlino A. CaMKII inhibition due to TRIC-B loss-of-function dysregulates SMAD signaling in osteogenesis imperfecta. Matrix Biol 2023; 120:43-59. [PMID: 37178987 PMCID: PMC11123566 DOI: 10.1016/j.matbio.2023.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 05/02/2023] [Accepted: 05/10/2023] [Indexed: 05/15/2023]
Abstract
Ca2+ is a second messenger that regulates a variety of cellular responses in bone, including osteoblast differentiation. Mutations in trimeric intracellular cation channel B (TRIC-B), an endoplasmic reticulum channel specific for K+, a counter ion for Ca2+flux, affect bone and cause a recessive form of osteogenesis imperfecta (OI) with a still puzzling mechanism. Using a conditional Tmem38b knock out mouse, we demonstrated that lack of TRIC-B in osteoblasts strongly impairs skeleton growth and structure, leading to bone fractures. At the cellular level, delayed osteoblast differentiation and decreased collagen synthesis were found consequent to the Ca2+ imbalance and associated with reduced collagen incorporation in the extracellular matrix and poor mineralization. The impaired SMAD signaling detected in mutant mice, and validated in OI patient osteoblasts, explained the osteoblast malfunction. The reduced SMAD phosphorylation and nuclear translocation were mainly caused by alteration in Ca2+ calmodulin kinase II (CaMKII)-mediated signaling and to a less extend by a lower TGF-β reservoir. SMAD signaling, osteoblast differentiation and matrix mineralization were only partially rescued by TGF-β treatment, strengthening the impact of CaMKII-SMAD axes on osteoblast function. Our data established the TRIC-B role in osteoblasts and deepened the contribution of the CaMKII-SMAD signaling in bone.
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Affiliation(s)
- Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Barbara M Contento
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Nadia Garibaldi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Marta Filibian
- Centro Grandi Strumenti, University of Pavia, Pavia, Italy; INFN, Istituto Nazionale di Fisica Nucleare-Pavia Unit, Pavia, Italy
| | - Stephan Sonntag
- PolyGene AG, Rümlang, Switzerland; LIMES-Institute, University of Bonn, Bonn , Germany
| | | | - Francesca Tonelli
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Marco Biggiogera
- Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
| | - Marisa Brini
- Department of Biology, University of Padova, Padova, Italy; Centro Studi per la Neurodegenerazione (CESNE), University of Padova, Padova, Italy
| | - Andrea Salmaso
- Department of Biology, University of Padova, Padova, Italy
| | - Milena Jovanovic
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shiver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, United States of America
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shiver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, United States of America
| | - Antonio Rossi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
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16
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Panzaru MC, Florea A, Caba L, Gorduza EV. Classification of osteogenesis imperfecta: Importance for prophylaxis and genetic counseling. World J Clin Cases 2023; 11:2604-2620. [PMID: 37214584 PMCID: PMC10198117 DOI: 10.12998/wjcc.v11.i12.2604] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/18/2023] [Accepted: 03/27/2023] [Indexed: 04/25/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a genetically heterogeneous monogenic disease characterized by decreased bone mass, bone fragility, and recurrent fractures. The phenotypic spectrum varies considerably ranging from prenatal fractures with lethal outcomes to mild forms with few fractures and normal stature. The basic mechanism is a collagen-related defect, not only in synthesis but also in folding, processing, bone mineralization, or osteoblast function. In recent years, great progress has been made in identifying new genes and molecular mechanisms underlying OI. In this context, the classification of OI has been revised several times and different types are used. The Sillence classification, based on clinical and radiological characteristics, is currently used as a grading of clinical severity. Based on the metabolic pathway, the functional classification allows identifying regulatory elements and targeting specific therapeutic approaches. Genetic classification has the advantage of identifying the inheritance pattern, an essential element for genetic counseling and prophylaxis. Although genotype-phenotype correlations may sometimes be challenging, genetic diagnosis allows a personalized management strategy, accurate family planning, and pregnancy management decisions including options for mode of delivery, or early antenatal OI treatment. Future research on molecular pathways and pathogenic variants involved could lead to the development of genotype-based therapeutic approaches. This narrative review summarizes our current understanding of genes, molecular mechanisms involved in OI, classifications, and their utility in prophylaxis.
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Affiliation(s)
- Monica-Cristina Panzaru
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Andreea Florea
- Department of Medical Genetics - Medical Genetics resident, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Lavinia Caba
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
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17
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Ghosh DK, Udupa P, Shrikondawar AN, Bhavani GS, Shah H, Ranjan A, Girisha KM. Mutant MESD links cellular stress to type I collagen aggregation in osteogenesis imperfecta type XX. Matrix Biol 2023; 115:81-106. [PMID: 36526215 PMCID: PMC7615836 DOI: 10.1016/j.matbio.2022.12.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 11/19/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022]
Abstract
Aberrant forms of endoplasmic reticulum (ER)-resident chaperones are implicated in loss of protein quality control in rare diseases. Here we report a novel mutation (p.Asp233Asn) in the ER retention signal of MESD by whole exome sequencing of an individual diagnosed with osteogenesis imperfecta (OI) type XX. While MESDD233N has similar stability and chaperone activity as wild-type MESD, its mislocalization to cytoplasm leads to imbalance of ER proteostasis, resulting in improper folding and aggregation of proteins, including LRP5 and type I collagen. Aggregated LRP5 loses its plasma membrane localization to disrupt the expression of WNT-responsive genes, such as BMP2, BMP4, in proband fibroblasts. We show that MESD is a direct chaperone of pro-α1(I) [COL1A1], and absence of MESDD233N in ER results in cytosolic type I collagen aggregates that remain mostly not secreted. While cytosolic type I collagen aggregates block the intercellular nanotubes, decreased extracellular type I collagen also results in loss of interaction of ITGB1 with type I collagen and weaker attachment of fibroblasts to matrix. Although proband fibroblasts show increased autophagy to degrade the aggregated type I collagen, an overall cellular stress overwhelms the proband fibroblasts. In summary, we present an essential chaperone function of MESD for LRP5 and type I collagen and demonstrating how the D233N mutation in MESD correlates with impaired WNT signaling and proteostasis in OI.
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Affiliation(s)
- Debasish Kumar Ghosh
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
| | - Prajna Udupa
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Akshaykumar Nanaji Shrikondawar
- Computational and Functional Genomics Group, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, Telangana, India
| | - Gandham SriLakshmi Bhavani
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Hitesh Shah
- Department of Pediatric Orthopedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Akash Ranjan
- Computational and Functional Genomics Group, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, Telangana, India
| | - Katta M Girisha
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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18
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Tonelli F, Leoni L, Daponte V, Gioia R, Cotti S, Fiedler IAK, Larianova D, Willaert A, Coucke PJ, Villani S, Busse B, Besio R, Rossi A, Witten PE, Forlino A. Zebrafish Tric-b is required for skeletal development and bone cells differentiation. Front Endocrinol (Lausanne) 2023; 14:1002914. [PMID: 36755921 PMCID: PMC9899828 DOI: 10.3389/fendo.2023.1002914] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 01/03/2023] [Indexed: 01/24/2023] Open
Abstract
INTRODUCTION Trimeric intracellular potassium channels TRIC-A and -B are endoplasmic reticulum (ER) integral membrane proteins, involved in the regulation of calcium release mediated by ryanodine (RyRs) and inositol 1,4,5-trisphosphate (IP3Rs) receptors, respectively. While TRIC-A is mainly expressed in excitable cells, TRIC-B is ubiquitously distributed at moderate level. TRIC-B deficiency causes a dysregulation of calcium flux from the ER, which impacts on multiple collagen specific chaperones and modifying enzymatic activity, leading to a rare form of osteogenesis imperfecta (OI Type XIV). The relevance of TRIC-B on cell homeostasis and the molecular mechanism behind the disease are still unknown. RESULTS In this study, we exploited zebrafish to elucidate the role of TRIC-B in skeletal tissue. We demonstrated, for the first time, that tmem38a and tmem38b genes encoding Tric-a and -b, respectively are expressed at early developmental stages in zebrafish, but only the latter has a maternal expression. Two zebrafish mutants for tmem38b were generated by CRISPR/Cas9, one carrying an out of frame mutation introducing a premature stop codon (tmem38b-/- ) and one with an in frame deletion that removes the highly conserved KEV domain (tmem38bΔ120-7/Δ120-7 ). In both models collagen type I is under-modified and partially intracellularly retained in the endoplasmic reticulum, as described in individuals affected by OI type XIV. Tmem38b-/- showed a mild skeletal phenotype at the late larval and juvenile stages of development whereas tmem38bΔ120-7/Δ120-7 bone outcome was limited to a reduced vertebral length at 21 dpf. A caudal fin regeneration study pointed towards impaired activity of osteoblasts and osteoclasts associated with mineralization impairment. DISCUSSION Our data support the requirement of Tric-b during early development and for bone cell differentiation.
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Affiliation(s)
- Francesca Tonelli
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Laura Leoni
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Valentina Daponte
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Roberta Gioia
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Silvia Cotti
- Department of Biology, Ghent University, Ghent, Belgium
| | - Imke A. K. Fiedler
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Andy Willaert
- Department of Biomolecular Medicine, Center of Medical Genetics, Ghent University-University Hospital, Ghent, Belgium
| | - Paul J. Coucke
- Department of Biomolecular Medicine, Center of Medical Genetics, Ghent University-University Hospital, Ghent, Belgium
| | - Simona Villani
- Department of Public Health and Experimental and Forensic Medicine, Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia, Italy
| | - Björn Busse
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Antonio Rossi
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | | | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
- *Correspondence: Antonella Forlino,
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19
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Thornley P, Bishop N, Baker D, Brock J, Arundel P, Burren C, Smithson S, DeVile C, Crowe B, Allgrove J, Saraff V, Shaw N, Balasubramanian M. Non-collagen pathogenic variants resulting in the osteogenesis imperfecta phenotype in children: a single-country observational cohort study. Arch Dis Child 2022; 107:486-490. [PMID: 34750202 DOI: 10.1136/archdischild-2021-322911] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 10/21/2021] [Indexed: 11/03/2022]
Abstract
BACKGROUND/OBJECTIVES In England, children (0-18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a 'Highly Specialised Service' (HSS OI); affected children with a genetic origin for their disease that is not in COL1A1 or COL1A2 form the majority of the 'atypical' group, which has set criteria for entry into the service. We have used the data from the service to assess the range and frequency of non-collagen pathogenic variants resulting in OI in a single country. METHODS Children with atypical OI were identified through the HSS OI service database. All genetic testing for children with OI in the service were undertaken at the Sheffield Diagnostic Genetics Service. Variant data were extracted and matched to individual patients. This study was done as part of a service evaluation project registered with the Sheffield Children's Hospital Clinical Governance Department. RESULTS One hundred of 337 children in the HSS met the 'atypical' criteria. Eighty have had genetic testing undertaken; 72 had genetic changes detected, 67 in 13 genes known to be causative for OI. The most frequently affected genes were IFITM5 (22), P3H1 (12), SERPINF1 (8) and BMP1 (6). CONCLUSION Among children with more severe forms of OI (approximately one-third of all children with OI), around 20% have pathogenic variants in non-collagen genes. IFITM5 was the most commonly affected gene, followed by genes within the P3H1 complex. These data provide additional information regarding the likelihood of different genetic origins of the disease in children with OI, which may influence clinical care.
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Affiliation(s)
- Patrick Thornley
- The University of Sheffield Faculty of Medicine Dentistry and Health, Sheffield, UK
| | - Nicholas Bishop
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK.,Highly Specialised Osteogenesis Imperfecta Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
| | - Duncan Baker
- Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
| | - Joanna Brock
- Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
| | - Paul Arundel
- Highly Specialised Osteogenesis Imperfecta Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
| | - Christine Burren
- Department of Paediatric Endocrinology and Diabetes, Bristol Royal Hospital for Children, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Sarah Smithson
- Department of Clinical Genetics, St Michaels Hospital, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Catherine DeVile
- Department of Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Belinda Crowe
- Department of Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Jeremy Allgrove
- Department of Endocrinology, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK
| | - Vrinda Saraff
- Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Nick Shaw
- Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.,Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Meena Balasubramanian
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK .,Highly Specialised Osteogenesis Imperfecta Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.,Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
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20
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Tüysüz B, Elkanova L, Uludağ Alkaya D, Güleç Ç, Toksoy G, Güneş N, Yazan H, Bayhan AI, Yıldırım T, Yeşil G, Uyguner ZO. Osteogenesis imperfecta in 140 Turkish families: Molecular spectrum and, comparison of long-term clinical outcome of those with COL1A1/A2 and biallelic variants. Bone 2022; 155:116293. [PMID: 34902613 DOI: 10.1016/j.bone.2021.116293] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/01/2021] [Accepted: 12/04/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous group of diseases characterized by increased bone fragility and deformities. Although most patients with OI have heterozygous mutations in COL1A1 or COL1A2, 17 genes have been reported to cause OI, most of which are autosomal recessive (AR) inherited, during the last years. The aim of this study is to determine the mutation spectrum in Turkish OI cohort and to investigate the genotype-phenotype correlation. METHODS 150 patients from 140 Turkish families with OI phenotype were included in this study. Mutations in OI-related genes were identified using targeted gene panel, MLPA analysis for COL1A1 and whole exome sequencing. 113 patients who had OI disease-causing variants were followed for 1-20 years. RESULTS OI disease-causing variants were detected in 117 families, of which 62.4% in COL1A1/A2, 35.9% in AR-related genes. A heterozygous variant in IFITM5 and a hemizygous in MBTPS2 were also described, one in each patient. Eighteen biallelic variants (13 novel) were identified in nine genes (FKBP10, P3H1, SERPINF1, TMEM38B, WNT1, BMP1, CRTAP, FAM46A, MESD) among which FKBP10, P3H1 and SERPINF1 were most common. The most severe phenotypes were in patients with FKBP10, SERPINF1, CRTAP, FAM46A and MESD variants. P3H1 patients had moderate, while BMP1 had the mild phenotype. Clinical phenotypes were variable in patients with WNT1 and TMEM38B mutations. We also found mutations in ten genes (PLS3, LRP5, ANO5, SLC34A1, EFEMP2, PRDM5, GORAB, OCRL1, TNFRSF11B, DPH1) associated with diseases presenting clinical features which overlap OI, in eleven families. CONCLUSION We identified disease-causing mutations in 83.6% in a large Turkish pediatric OI cohort. 40 novel variants were described. Clinical features and long-term follow-up findings of AR inherited OI types and especially very rare biallelic variants were presented for the first time. Unlike previously reported studies, the mutations that we found in P3H1 were all missense, causing a moderate phenotype.
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Affiliation(s)
- Beyhan Tüysüz
- Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey.
| | - Leyla Elkanova
- Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
| | - Dilek Uludağ Alkaya
- Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
| | - Çağrı Güleç
- Department of Medical Genetics, Istanbul University, Medical Faculty, Istanbul, Turkey
| | - Güven Toksoy
- Department of Medical Genetics, Istanbul University, Medical Faculty, Istanbul, Turkey
| | - Nilay Güneş
- Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
| | - Hakan Yazan
- Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
| | - A Ilhan Bayhan
- Department of Orthopedics and Traumatology, University of Health Sciences Turkey, Baltalimani Bone Diseases Training and Research Center, Istanbul, Turkey
| | - Timur Yıldırım
- Department of Orthopedics and Traumatology, University of Health Sciences Turkey, Baltalimani Bone Diseases Training and Research Center, Istanbul, Turkey
| | - Gözde Yeşil
- Department of Medical Genetics, Bezmialem University, Istanbul, Turkey
| | - Z Oya Uyguner
- Department of Medical Genetics, Istanbul University, Medical Faculty, Istanbul, Turkey
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21
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Jovanovic M, Guterman-Ram G, Marini JC. Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types. Endocr Rev 2022; 43:61-90. [PMID: 34007986 PMCID: PMC8755987 DOI: 10.1210/endrev/bnab017] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Osteogenesis imperfecta (OI) is a phenotypically and genetically heterogeneous skeletal dysplasia characterized by bone fragility, growth deficiency, and skeletal deformity. Previously known to be caused by defects in type I collagen, the major protein of extracellular matrix, it is now also understood to be a collagen-related disorder caused by defects in collagen folding, posttranslational modification and processing, bone mineralization, and osteoblast differentiation, with inheritance of OI types spanning autosomal dominant and recessive as well as X-linked recessive. This review provides the latest updates on OI, encompassing both classical OI and rare forms, their mechanism, and the signaling pathways involved in their pathophysiology. There is a special emphasis on mutations in type I procollagen C-propeptide structure and processing, the later causing OI with strikingly high bone mass. Types V and VI OI, while notably different, are shown to be interrelated by the interferon-induced transmembrane protein 5 p.S40L mutation that reveals the connection between the bone-restricted interferon-induced transmembrane protein-like protein and pigment epithelium-derived factor pathways. The function of regulated intramembrane proteolysis has been extended beyond cholesterol metabolism to bone formation by defects in regulated membrane proteolysis components site-2 protease and old astrocyte specifically induced-substance. Several recently proposed candidate genes for new types of OI are also presented. Discoveries of new OI genes add complexity to already-challenging OI management; current and potential approaches are summarized.
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Affiliation(s)
- Milena Jovanovic
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Gali Guterman-Ram
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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22
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Ichimura A. Elucidation of the Physiological Functions of Membrane Proteins as Novel Drug Target Candidate Molecules. Biol Pharm Bull 2021; 44:1167-1173. [PMID: 34471043 DOI: 10.1248/bpb.b21-00296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
For pharmaceutical research focused on identifying novel drug target candidate molecules, it is essential to explore unknown biological phenomena, elucidate underlying molecular mechanisms and regulate biological processes based on these findings. Proteins expressed on the plasma membrane and endoplasmic reticulum (ER) membrane play important roles in linking extracellular environmental information to intracellular processes. Stimulating membranous proteins induces various kinds of changes in cells, such as alterations in gene expression levels and enzymatic activities. However, the physiological functions and endogenous ligands of many G-protein-coupled receptors (GPCRs) have not been determined, although GPCRs already constitute a large class of drug-target membrane proteins. Furthermore, the precise physiological roles played by many ER membrane proteins have not been elucidated to date. In this review article, I summarize the results of our recent studies, including the observations that the lipid sensor FFAR4/GPR120 controlled systemic energy homeostasis and that the ER membrane monovalent cation channel trimeric intracellular cation (TRIC)-B and the plasma membrane divalent cation channel transient receptor potential melastatin 7 (TRPM7) regulated bone formation. I further describe the therapeutic significance of these membranous protein-related biological processes.
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Affiliation(s)
- Atsuhiko Ichimura
- Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University
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23
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Abstract
Osteogenesis imperfecta (OI) is a disease characterised by altered bone tissue material properties together with abnormal micro and macro-architecture and thus bone fragility, increased bone turnover and hyperosteocytosis. Increasingly appreciated are the soft tissue changes, sarcopenia in particular. Approaches to treatment are now multidisciplinary, with bisphosphonates having been the primary pharmacological intervention over the last 20 years. Whilst meta-analyses suggest that anti-fracture efficacy across the life course is equivocal, there is good evidence that for children bisphosphonates reduce fracture risk, increase vertebral size and improve vertebral shape, as well as improving motor function and mobility. The genetics of OI continues to provide insights into the molecular pathogenesis of the disease, although the pathophysiology is less clear. The complexity of the multi-scale interactions of bone tissue with cellular function are gradually being disentangled, but the fundamental question of why increased tissue brittleness should be associated with so many other changes is unclear; ER stress, pro-inflammatory cytokines, accelerated senesence and altered matrix component release might all contribute, but a unifying hypothesis remains elusive. New approaches to therapy are focussed on increasing bone mass, following the paradigm established by the treatment of postmenopausal osteoporosis. For adults, this brings the prospect of restoring previously lost bone - for children, particularly at the severe end of the spectrum, the possibility of further reducing fracture frequency and possibly altering growth and long term function are attractive. The alternatives that might affect tissue brittleness are autophagy enhancement (through the removal of abnormal type I collagen aggregates) and stem cell transplantation - both still at the preclinical stage of assessment. Preclinical assessment is not supportive of targeting inflammatory pathways, although understanding why TGFb signalling is increased, and whether that presents a treatment target in OI, remains to be established.
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Affiliation(s)
- Fawaz Arshad
- Academic Unit of Child Health, Sheffield Children's Hospital, Department of Oncology and Metabolism, University of Sheffield, S10 2TH, UK
| | - Nick Bishop
- Academic Unit of Child Health, Sheffield Children's Hospital, Department of Oncology and Metabolism, University of Sheffield, S10 2TH, UK.
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24
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Ramzan K, Alotaibi M, Huma R, Afzal S. Detection of a Recurrent TMEM38B Gene Deletion Associated with Recessive Osteogenesis Imperfecta. Discoveries (Craiova) 2021; 9:e124. [PMID: 34036147 PMCID: PMC8140756 DOI: 10.15190/d.2021.3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Osteogenesis imperfecta is a clinically and genetically group of heterogeneous disorders associated with decreased bone density, brittle bones, bone deformity, recurrent fractures, and growth retardation. Osteogenesis imperfecta is commonly associated with mutations of the genes encoding for type I collagen (COL1A1/COL1A2). Mutations in other genes, some associated with type I collagen post-translational processing, have also been identified as the cause of osteogenesis imperfecta. Mutations in the transmembrane protein 38B (TMEM38B) gene have been reported in a rare autosomal recessive form of osteogenesis imperfecta. TMEM38B encodes TRIC-B - a trimeric intracellular cation channel type B which is essential to modulate intracellular calcium signaling. In this study, we are reporting a case of osteogenesis imperfecta type XIV from a Saudi consanguineous family. Our patient was an eight-month-old child with short limbs, club feet, and lower limb deformities with developmental delay. Radiological findings were consistent with the evidence of osteogenesis imperfecta. There was no evidence of impaired hearing or blue sclera and based on the clinical assessment, we classified our patient as a non-syndromic osteogenesis imperfecta. A pathogenic deletion in the chromosome 9q31.2 region, partially encompassing the TMEM38B gene, was detected using chromosomal microarray analysis. This study expands our knowledge about the rare type of osteogenesis imperfecta in our consanguineous population. Besides, it emphasizes the use of genomic medicine in clinical practices to formulate early interventions to clinically improve the patient’s condition.
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Affiliation(s)
- Khushnooda Ramzan
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Maha Alotaibi
- Department of Genetics, Children's Hospital, King Saud Medical City, Riyadh, Saudi Arabia
| | - Rozeena Huma
- King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Sibtain Afzal
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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25
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He F, Yu J, Yang J, Wang S, Zhuang A, Shi H, Gu X, Xu X, Chai P, Jia R. m 6A RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma. Mol Ther 2021; 29:2121-2133. [PMID: 33601055 DOI: 10.1016/j.ymthe.2021.02.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/22/2021] [Accepted: 02/10/2021] [Indexed: 12/11/2022] Open
Abstract
Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common and deadly eye cancer in adults. Both UM and CM originate from melanocytes and exhibit an aggressive growth pattern with high rates of metastasis and mortality. The integral membrane glycoprotein beta-secretase 2 (BACE2), an enzyme that cleaves amyloid precursor protein into amyloid beta peptide, has been reported to play a vital role in vertebrate pigmentation and metastatic melanoma. However, the role of BACE2 in ocular melanoma remains unclear. In this study, we showed that BACE2 was significantly upregulated in ocular melanoma, and inhibition of BACE2 significantly impaired tumor progression both in vitro and in vivo. Notably, we identified that transmembrane protein 38B (TMEM38B), whose expression was highly dependent on BACE2, modulated calcium release from endoplasmic reticulum (ER). Inhibition of the BACE2/TMEM38B axis could trigger exhaustion of intracellular calcium release and inhibit tumor progression. We further demonstrated that BACE2 presented an increased level of N6-methyladenosine (m6A) RNA methylation, which led to the upregulation of BACE2 mRNA. To our knowledge, this study provides a novel pattern of BACE2-mediated intracellular calcium release in ocular melanoma progression, and our findings suggest that m6A/BACE2/TMEM38b could be a potential therapeutic axis for ocular melanoma.
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Affiliation(s)
- Fanglin He
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200001, China
| | - Jie Yu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200001, China
| | - Jie Yang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200001, China
| | - Shaoyun Wang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200001, China
| | - Ai Zhuang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200001, China
| | - Hanhan Shi
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200001, China
| | - Xiang Gu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200001, China
| | - Xiaofang Xu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200001, China
| | - Peiwei Chai
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200001, China
| | - Renbing Jia
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200001, China.
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26
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El-Gazzar A, Högler W. Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis. Int J Mol Sci 2021; 22:ijms22020625. [PMID: 33435159 PMCID: PMC7826666 DOI: 10.3390/ijms22020625] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/07/2021] [Accepted: 01/07/2021] [Indexed: 12/13/2022] Open
Abstract
Bone material strength is determined by several factors, such as bone mass, matrix composition, mineralization, architecture and shape. From a clinical perspective, bone fragility is classified as primary (i.e., genetic and rare) or secondary (i.e., acquired and common) osteoporosis. Understanding the mechanism of rare genetic bone fragility disorders not only advances medical knowledge on rare diseases, it may open doors for drug development for more common disorders (i.e., postmenopausal osteoporosis). In this review, we highlight the main disease mechanisms underlying the development of human bone fragility associated with low bone mass known to date. The pathways we focus on are type I collagen processing, WNT-signaling, TGF-ß signaling, the RANKL-RANK system and the osteocyte mechanosensing pathway. We demonstrate how the discovery of most of these pathways has led to targeted, pathway-specific treatments.
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Affiliation(s)
| | - Wolfgang Högler
- Correspondence: ; Tel.: +43-(0)5-7680-84-22001; Fax: +43-(0)5-7680-84-22004
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27
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Zhytnik L, Simm K, Salumets A, Peters M, Märtson A, Maasalu K. Reproductive options for families at risk of Osteogenesis Imperfecta: a review. Orphanet J Rare Dis 2020; 15:128. [PMID: 32460820 PMCID: PMC7251694 DOI: 10.1186/s13023-020-01404-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023] Open
Abstract
Background Osteogenesis Imperfecta (OI) is a rare genetic disorder involving bone fragility. OI patients typically suffer from numerous fractures, skeletal deformities, shortness of stature and hearing loss. The disorder is characterised by genetic and clinical heterogeneity. Pathogenic variants in more than 20 different genes can lead to OI, and phenotypes can range from mild to lethal forms. As a genetic disorder which undoubtedly affects quality of life, OI significantly alters the reproductive confidence of families at risk. The current review describes a selection of the latest reproductive approaches which may be suitable for prospective parents faced with a risk of OI. The aim of the review is to alleviate suffering in relation to family planning around OI, by enabling prospective parents to make informed and independent decisions. Main body The current review provides a comprehensive overview of possible reproductive options for people with OI and for unaffected carriers of OI pathogenic genetic variants. The review considers reproductive options across all phases of family planning, including pre-pregnancy, fertilisation, pregnancy, and post-pregnancy. Special attention is given to the more modern techniques of assisted reproduction, such as preconception carrier screening, preimplantation genetic testing for monogenic diseases and non-invasive prenatal testing. The review outlines the methodologies of the different reproductive approaches available to OI families and highlights their advantages and disadvantages. These are presented as a decision tree, which takes into account the autosomal dominant and autosomal recessive nature of the OI variants, and the OI-related risks of people without OI. The complex process of decision-making around OI reproductive options is also discussed from an ethical perspective. Conclusion The rapid development of molecular techniques has led to the availability of a wide variety of reproductive options for prospective parents faced with a risk of OI. However, such options may raise ethical concerns in terms of methodologies, choice management and good clinical practice in reproductive care, which are yet to be fully addressed.
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Affiliation(s)
- Lidiia Zhytnik
- Clinic of Traumatology and Orthopaedics, Tartu University Hospital, Tartu, Estonia.
| | - Kadri Simm
- Institute of Philosophy and Semiotics, Faculty of Arts and Humanities, University of Tartu, Tartu, Estonia.,Centre of Ethics, University of Tartu, Tartu, Estonia
| | - Andres Salumets
- Competence Centre on Health Technologies, Tartu, Estonia.,Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.,Institute of Genomics, University of Tartu, Tartu, Estonia.,COMBIVET ERA Chair, Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, Tartu, Estonia
| | - Maire Peters
- Competence Centre on Health Technologies, Tartu, Estonia.,Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
| | - Aare Märtson
- Clinic of Traumatology and Orthopaedics, Tartu University Hospital, Tartu, Estonia.,Department of Traumatology and Orthopaedics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
| | - Katre Maasalu
- Clinic of Traumatology and Orthopaedics, Tartu University Hospital, Tartu, Estonia.,Department of Traumatology and Orthopaedics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
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28
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Ohata Y, Takeyari S, Nakano Y, Kitaoka T, Nakayama H, Bizaoui V, Yamamoto K, Miyata K, Yamamoto K, Fujiwara M, Kubota T, Michigami T, Yamamoto K, Yamamoto T, Namba N, Ebina K, Yoshikawa H, Ozono K. Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta. Osteoporos Int 2019; 30:2333-2342. [PMID: 31363794 PMCID: PMC7083816 DOI: 10.1007/s00198-019-05076-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 06/26/2019] [Indexed: 12/21/2022]
Abstract
UNLABELLED To elucidate mutation spectrum and genotype-phenotype correlations in Japanese patients with OI, we conducted comprehensive genetic analyses using NGS, as this had not been analyzed comprehensively in this patient population. Most mutations were located on COL1A1 and COL1A2. Glycine substitutions in COL1A1 resulted in the severe phenotype. INTRODUCTION Most cases of osteogenesis imperfecta (OI) are caused by mutations in COL1A1 or COL1A2, which encode α chains of type I collagen. However, mutations in at least 16 other genes also cause OI. The mutation spectrum in Japanese patients with OI has not been comprehensively analyzed, as it is difficult to identify using classical Sanger sequencing. In this study, we aimed to reveal the mutation spectrum and genotype-phenotype correlations in Japanese patients with OI using next-generation sequencing (NGS). METHODS We designed a capture panel for sequencing 15 candidate OI genes and 19 candidate genes that are associated with bone fragility or Wnt signaling. Using NGS, we examined 53 Japanese patients with OI from unrelated families. RESULTS Pathogenic mutations were detected in 43 out of 53 individuals. All mutations were heterozygous. Among the 43 individuals, 40 variants were identified including 15 novel mutations. We found these mutations in COL1A1 (n = 30, 69.8%), COL1A2 (n = 12, 27.9%), and IFITM5 (n = 1, 2.3%). Patients with glycine substitution on COL1A1 had a higher frequency of fractures and were more severely short-statured. Although no significant genotype-phenotype correlation was observed for bone mineral density, the trabecular bone score was significantly lower in patients with glycine substitutions. CONCLUSION We identified pathogenic mutations in 81% of our Japanese patients with OI. Most mutations were located on COL1A1 and COL1A2. This study revealed that glycine substitutions on COL1A1 resulted in the severe phenotype among Japanese patients with OI.
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Affiliation(s)
- Y Ohata
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - S Takeyari
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Y Nakano
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - T Kitaoka
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - H Nakayama
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
- The Japan Environment and Children's Study, Osaka Unit Center, Suita, Japan
| | - V Bizaoui
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
- Department of Medical Genetics, Reference Center for Skeletal Dysplasia, Hôpital Necker - Enfants Malades, Paris, France
| | - K Yamamoto
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
| | - K Miyata
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - K Yamamoto
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
- Department of Pediatrics, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - M Fujiwara
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
- The First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Japan
| | - T Kubota
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - T Michigami
- Department of Bone and Mineral Research, Osaka Women's and Children's Hospital, Izumi, Japan
| | - K Yamamoto
- Department of Pediatric Nephrology and Metabolism, Osaka Women's and Children's Hospital, Izumi, Japan
| | - T Yamamoto
- Department of Pediatrics, Minoh City Hospital, Minoh, Japan
| | - N Namba
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
- Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization (JCHO), Osaka, Japan
| | - K Ebina
- Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - H Yoshikawa
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - K Ozono
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.
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Besio R, Chow CW, Tonelli F, Marini JC, Forlino A. Bone biology: insights from osteogenesis imperfecta and related rare fragility syndromes. FEBS J 2019; 286:3033-3056. [PMID: 31220415 PMCID: PMC7384889 DOI: 10.1111/febs.14963] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 05/06/2019] [Accepted: 06/14/2019] [Indexed: 12/11/2022]
Abstract
The limited accessibility of bone and its mineralized nature have restricted deep investigation of its biology. Recent breakthroughs in identification of mutant proteins affecting bone tissue homeostasis in rare skeletal diseases have revealed novel pathways involved in skeletal development and maintenance. The characterization of new dominant, recessive and X-linked forms of the rare brittle bone disease osteogenesis imperfecta (OI) and other OI-related bone fragility disorders was a key player in this advance. The development of in vitro models for these diseases along with the generation and characterization of murine and zebrafish models contributed to dissecting previously unknown pathways. Here, we describe the most recent advances in the understanding of processes involved in abnormal bone mineralization, collagen processing and osteoblast function, as illustrated by the characterization of new causative genes for OI and OI-related fragility syndromes. The coordinated role of the integral membrane protein BRIL and of the secreted protein PEDF in modulating bone mineralization as well as the function and cross-talk of the collagen-specific chaperones HSP47 and FKBP65 in collagen processing and secretion are discussed. We address the significance of WNT ligand, the importance of maintaining endoplasmic reticulum membrane potential and of regulating intramembrane proteolysis in osteoblast homeostasis. Moreover, we also examine the relevance of the cytoskeletal protein plastin-3 and of the nucleotidyltransferase FAM46A. Thanks to these advances, new targets for the development of novel therapies for currently incurable rare bone diseases have been and, likely, will be identified, supporting the important role of basic science for translational approaches.
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Affiliation(s)
- Roberta Besio
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Chi-Wing Chow
- Bone and Extracellular Matrix Branch, NICHD, National Institute of Health, Bethesda, MD 20892, USA
| | - Francesca Tonelli
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
| | - Joan C Marini
- Bone and Extracellular Matrix Branch, NICHD, National Institute of Health, Bethesda, MD 20892, USA
| | - Antonella Forlino
- Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
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Lleras-Forero L, Winkler C, Schulte-Merker S. Zebrafish and medaka as models for biomedical research of bone diseases. Dev Biol 2019; 457:191-205. [PMID: 31325453 DOI: 10.1016/j.ydbio.2019.07.009] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 07/13/2019] [Indexed: 12/17/2022]
Abstract
The identification of disease-causing mutations has in recent years progressed immensely due to whole genome sequencing approaches using patient material. The task accordingly is shifting from gene identification to functional analysis of putative disease-causing genes, preferably in an in vivo setting which also allows testing of drug candidates or biotherapeutics in whole animal disease models. In this review, we highlight the advances made in the field of bone diseases using small laboratory fish, focusing on zebrafish and medaka. We particularly highlight those human conditions where teleost models are available.
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Affiliation(s)
- L Lleras-Forero
- Institute for Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Mendelstrasse 7, 48149 Münster, Germany; CiM Cluster of Excellence (EXC-1003-CiM), Münster, Germany.
| | - C Winkler
- Department of Biological Sciences and Centre for Bioimaging Sciences, National University of Singapore, 14 Science Drive 04, 117558 Singapore
| | - S Schulte-Merker
- Institute for Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Mendelstrasse 7, 48149 Münster, Germany; CiM Cluster of Excellence (EXC-1003-CiM), Münster, Germany.
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Monies D, Abouelhoda M, Assoum M, Moghrabi N, Rafiullah R, Almontashiri N, Alowain M, Alzaidan H, Alsayed M, Subhani S, Cupler E, Faden M, Alhashem A, Qari A, Chedrawi A, Aldhalaan H, Kurdi W, Khan S, Rahbeeni Z, Alotaibi M, Goljan E, Elbardisy H, ElKalioby M, Shah Z, Alruwaili H, Jaafar A, Albar R, Akilan A, Tayeb H, Tahir A, Fawzy M, Nasr M, Makki S, Alfaifi A, Akleh H, Yamani S, Bubshait D, Mahnashi M, Basha T, Alsagheir A, Abu Khaled M, Alsaleem K, Almugbel M, Badawi M, Bashiri F, Bohlega S, Sulaiman R, Tous E, Ahmed S, Algoufi T, Al-Mousa H, Alaki E, Alhumaidi S, Alghamdi H, Alghamdi M, Sahly A, Nahrir S, Al-Ahmari A, Alkuraya H, Almehaidib A, Abanemai M, Alsohaibaini F, Alsaud B, Arnaout R, Abdel-Salam GMH, Aldhekri H, AlKhater S, Alqadi K, Alsabban E, Alshareef T, Awartani K, Banjar H, Alsahan N, Abosoudah I, Alashwal A, Aldekhail W, Alhajjar S, Al-Mayouf S, Alsemari A, Alshuaibi W, Altala S, Altalhi A, Baz S, Hamad M, Abalkhail T, Alenazi B, Alkaff A, Almohareb F, Al Mutairi F, Alsaleh M, Alsonbul A, Alzelaye S, Bahzad S, Manee AB, Jarrad O, Meriki N, Albeirouti B, Alqasmi A, AlBalwi M, Makhseed N, et alMonies D, Abouelhoda M, Assoum M, Moghrabi N, Rafiullah R, Almontashiri N, Alowain M, Alzaidan H, Alsayed M, Subhani S, Cupler E, Faden M, Alhashem A, Qari A, Chedrawi A, Aldhalaan H, Kurdi W, Khan S, Rahbeeni Z, Alotaibi M, Goljan E, Elbardisy H, ElKalioby M, Shah Z, Alruwaili H, Jaafar A, Albar R, Akilan A, Tayeb H, Tahir A, Fawzy M, Nasr M, Makki S, Alfaifi A, Akleh H, Yamani S, Bubshait D, Mahnashi M, Basha T, Alsagheir A, Abu Khaled M, Alsaleem K, Almugbel M, Badawi M, Bashiri F, Bohlega S, Sulaiman R, Tous E, Ahmed S, Algoufi T, Al-Mousa H, Alaki E, Alhumaidi S, Alghamdi H, Alghamdi M, Sahly A, Nahrir S, Al-Ahmari A, Alkuraya H, Almehaidib A, Abanemai M, Alsohaibaini F, Alsaud B, Arnaout R, Abdel-Salam GMH, Aldhekri H, AlKhater S, Alqadi K, Alsabban E, Alshareef T, Awartani K, Banjar H, Alsahan N, Abosoudah I, Alashwal A, Aldekhail W, Alhajjar S, Al-Mayouf S, Alsemari A, Alshuaibi W, Altala S, Altalhi A, Baz S, Hamad M, Abalkhail T, Alenazi B, Alkaff A, Almohareb F, Al Mutairi F, Alsaleh M, Alsonbul A, Alzelaye S, Bahzad S, Manee AB, Jarrad O, Meriki N, Albeirouti B, Alqasmi A, AlBalwi M, Makhseed N, Hassan S, Salih I, Salih MA, Shaheen M, Sermin S, Shahrukh S, Hashmi S, Shawli A, Tajuddin A, Tamim A, Alnahari A, Ghemlas I, Hussein M, Wali S, Murad H, Meyer BF, Alkuraya FS. Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Am J Hum Genet 2019; 104:1182-1201. [PMID: 31130284 DOI: 10.1016/j.ajhg.2019.04.011] [Show More Authors] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 04/11/2019] [Indexed: 12/16/2022] Open
Abstract
We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.
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Affiliation(s)
- Dorota Monies
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Mohammed Abouelhoda
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Mirna Assoum
- Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Nabil Moghrabi
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Rafiullah Rafiullah
- Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Naif Almontashiri
- Clinical Molecular and Biochemical Genetics, Taibah University, Madinah 42353, Saudi Arabia
| | - Mohammed Alowain
- Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Hamad Alzaidan
- Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Moeen Alsayed
- Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Shazia Subhani
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Edward Cupler
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia
| | - Maha Faden
- Genetics and Metabolism, King Saud Medical Complex, Riyadh 12746, Saudi Arabia
| | - Amal Alhashem
- Pediatrics Department, Prince Sultan Military Medical Complex, Riyadh 12233, Saudi Arabia
| | - Alya Qari
- Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Aziza Chedrawi
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Hisham Aldhalaan
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Wesam Kurdi
- Obstetrics and Gynecology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Sameena Khan
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Zuhair Rahbeeni
- Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Maha Alotaibi
- Genetics and Metabolism, King Saud Medical Complex, Riyadh 12746, Saudi Arabia
| | - Ewa Goljan
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Hadeel Elbardisy
- Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Mohamed ElKalioby
- Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Zeeshan Shah
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Hibah Alruwaili
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Amal Jaafar
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Ranad Albar
- Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia
| | - Asma Akilan
- Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Hamsa Tayeb
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Asma Tahir
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Mohammed Fawzy
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Mohammed Nasr
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Shaza Makki
- Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Abdullah Alfaifi
- Pediatrics Department, Security Forces Hospital, Riyadh 11481, Saudi Arabia
| | - Hanna Akleh
- Academic and Training Affairs, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Suad Yamani
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Dalal Bubshait
- Pediatrics Department, King Fahad Hospital of the University, Al-Khobar 31952, Saudi Arabia
| | - Mohammed Mahnashi
- Genetics and Medicine, King Fahd Central Hospital, Gizan 82666, Saudi Arabia
| | - Talal Basha
- Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia
| | - Afaf Alsagheir
- Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Musad Abu Khaled
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Khalid Alsaleem
- Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Maisoon Almugbel
- Obstetrics and Gynecology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Manal Badawi
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Fahad Bashiri
- Department of Pediatrics, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh 11461, Saudi Arabia
| | - Saeed Bohlega
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Raashida Sulaiman
- Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Ehab Tous
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Syed Ahmed
- Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Talal Algoufi
- Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Hamoud Al-Mousa
- Allergy - Immunology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Emadia Alaki
- Allergy - Immunology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Susan Alhumaidi
- Pediatrics Department, King Saud Medical City, Riyadh 12746, Saudi Arabia
| | - Hadeel Alghamdi
- Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia
| | - Malak Alghamdi
- Pediatrics Department, King Saud Medical City, Riyadh 12746, Saudi Arabia
| | - Ahmed Sahly
- Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Shapar Nahrir
- Pediatrics Department, King Saud Medical City, Riyadh 12746, Saudi Arabia
| | - Ali Al-Ahmari
- Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Hisham Alkuraya
- Vitreoretinal Surgery, Specialized Medical Centre, Riyadh 11564, Saudi Arabia
| | - Ali Almehaidib
- Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Mohammed Abanemai
- Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Fahad Alsohaibaini
- Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Bandar Alsaud
- Allergy - Immunology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Rand Arnaout
- Allergy - Immunology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | | | - Hasan Aldhekri
- Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Suzan AlKhater
- Pediatrics Department, King Fahad Hospital of the University, Al-Khobar 31952, Saudi Arabia; Department of Pediatrics, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 34221, Saudi Arabia
| | - Khalid Alqadi
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Essam Alsabban
- Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Turki Alshareef
- Pediatric Nephrology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Khalid Awartani
- Obstetrics and Gynecology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Hanaa Banjar
- Pediatric Pulmonology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Nada Alsahan
- Obstetrics and Gynecology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Ibraheem Abosoudah
- Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia
| | - Abdullah Alashwal
- Pediatric Endocrine and Metabolism, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Wajeeh Aldekhail
- Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Sami Alhajjar
- Pediatric Infectious Diseases, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Sulaiman Al-Mayouf
- Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Abdulaziz Alsemari
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Walaa Alshuaibi
- Pediatrics Department, King Khalid University Hospital, Riyadh 12372, Saudi Arabia
| | - Saeed Altala
- Pediatrics Department, Armed Forces Hospital, Khamis Mushait 62451, Saudi Arabia
| | - Abdulhadi Altalhi
- Pediatric Nephrology, King Saud Medical City, Riyadh 12746, Saudi Arabia
| | - Salah Baz
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Muddathir Hamad
- Pediatrics Department, King Khalid University Hospital, Riyadh 12372, Saudi Arabia
| | - Tariq Abalkhail
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Badi Alenazi
- Pediatrics Department, Alyamama Hospital, Riyadh 14222, Saudi Arabia
| | - Alya Alkaff
- Obstetrics and Gynecology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Fahad Almohareb
- Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Fuad Al Mutairi
- King Abdullah International Medical Research Centre, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11564, Saudi Arabia; Medical Genetic Division, Department of Pediatrics, King Abdulaziz Medical City, Riyadh 14611, Saudi Arabia
| | - Mona Alsaleh
- Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Abdullah Alsonbul
- Pediatric Rheumatology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Somaya Alzelaye
- Pediatric Endocrine and Diabetes, Al Qunfudah General Hospital, Al Qunfudhah 28821, Saudi Arabia
| | - Shakir Bahzad
- Kuwait Medical Genetics Center, Kuwait City 65000, Kuwait
| | - Abdulaziz Bin Manee
- Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Ola Jarrad
- Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Neama Meriki
- Maternal and Fetal Medicine, King Khalid University Hospital, Riyadh 12372, Saudi Arabia
| | - Bassem Albeirouti
- Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia
| | - Amal Alqasmi
- Pediatrics Department, King Saud Medical City, Riyadh 12746, Saudi Arabia
| | - Mohammed AlBalwi
- Department of Pathology and Laboratory Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh 11426, Saudi Arabia
| | - Nawal Makhseed
- Pediatrics Department, Alsoor Clinic, Kuwait City 65000, Kuwait
| | - Saeed Hassan
- Pediatrics Department, King Khalid University Hospital, Riyadh 12372, Saudi Arabia
| | - Isam Salih
- Hepatic-Pancreatic Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Mustafa A Salih
- Department of Pediatrics, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh 11461, Saudi Arabia
| | - Marwan Shaheen
- Hematology and Bone Marrow Transplant, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Saadeh Sermin
- Pediatric Nephrology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Shamsad Shahrukh
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia
| | - Shahrukh Hashmi
- Hematology and Bone Marrow Transplant, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Ayman Shawli
- Department of Pediatrics, King Abdulaziz Medical City, Jeddah 9515, Saudi Arabia
| | - Ameen Tajuddin
- Neurology, King Fahad Hospital, Medina 59046, Saudi Arabia
| | - Abdullah Tamim
- Pediatrics Neurology, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia
| | - Ahmed Alnahari
- Pediatric Department, King Fahad Central Hospital, Gizan, 82666, Saudi Arabia
| | - Ibrahim Ghemlas
- Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Maged Hussein
- Nephrology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Sami Wali
- Pediatrics Department, Prince Sultan Military Medical Complex, Riyadh 12233, Saudi Arabia
| | - Hatem Murad
- Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Brian F Meyer
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Fowzan S Alkuraya
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
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Zhytnik L, Maasalu K, Duy BH, Pashenko A, Khmyzov S, Reimann E, Prans E, Kõks S, Märtson A. IFITM5 pathogenic variant causes osteogenesis imperfecta V with various phenotype severity in Ukrainian and Vietnamese patients. Hum Genomics 2019; 13:25. [PMID: 31159867 PMCID: PMC6547447 DOI: 10.1186/s40246-019-0209-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 05/20/2019] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Osteogenesis imperfecta (OI) covers a spectrum of bone fragility disorders. OI is classified into five types; however, the genetic causes of OI might hide in pathogenic variants of 20 different genes. Often clinical OI types mimic each other. This sometimes makes it impossible to identify the OI type clinically, which can be a risk for patients. Up to 90% of OI types I-IV are caused by pathogenic variants in the COL1A1/2 genes. OI type V is caused by the c.-14C > T pathogenic variant in the 5'UTR of the IFITM5 gene and is characterized by hyperplastic callus formation and the ossification of interosseous membranes. RESULTS In the current study, we performed IFITM5 5'UTR region mutational analysis using Sanger sequencing on 90 patients who were negative for COL1A1/2 pathogenic variants. We also investigated the phenotypes of five patients with genetically confirmed OI type V. The proportion of OI type V patients in our cohort of all OI patients was 1.48%. In one family, there was a history of OI in at least three generations. Phenotype severity differed from mild to extremely severe among patients, but all patients harbored the same typical pathogenic variant. One patient had no visible symptoms of OI type V and was suspected to have had OI type IV previously. We also identified a case of extremely severe hyperplastic callus in a 15-year-old male, who has hearing loss and brittleness of teeth. CONCLUSIONS OI type V is underlined with some unique clinical features; however, not all patients develop them. The phenotype spectrum might be even broader than previously suspected, including typical OI features: teeth brittleness, bluish sclera, hearing loss, long bones deformities, and joint laxity. We suggest that all patients negative for COL1A1/2 pathogenic variants be tested for the presence of an IFITM5 pathogenic variant, even if they are not expressing typical OI type V symptoms. Further studies on the pathological nature and hyperplastic callus formation mechanisms of OI type V are necessary.
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Affiliation(s)
- Lidiia Zhytnik
- Department of Traumatology and Orthopeadics, University of Tartu, Puusepa 8, 51014, Tartu, Estonia.
| | - Katre Maasalu
- Department of Traumatology and Orthopeadics, University of Tartu, Puusepa 8, 51014, Tartu, Estonia.,Clinic of Traumatology and Orthopeadics, Tartu University Hospital, Puusepa 8, 51014, Tartu, Estonia
| | - Binh Ho Duy
- Hue University of Medicine and Pharmacy, Hue University, Hue, Vietnam
| | - Andrey Pashenko
- Department of Pediatric Orthopedics, Sytenko Institute of Spine and Joint Pathology, AMS Ukraine, Pushkinska 80, Kharkiv, 61024, Ukraine
| | - Sergey Khmyzov
- Department of Pediatric Orthopedics, Sytenko Institute of Spine and Joint Pathology, AMS Ukraine, Pushkinska 80, Kharkiv, 61024, Ukraine
| | - Ene Reimann
- Centre of Translational Medicine, University of Tartu, Ravila 14a, 50411, Tartu, Estonia.,Department of Pathophysiology, University of Tartu, Ravila 19, 50411, Tartu, Estonia
| | - Ele Prans
- Department of Pathophysiology, University of Tartu, Ravila 19, 50411, Tartu, Estonia
| | - Sulev Kõks
- Perron Institute for Neurological and Translational Science, QEII Medical Centre, Nedlands, WA, Australia
| | - Aare Märtson
- Department of Traumatology and Orthopeadics, University of Tartu, Puusepa 8, 51014, Tartu, Estonia.,Clinic of Traumatology and Orthopeadics, Tartu University Hospital, Puusepa 8, 51014, Tartu, Estonia
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Wang M, Guo Y, Rong P, Xu H, Gong L, Deng H, Yuan L. COL1A2 p.Gly1066Val variant identified in a Han Chinese family with osteogenesis imperfecta type I. Mol Genet Genomic Med 2019; 7:e619. [PMID: 30829463 PMCID: PMC6503011 DOI: 10.1002/mgg3.619] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 02/04/2019] [Accepted: 02/11/2019] [Indexed: 12/30/2022] Open
Abstract
Background Osteogenesis imperfecta (OI), a genetically determined connective tissue disorder, is characterized by increased bone fragility and reduced bone mass. Clinical presentation severity ranges from very mild types with nearly no fractures to intrauterine fractures and perinatal lethality. It can be accompanied by blue sclerae, dentinogenesis imperfecta (DI), hearing loss, muscle weakness, ligament laxity, and skin fragility. This study sought to identify pathogenic gene variants in a four‐generation Han Chinese family with OI type I. Methods In order to unveil the molecular genetic factors underlying the disease phenotype, whole exome sequencing in a member, with OI type I, of a Han Chinese family from Hunan, China was performed. The variant identified by whole exome sequencing was further tested by Sanger sequencing in the family members. Results A heterozygous missense variant (NM_000089.3: c.3197G>T; NP_000080.2: p.Gly1066Val) in the collagen type I alpha 2 chain gene (COL1A2) was identified in four patients. It co‐segregated with the disease in the family. Conclusion The sequence variant may be a disease‐causing factor resulting in abnormal type I procollagen synthesis and leading to OI type I. This finding has significant implications for genetic counseling and clinical monitoring of high‐risk families and may be helpful for understanding pathogenic mechanism of OI and developing therapies.
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Affiliation(s)
- Mingyuan Wang
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yi Guo
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.,Department of Medical Information, Information Security and Big Data Research Institute, Central South University, Changsha, China
| | - Pengfei Rong
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Hongbo Xu
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Lina Gong
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Hao Deng
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.,Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Lamei Yuan
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
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Structural basis for activity of TRIC counter-ion channels in calcium release. Proc Natl Acad Sci U S A 2019; 116:4238-4243. [PMID: 30770441 DOI: 10.1073/pnas.1817271116] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Trimeric intracellular cation (TRIC) channels are thought to provide counter-ion currents that facilitate the active release of Ca2+ from intracellular stores. TRIC activity is controlled by voltage and Ca2+ modulation, but underlying mechanisms have remained unknown. Here we describe high-resolution crystal structures of vertebrate TRIC-A and TRIC-B channels, both in Ca2+-bound and Ca2+-free states, and we analyze conductance properties in structure-inspired mutagenesis experiments. The TRIC channels are symmetric trimers, wherein we find a pore in each protomer that is gated by a highly conserved lysine residue. In the resting state, Ca2+ binding at the luminal surface of TRIC-A, on its threefold axis, stabilizes lysine blockage of the pores. During active Ca2+ release, luminal Ca2+ depletion removes inhibition to permit the lysine-bearing and voltage-sensing helix to move in response to consequent membrane hyperpolarization. Diacylglycerol is found at interprotomer interfaces, suggesting a role in metabolic control.
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Prabhu SS, Fortier K, May MC, Reebye UN. Implant therapy for a patient with osteogenesis imperfecta type I: review of literature with a case report. Int J Implant Dent 2018; 4:36. [PMID: 30467787 PMCID: PMC6250748 DOI: 10.1186/s40729-018-0148-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 10/11/2018] [Indexed: 01/14/2023] Open
Abstract
Bone fragility and skeletal irregularities are the characteristic features of osteogenesis imperfecta (OI). Many patients with OI have weakened maxillary and mandibular bone, leading to poor oral hygiene and subsequent loss of teeth. Improvements in implant therapy have allowed for OI patients to achieve dental restoration. However, there is limited available literature on implant therapy for patients with OI. The greatest challenge in the restoration process for OI patients in an outpatient setting is ensuring primary stability and osseointegration. Improvements in synthetic grafts improve successful implant placement and prevent predisposing patients to unnecessary procedures. This report details the successful restoration process of an OI type I patient’s maxillary arch in addition to a review of the currently available literature.
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Affiliation(s)
- Shamit S Prabhu
- Wake Forest School of Medicine, Winston-Salem, USA. .,Triangle Implant Center, 5318 NC Highway 55, Suite 106, Durham, NC, 27713, USA.
| | - Kevin Fortier
- Boston University Henry M. Goldman School of Dental Medicine, Boston, USA
| | - Michael C May
- Virginia Commonwealth University School of Dentistry, Richmond, USA
| | - Uday N Reebye
- Triangle Implant Center, 5318 NC Highway 55, Suite 106, Durham, NC, 27713, USA
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Abstract
Bone disease in the neonatal period has often been regarded as an issue affecting premature infants, or a collection of rare and ultra-rare disorders that most neonatologists will see only once or twice each year, or possibly each decade. The emergence of targeted therapies for some of these rare disorders means that neonatologists may be faced with diagnostic dilemmas that need a rapid solution in order to access management options that did not previously exist. The diagnostic modalities available to the neonatologist have not changed a great deal in recent years; blood tests and radiographs still form the mainstays with other techniques usually reserved for research studies, but rapid access to genomic testing is emergent. This paper provides an update around diagnosis and management of bone problems likely to present to the neonatologist.
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Affiliation(s)
- Stephanie A Borg
- Academic Unit of Child Health, Department of Oncology and Metabolism, University of Sheffield, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH.
| | - Nicholas J Bishop
- Academic Unit of Child Health, Department of Oncology and Metabolism, University of Sheffield, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH.
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Balasubramanian M, Jones R, Milne E, Marshall C, Arundel P, Smith K, Bishop NJ. Autism and heritable bone fragility: A true association? Bone Rep 2018; 8:156-162. [PMID: 29955634 PMCID: PMC6020266 DOI: 10.1016/j.bonr.2018.04.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 03/14/2018] [Accepted: 04/16/2018] [Indexed: 02/07/2023] Open
Abstract
Objectives Osteogenesis Imperfecta (OI) is a heterogeneous condition mainly characterised by bone fragility; intelligence is reported to be normal. However, a minority of children seen also show symptomology consistent with an ‘Autism Spectrum Disorder’. A joint genetics and psychology research study was undertaken to identify these patients using ‘Gold Standard’ research tools: Autism Diagnostic Inventory Revised (ADI-R); Autism Diagnostic Observation Schedule (ADOS) and undertake genetic analyses in them. Method A cohort of n = 7 children with autistic traits and severe/complex OI were recruited to the study. The study was set-up to explore whether there was a genetic link between bone fragility and autism in a sub-set of patients with bone fragility identified with autism traits in our complex/severe OI clinic. This was not set-up as a prevalence study but rather an exploration of genetics in association with ADI/ADOS confirmed ASD and bone fragility. ADI& ADOS Standardised tools were used to confirm autism diagnosis. ADI and ADOS were completed by the Clinical Psychologist; ADI comprises a 93 item semi-structured clinical review with a diagnostic algorithm diagnosing Autism; ADOS is a semi-structured assessment of socialisation, communication and play/imagination which also provides a diagnostic algorithm. Exome sequencing In patients recruited, those that fulfilled research criteria for diagnosis of autism using above tools were recruited to trio whole exome sequencing (WES). Results one patient had compound heterozygous variants in NBAS; one patient had a variant in NRX1; one patient had a maternally inherited PLS3 variant; all the other patients in this cohort had pathogenic variants in COL1A1/COL1A2. Conclusions Although, not set out as an objective, we were able to establish that identifying autism had important clinical and social benefits for patients and their families in ensuring access to services, appropriate schooling, increased understanding of behaviour and support. Lay summary It is important for clinicians looking after children with brittle bone disease, also referred to as Osteogenesis Imperfecta (OI) to be aware of early features of developmental delay/autistic traits especially with severe forms of OI as the emphasis is on their mobility and bone health. Ensuring appropriate assessment and access to services early-on will enable these patients to achieve their potential. Further investigations of genomics in bone fragility in relation to autism are required and dual diagnosis is essential for high quality clinical and educational provision.
Osteogenesis Imperfecta is the commonest form of heritable bone fragility disorder with an incidence of 1 in 15,000 live births Intelligence is usually reported to be normal; however, this study describes association of autistic traits with OI It is important to undertake autism assessments early in case of clinical suspicion of ASD as children with OI would benefit from early educational intervention Early identification and clarification of diagnosis of ASD in children with OI will ensure that children are able to achieve their full potential.
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Affiliation(s)
- Meena Balasubramanian
- Highly Specialised Severe, Complex & Atypical OI Service, Sheffield Children's NHS Foundation Trust, UK.,Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, UK.,Academic Unit of Child Health, University of Sheffield, UK
| | - Rebecca Jones
- Department of Psychology, Sheffield Children's NHS Foundation Trust, UK
| | | | | | - Paul Arundel
- Highly Specialised Severe, Complex & Atypical OI Service, Sheffield Children's NHS Foundation Trust, UK
| | - Kath Smith
- Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, UK
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Maddirevula S, Alsahli S, Alhabeeb L, Patel N, Alzahrani F, Shamseldin HE, Anazi S, Ewida N, Alsaif HS, Mohamed JY, Alazami AM, Ibrahim N, Abdulwahab F, Hashem M, Abouelhoda M, Monies D, Al Tassan N, Alshammari M, Alsagheir A, Seidahmed MZ, Sogati S, Aglan MS, Hamad MH, Salih MA, Hamed AA, Alhashmi N, Nabil A, Alfadli F, Abdel-Salam GMH, Alkuraya H, Peitee WO, Keng WT, Qasem A, Mushiba AM, Zaki MS, Fassad MR, Alfadhel M, Alexander S, Sabr Y, Temtamy S, Ekbote AV, Ismail S, Hosny GA, Otaify GA, Amr K, Al Tala S, Khan AO, Rizk T, Alaqeel A, Alsiddiky A, Singh A, Kapoor S, Alhashem A, Faqeih E, Shaheen R, Alkuraya FS. Expanding the phenome and variome of skeletal dysplasia. Genet Med 2018; 20:1609-1616. [PMID: 29620724 DOI: 10.1038/gim.2018.50] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 02/13/2018] [Indexed: 12/15/2022] Open
Abstract
PURPOSE To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. METHODS Detailed phenotyping and next-generation sequencing (panel and exome). RESULTS Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. CONCLUSION By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.
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Affiliation(s)
- Sateesh Maddirevula
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Saud Alsahli
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Lamees Alhabeeb
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Nisha Patel
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Fatema Alzahrani
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Hanan E Shamseldin
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Shams Anazi
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Nour Ewida
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Hessa S Alsaif
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Jawahir Y Mohamed
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Anas M Alazami
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Niema Ibrahim
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Firdous Abdulwahab
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mais Hashem
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mohamed Abouelhoda
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Dorota Monies
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Nada Al Tassan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Muneera Alshammari
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Afaf Alsagheir
- Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | - Samira Sogati
- Department of Medical Genetics, King Fahad General Hospital, Jeddah, Saudi Arabia
| | - Mona S Aglan
- Clinical Genetics Department, Human Genetics & Genome Research Division, Center of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
| | - Muddathir H Hamad
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mustafa A Salih
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Ahlam A Hamed
- Department of Pediatrics and Child Health, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
| | | | - Amira Nabil
- Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Fatima Alfadli
- Department of Pediatrics, Maternity and Children's Hospital, Medina, Saudi Arabia
| | - Ghada M H Abdel-Salam
- Clinical Genetics Department, Human Genetics & Genome Research Division, Center of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
| | - Hisham Alkuraya
- Global Eye Care, Specialized Medical Center Hospital, Riyadh, Saudi Arabia
| | | | - W T Keng
- Clinical Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Abdullah Qasem
- Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia
| | - Aziza M Mushiba
- Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Maha S Zaki
- Clinical Genetics Department, Human Genetics & Genome Research Division, Center of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
| | - Mahmoud R Fassad
- The Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Majid Alfadhel
- King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Genetics Division, Department of Pediatrics, King Abdulaziz Medical City, MNGHA, Riyadh, Saudi Arabia
| | - Saji Alexander
- Department of Paediatric Endocrinology and Diabetes, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | - Yasser Sabr
- Department of Obstetrics and Gynecology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Samia Temtamy
- Clinical Genetics Department, Human Genetics & Genome Research Division, Center of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
| | - Alka V Ekbote
- Clinical Genetics Unit, Christian Medical College, Vellore, India
| | - Samira Ismail
- Clinical Genetics Department, Human Genetics & Genome Research Division, Center of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
| | | | - Ghada A Otaify
- Clinical Genetics Department, Human Genetics & Genome Research Division, Center of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
| | - Khalda Amr
- Clinical Genetics Department, Human Genetics & Genome Research Division, Center of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
| | - Saeed Al Tala
- Department of Pediatrics, Armed Forces Hospital Program Southwest Region, Khamis Mushait, Saudi Arabia
| | - Arif O Khan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Tamer Rizk
- Department of Pediatric Neurology, Dr. Sulaiman Al Habib Hospital, Riyadh, Saudi Arabia
| | - Aida Alaqeel
- Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia
| | - Abdulmonem Alsiddiky
- Department of Orthopedics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Ankur Singh
- Department of Pediatrics, Genetic Clinic, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Seema Kapoor
- Department of Pediatrics, Maulana Azad Medical College, New Delhi, India
| | - Amal Alhashem
- Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia.,Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Eissa Faqeih
- Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Ranad Shaheen
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
| | - Fowzan S Alkuraya
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. .,Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. .,Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia. .,Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
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Crystal structures of the TRIC trimeric intracellular cation channel orthologues. Cell Res 2017; 26:1288-1301. [PMID: 27909292 PMCID: PMC5143425 DOI: 10.1038/cr.2016.140] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 10/23/2016] [Accepted: 10/27/2016] [Indexed: 12/30/2022] Open
Abstract
Ca2+ release from the sarcoplasmic reticulum (SR) and endoplasmic reticulum (ER) is crucial for muscle contraction, cell growth, apoptosis, learning and memory. The trimeric intracellular cation (TRIC) channels were recently identified as cation channels balancing the SR and ER membrane potentials, and are implicated in Ca2+ signaling and homeostasis. Here we present the crystal structures of prokaryotic TRIC channels in the closed state and structure-based functional analyses of prokaryotic and eukaryotic TRIC channels. Each trimer subunit consists of seven transmembrane (TM) helices with two inverted repeated regions. The electrophysiological, biochemical and biophysical analyses revealed that TRIC channels possess an ion-conducting pore within each subunit, and that the trimer formation contributes to the stability of the protein. The symmetrically related TM2 and TM5 helices are kinked at the conserved glycine clusters, and these kinks are important for the channel activity. Furthermore, the kinks of the TM2 and TM5 helices generate lateral fenestrations at each subunit interface. Unexpectedly, these lateral fenestrations are occupied with lipid molecules. This study provides the structural and functional framework for the molecular mechanism of this ion channel superfamily.
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Essawi O, Symoens S, Fannana M, Darwish M, Farraj M, Willaert A, Essawi T, Callewaert B, De Paepe A, Malfait F, Coucke PJ. Genetic analysis of osteogenesis imperfecta in the Palestinian population: molecular screening of 49 affected families. Mol Genet Genomic Med 2017; 6:15-26. [PMID: 29150909 PMCID: PMC5823677 DOI: 10.1002/mgg3.331] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Revised: 07/09/2017] [Accepted: 07/10/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Osteogenesis imperfecta (OI) is a heterogeneous hereditary connective tissue disorder clinically hallmarked by increased susceptibility to bone fractures. METHODS We analyzed a cohort of 77 diagnosed OI patients from 49 unrelated Palestinian families. Next-generation sequencing technology was used to screen a panel of known OI genes. RESULTS In 41 probands, we identified 28 different disease-causing variants of 9 different known OI genes. Eleven of the variants are novel. Ten of the 28 variants are located in COL1A1, five in COL1A2, three in BMP1, three in FKBP10, two in TMEM38B, two in P3H1, and one each in CRTAP, SERPINF1, and SERPINH1. The absence of disease-causing variants in the remaining eight probands suggests further genetic heterogeneity in OI. In general, most OI patients (90%) harbor mainly variants in type I collagen resulting in an autosomal dominant inheritance pattern. However, in our cohort almost 61% (25/41) were affected with autosomal recessive OI. Moreover, we document a 21-kb genomic deletion in the TMEM38B gene identified in 29% (12/41) of the tested probands, making it the most frequent OI-causing variant in the Palestinian population. CONCLUSION This is the first genetic screening of an OI cohort from the Palestinian population. Our data are important for genetic counseling of OI patients and families in highly consanguineous populations.
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Affiliation(s)
- Osama Essawi
- Department Master Program in Clinical Laboratory Science, Birzeit University, Birzeit, Palestine.,Center for Medical Genetics, Ghent University, Ghent, Belgium
| | - Sofie Symoens
- Center for Medical Genetics, Ghent University, Ghent, Belgium
| | - Maha Fannana
- Dr. Al Rantisi Specialized Children Hospital, Gaza, Palestine
| | | | - Mohammad Farraj
- Department Master Program in Clinical Laboratory Science, Birzeit University, Birzeit, Palestine
| | - Andy Willaert
- Center for Medical Genetics, Ghent University, Ghent, Belgium
| | - Tamer Essawi
- Department Master Program in Clinical Laboratory Science, Birzeit University, Birzeit, Palestine
| | - Bert Callewaert
- Center for Medical Genetics, Ghent University, Ghent, Belgium
| | - Anne De Paepe
- Center for Medical Genetics, Ghent University, Ghent, Belgium
| | | | - Paul J Coucke
- Center for Medical Genetics, Ghent University, Ghent, Belgium
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Lim J, Grafe I, Alexander S, Lee B. Genetic causes and mechanisms of Osteogenesis Imperfecta. Bone 2017; 102:40-49. [PMID: 28232077 PMCID: PMC5607741 DOI: 10.1016/j.bone.2017.02.004] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 01/07/2017] [Accepted: 02/11/2017] [Indexed: 12/25/2022]
Abstract
Osteogenesis Imperfecta (OI) is a genetic disorder characterized by various clinical features including bone deformities, low bone mass, brittle bones, and connective tissue manifestations. The predominant cause of OI is due to mutations in the two genes that encode type I collagen. However, recent advances in sequencing technology has led to the discovery of novel genes that are implicated in recessive and dominant OI. These include genes that regulate the post-translational modification, secretion and processing of type I collagen as well as those required for osteoblast differentiation and bone mineralization. As such, OI has become a spectrum of genetic disorders informing about the determinants of both bone quantity and quality. Here we summarize the known genetic causes of OI, animal models that recapitulate the human disease and mechanisms that underlie disease pathogenesis. Additionally, we discuss the effects of disrupted collagen networks on extracellular matrix signaling and its impact on disease progression.
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Affiliation(s)
- Joohyun Lim
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ingo Grafe
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Stefanie Alexander
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
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Webb EA, Balasubramanian M, Fratzl-Zelman N, Cabral WA, Titheradge H, Alsaedi A, Saraff V, Vogt J, Cole T, Stewart S, Crabtree NJ, Sargent BM, Gamsjaeger S, Paschalis EP, Roschger P, Klaushofer K, Shaw NJ, Marini JC, Högler W. Phenotypic Spectrum in Osteogenesis Imperfecta Due to Mutations in TMEM38B: Unraveling a Complex Cellular Defect. J Clin Endocrinol Metab 2017; 102:2019-2028. [PMID: 28323974 PMCID: PMC5470761 DOI: 10.1210/jc.2016-3766] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 03/09/2017] [Indexed: 12/19/2022]
Abstract
CONTEXT Recessive mutations in TMEM38B cause type XIV osteogenesis imperfecta (OI) by dysregulating intracellular calcium flux. OBJECTIVES Clinical and bone material phenotype description and osteoblast differentiation studies. DESIGN AND SETTING Natural history study in pediatric research centers. PATIENTS Eight patients with type XIV OI. MAIN OUTCOME MEASURES Clinical examinations included bone mineral density, radiographs, echocardiography, and muscle biopsy. Bone biopsy samples (n = 3) were analyzed using histomorphometry, quantitative backscattered electron microscopy, and Raman microspectroscopy. Cellular differentiation studies were performed on proband and control osteoblasts and normal murine osteoclasts. RESULTS Type XIV OI clinical phenotype ranges from asymptomatic to severe. Previously unreported features include vertebral fractures, periosteal cloaking, coxa vara, and extraskeletal features (muscular hypotonia, cardiac abnormalities). Proband lumbar spine bone density z score was reduced [median -3.3 (range -4.77 to +0.1; n = 7)] and increased by +1.7 (1.17 to 3.0; n = 3) following bisphosphonate therapy. TMEM38B mutant bone has reduced trabecular bone volume, osteoblast, and particularly osteoclast numbers, with >80% reduction in bone resorption. Bone matrix mineralization is normal and nanoporosity low. We demonstrate a complex osteoblast differentiation defect with decreased expression of early markers and increased expression of late and mineralization-related markers. Predominance of trimeric intracellular cation channel type B over type A expression in murine osteoclasts supports an intrinsic osteoclast defect underlying low bone turnover. CONCLUSIONS OI type XIV has a bone histology, matrix mineralization, and osteoblast differentiation pattern that is distinct from OI with collagen defects. Probands are responsive to bisphosphonates and some show muscular and cardiovascular features possibly related to intracellular calcium flux abnormalities.
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Affiliation(s)
- Emma A. Webb
- Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham B4 6NH, United Kingdom
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom
| | - Meena Balasubramanian
- Sheffield Clinical Genetics Service, Sheffield Children’s National Health Service Foundation Trust, Sheffield S10 2TH United Kingdom
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt Trama Centre Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria
| | - Wayne A. Cabral
- Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892
| | - Hannah Titheradge
- Department of Clinical Genetics, Birmingham Women’s Hospital, Birmingham B15 2DG, United Kingdom
| | - Atif Alsaedi
- Department of Clinical Genetics, Birmingham Women’s Hospital, Birmingham B15 2DG, United Kingdom
| | - Vrinda Saraff
- Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham B4 6NH, United Kingdom
| | - Julie Vogt
- Department of Clinical Genetics, Birmingham Women’s Hospital, Birmingham B15 2DG, United Kingdom
| | - Trevor Cole
- Department of Clinical Genetics, Birmingham Women’s Hospital, Birmingham B15 2DG, United Kingdom
| | - Susan Stewart
- Department of Clinical Genetics, Birmingham Women’s Hospital, Birmingham B15 2DG, United Kingdom
| | - Nicola J. Crabtree
- Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham B4 6NH, United Kingdom
| | - Brandi M. Sargent
- Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892
| | - Sonja Gamsjaeger
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt Trama Centre Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria
| | - Eleftherios P. Paschalis
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt Trama Centre Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria
| | - Paul Roschger
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt Trama Centre Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria
| | - Klaus Klaushofer
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt Trama Centre Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria
| | - Nick J. Shaw
- Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham B4 6NH, United Kingdom
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom
| | - Joan C. Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892
| | - Wolfgang Högler
- Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham B4 6NH, United Kingdom
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom
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Ou X, Guo J, Wang L, Yang H, Liu X, Sun J, Liu Z. Ion- and water-binding sites inside an occluded hourglass pore of a trimeric intracellular cation (TRIC) channel. BMC Biol 2017; 15:31. [PMID: 28431535 PMCID: PMC5401562 DOI: 10.1186/s12915-017-0372-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Accepted: 04/05/2017] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Trimeric intracellular cation (TRIC) channels are crucial for Ca2+ handling in eukaryotes and are involved in K+ uptake in prokaryotes. Recent studies on the representative members of eukaryotic and prokaryotic TRIC channels demonstrated that they form homotrimeric units with the ion-conducting pores contained within each individual monomer. RESULTS Here we report detailed insights into the ion- and water-binding sites inside the pore of a TRIC channel from Sulfolobus solfataricus (SsTRIC). Like the mammalian TRIC channels, SsTRIC is permeable to both K+ and Na+ with a slight preference for K+, and is nearly impermeable to Ca2+, Mg2+, or Cl-. In the 2.2-Å resolution K+-bound structure of SsTRIC, ion/water densities have been well resolved inside the pore. At the central region, a filter-like structure is shaped by the kinks on the second and fifth transmembrane helices and two nearby phenylalanine residues. Below the filter, the cytoplasmic vestibule is occluded by a plug-like motif attached to an array of pore-lining charged residues. CONCLUSIONS The asymmetric filter-like structure at the pore center of SsTRIC might serve as the basis for the channel to bind and select monovalent cations. A Velcro-like plug-pore interacting model has been proposed and suggests a unified framework accounting for the gating mechanisms of prokaryotic and eukaryotic TRIC channels.
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Affiliation(s)
- Xiaomin Ou
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jianli Guo
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Longfei Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Hanting Yang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiuying Liu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jianyuan Sun
- State Key Laboratory of Brain & Cognitive Sciences, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhenfeng Liu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
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Marr C, Seasman A, Bishop N. Managing the patient with osteogenesis imperfecta: a multidisciplinary approach. J Multidiscip Healthc 2017; 10:145-155. [PMID: 28435282 PMCID: PMC5388361 DOI: 10.2147/jmdh.s113483] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous heritable connective tissue disorder characterized by low bone density. The type and severity of OI are variable. The primary manifestations are fractures, bone deformity, and bone pain, resulting in reduced mobility and function to complete everyday tasks. OI affects not only the physical but also the social and emotional well-being of children, young people, and their families. As such, medical, surgical, and allied health professionals’ assessments all play a role in the management of these children. The multidisciplinary approach to the treatment of children and young people living with OI seeks to provide well-coordinated, comprehensive assessments, and interventions that place the child and family at the very center of their care. The coordinated efforts of a multidisciplinary team can support children with OI to fulfill their potential, maximizing function, independence, and well-being.
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Affiliation(s)
| | | | - Nick Bishop
- Academic Unit of Child Health, Department of Human Metabolism, University of Sheffield, Sheffield Children's NHS Foundation Trust, Sheffield, UK
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Kang H, Aryal A C S, Marini JC. Osteogenesis imperfecta: new genes reveal novel mechanisms in bone dysplasia. Transl Res 2017; 181:27-48. [PMID: 27914223 DOI: 10.1016/j.trsl.2016.11.005] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 11/04/2016] [Accepted: 11/07/2016] [Indexed: 12/20/2022]
Abstract
Osteogenesis imperfecta (OI) is a skeletal dysplasia characterized by fragile bones and short stature and known for its clinical and genetic heterogeneity which is now understood as a collagen-related disorder. During the last decade, research has made remarkable progress in identifying new OI-causing genes and beginning to understand the intertwined molecular and biochemical mechanisms of their gene products. Most cases of OI have dominant inheritance. Each new gene for recessive OI, and a recently identified gene for X-linked OI, has shed new light on its (often previously unsuspected) function in bone biology. Here, we summarize the literature that has contributed to our current understanding of the pathogenesis of OI.
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Affiliation(s)
- Heeseog Kang
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, Md
| | - Smriti Aryal A C
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, Md
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, Md.
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Abstract
Trimeric intracellular cation (TRIC) channel subtypes, namely TRIC-A and TRIC-B, are expressed in the endoplasmic/sarcoplasmic reticulum and nuclear envelope, and likely function as monovalent cation channels in various cell types. Our studies using knockout mice so far suggest that TRIC subtypes support Ca2+ release from intracellular stores by mediating counter-cationic fluxes. Several genetic mutations within the TRIC-B locus were recently identified in autosomal recessive osteogenesis imperfecta (OI) patients. However, the molecular mechanism by which the mutations cause human disease is not fully addressed. We found that Tric-b-knockout mice exhibit poor bone ossification and thus serve as an OI-model animal. Studies on Tric-b-knockout bones and cultured cell lines derived from the patients currently reveal the main part of the pathophysiological mechanism involved in the TRIC-B-mutated OI form. This mini-review focuses on the essential role of TRIC-B channels in bone ossification.
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47
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Marom R, Lee YC, Grafe I, Lee B. Pharmacological and biological therapeutic strategies for osteogenesis imperfecta. AMERICAN JOURNAL OF MEDICAL GENETICS. PART C, SEMINARS IN MEDICAL GENETICS 2016; 172:367-383. [PMID: 27813341 PMCID: PMC11955151 DOI: 10.1002/ajmg.c.31532] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility, low bone mass, and bone deformities. The majority of cases are caused by autosomal dominant pathogenic variants in the COL1A1 and COL1A2 genes that encode type I collagen, the major component of the bone matrix. The remaining cases are caused by autosomal recessively or dominantly inherited mutations in genes that are involved in the post-translational modification of type I collagen, act as type I collagen chaperones, or are members of the signaling pathways that regulate bone homeostasis. The main goals of treatment in OI are to decrease fracture incidence, relieve bone pain, and promote mobility and growth. This requires a multi-disciplinary approach, utilizing pharmacological interventions, physical therapy, orthopedic surgery, and monitoring nutrition with appropriate calcium and vitamin D supplementation. Bisphosphonate therapy, which has become the mainstay of treatment in OI, has proven beneficial in increasing bone mass, and to some extent reducing fracture risk. However, the response to treatment is not as robust as is seen in osteoporosis, and it seems less effective in certain types of OI, and in adult OI patients as compared to most pediatric cases. New pharmacological treatments are currently being developed, including anti-resorptive agents, anabolic treatment, and gene- and cell-therapy approaches. These therapies are under different stages of investigation from the bench-side, to pre-clinical and clinical trials. In this review, we will summarize the recent findings regarding the pharmacological and biological strategies for the treatment of patients with OI. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ronit Marom
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yi-Chien Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ingo Grafe
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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48
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Kämpe AJ, Mäkitie RE, Mäkitie O. New Genetic Forms of Childhood-Onset Primary Osteoporosis. Horm Res Paediatr 2016; 84:361-9. [PMID: 26517534 DOI: 10.1159/000439566] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 08/19/2015] [Indexed: 11/19/2022] Open
Abstract
Recent developments in genetic technology have given us the opportunity to look at diseases in a new and more detailed way. This Mini Review discusses monogenetic forms of childhood-onset primary osteoporosis, with the main focus on osteoporosis caused by mutations in WNT1 and PLS3, two of the most recently discovered genes underlying early-onset osteoporosis. The importance of WNT1 in the accrual and maintenance of bone mass through activation of canonical WNT signaling was recognized in 2013. WNT1 was shown to be a key ligand for the WNT-signaling pathway, which is of major importance in the regulation of bone formation. More recently, mutations in PLS3, located on the X chromosome, were shown to be the cause of X-linked childhood-onset primary osteoporosis affecting mainly males. The function of PLS3 in bone metabolism is still not completely understood, but it has been speculated to have an important role in mechanosensing by osteocytes and in matrix mineralization. In this new era of genetics, our knowledge on genetic causes of childhood-onset osteoporosis expands constantly. These discoveries bring new possibilities, but also new challenges. Guidelines are needed to implement this new genetic knowledge to clinical patient care and to guide genetic investigations in affected families.
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Affiliation(s)
- Anders J Kämpe
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
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49
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Pore architecture of TRIC channels and insights into their gating mechanism. Nature 2016; 538:537-541. [PMID: 27698420 DOI: 10.1038/nature19767] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 08/16/2016] [Indexed: 01/23/2023]
Abstract
Intracellular Ca2+ signalling processes are fundamental to muscle contraction, neurotransmitter release, cell growth and apoptosis. Release of Ca2+ from the intracellular stores is supported by a series of ion channels in sarcoplasmic or endoplasmic reticulum (SR/ER). Among them, two isoforms of the trimeric intracellular cation (TRIC) channel family, named TRIC-A and TRIC-B, modulate the release of Ca2+ through the ryanodine receptor or inositol triphosphate receptor, and maintain the homeostasis of ions within SR/ER lumen. Genetic ablations or mutations of TRIC channels are associated with hypertension, heart disease, respiratory defects and brittle bone disease. Despite the pivotal function of TRIC channels in Ca2+ signalling, their pore architectures and gating mechanisms remain unknown. Here we present the structures of TRIC-B1 and TRIC-B2 channels from Caenorhabditis elegans in complex with endogenous phosphatidylinositol-4,5-biphosphate (PtdIns(4,5)P2, also known as PIP2) lipid molecules. The TRIC-B1/B2 proteins and PIP2 assemble into a symmetrical homotrimeric complex. Each monomer contains an hourglass-shaped hydrophilic pore contained within a seven-transmembrane-helix domain. Structural and functional analyses unravel the central role of PIP2 in stabilizing the cytoplasmic gate of the ion permeation pathway and reveal a marked Ca2+-induced conformational change in a cytoplasmic loop above the gate. A mechanistic model has been proposed to account for the complex gating mechanism of TRIC channels.
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Enderli TA, Burtch SR, Templet JN, Carriero A. Animal models of osteogenesis imperfecta: applications in clinical research. Orthop Res Rev 2016; 8:41-55. [PMID: 30774469 PMCID: PMC6209373 DOI: 10.2147/orr.s85198] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Osteogenesis imperfecta (OI), commonly known as brittle bone disease, is a genetic disease characterized by extreme bone fragility and consequent skeletal deformities. This connective tissue disorder is caused by mutations in the quality and quantity of the collagen that in turn affect the overall mechanical integrity of the bone, increasing its vulnerability to fracture. Animal models of the disease have played a critical role in the understanding of the pathology and causes of OI and in the investigation of a broad range of clinical therapies for the disease. Currently, at least 20 animal models have been officially recognized to represent the phenotype and biochemistry of the 17 different types of OI in humans. These include mice, dogs, and fish. Here, we describe each of the animal models and the type of OI they represent, and present their application in clinical research for treatments of OI, such as drug therapies (ie, bisphosphonates and sclerostin) and mechanical (ie, vibrational) loading. In the future, different dosages and lengths of treatment need to be further investigated on different animal models of OI using potentially promising treatments, such as cellular and chaperone therapies. A combination of therapies may also offer a viable treatment regime to improve bone quality and reduce fragility in animals before being introduced into clinical trials for OI patients.
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Affiliation(s)
- Tanya A Enderli
- Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, USA,
| | - Stephanie R Burtch
- Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, USA,
| | - Jara N Templet
- Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, USA,
| | - Alessandra Carriero
- Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, USA,
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