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van Gurp JE, Lechner RL, Micha D, Maugeri A, Dulfer E, van Dijk FS, Keszthelyi D, Malfatti E, Kubo A, Voermans NC, Demirdas S. Tenascin-X Deficiency Causing Classical-Like Ehlers-Danlos Syndrome Type 1 in Humans is a Significant Risk Factor of Gastrointestinal and Tracheal Ruptures. Clin Transl Gastroenterol 2025; 16:e00821. [PMID: 39807789 PMCID: PMC11932583 DOI: 10.14309/ctg.0000000000000821] [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: 06/26/2024] [Accepted: 01/07/2025] [Indexed: 01/16/2025] Open
Abstract
INTRODUCTION Classical-like Ehlers-Danlos syndrome type 1 (clEDS1) is a very rare form of Ehlers-Danlos syndrome caused by tenascin-X deficiency, with only 56 individuals reported in medical literature. Tenascin-X is an extracellular matrix protein needed for collagen stability. Previous publications propose that individuals with clEDS1 might be at risk of gastrointestinal (GI) tract perforations and/or tracheal ruptures. The aim of this study was to characterize complications resulting from perforations of the GI tract and/or tracheal rupture in an international case series of individuals with clEDS1 due to disease-related tissue fragility. METHODS This case series includes individuals with confirmed clEDS1 and GI perforations and/or tracheal ruptures from participating centers. Researchers who previously reported such individuals were contacted for additional information. A retrospective assessment of clinical features was performed. RESULTS Fifteen individuals were included. Ten had spontaneous GI perforations, 7 of whom had multiple GI perforations. Almost all had severe diverticulosis. Three individuals experienced iatrogenic tracheal ruptures. DISCUSSION Severe GI complications, such as perforation, and tracheal rupture were observed in a substantial number of individuals with clEDS1. As these features seem significantly more common in clEDS1 than in the average population, we advise vigilance during intubation and GI endoscopic interventions of individuals with clEDS1. Routine referrals to clinical geneticists are recommended for patients with symptoms indicative of clEDS1, especially with unexplained GI perforations and connective tissue symptoms. Our findings offer valuable insights for the clinical management of clEDS1 and underscore the importance of specialized care, providing a foundation for improved clinical guidelines and preventive strategies.
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Affiliation(s)
- Jonneke E. van Gurp
- Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Rosan L. Lechner
- Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Dimitra Micha
- Department of Human Genetics, Amsterdam Reproduction and Development, Amsterdam Movement Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Alessandra Maugeri
- Department of Human Genetics, Amsterdam Reproduction and Development, Amsterdam Movement Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Eelco Dulfer
- Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands
| | - Fleur S. van Dijk
- National Ehlers Danlos Syndrome Service, London North West University Healthcare NHS Trust, Harrow, London, UK
- Department of Metabolism, Digestion and Reproduction, Section Genomics & Genetics, Imperial, London, UK
| | - Daniel Keszthelyi
- Department of Gastroenterology-Hepatology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Edoardo Malfatti
- APHP, Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, Henri Mondor Hospital, University Paris-Est, Créteil, France
| | - Akiharu Kubo
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Nicol C. Voermans
- Department of Neurology, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Serwet Demirdas
- Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
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Miller WL, Pandey AV, Flück CE. Disordered Electron Transfer: New Forms of Defective Steroidogenesis and Mitochondriopathy. J Clin Endocrinol Metab 2025; 110:e574-e582. [PMID: 39574227 PMCID: PMC11834722 DOI: 10.1210/clinem/dgae815] [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: 09/26/2024] [Indexed: 02/19/2025]
Abstract
Most disorders of steroidogenesis, such as forms of congenital adrenal hyperplasia (CAH) are caused by mutations in genes encoding the steroidogenic enzymes and are often recognized clinically by cortisol deficiency, hyper- or hypo-androgenism, and/or altered mineralocorticoid function. Most steroidogenic enzymes are forms of cytochrome P450. Most P450s, including several steroidogenic enzymes, are microsomal, requiring electron donation by P450 oxidoreductase (POR); however, several steroidogenic enzymes are mitochondrial P450s, requiring electron donation via ferredoxin reductase (FDXR) and ferredoxin (FDX). POR deficiency is a rare but well-described form of CAH characterized by impaired activity of 21-hydroxylase (P450c21, CYP21A2) and 17-hydroxylase/17,20-lyase (P450c17, CYP17A1); more severely affected individuals also have the Antley-Bixler skeletal malformation syndrome and disordered genital development in both sexes, and hence is easily recognized. The 17,20-lyase activity of P450c17 requires both POR and cytochrome b5 (b5), which promote electron transfer. Mutations of POR, b5, or P450c17 can cause selective 17,20-lyase deficiency. In addition to providing electrons to mitochondrial P450s, FDX, and FDXR are required for the synthesis of iron-sulfur clusters, which are used by many enzymes. Recent work has identified FDXR mutations in patients with visual impairment, optic atrophy, neuropathic hearing loss, and developmental delay, resembling the global neurologic disorders seen with mitochondrial diseases. Many of these patients have had life-threatening events or deadly infections, often without an apparent triggering event. Adrenal insufficiency has been predicted in such individuals but has only been documented recently. Neurologists, neonatologists, and geneticists should seek endocrine assistance in evaluating and treating patients with mutations in FDXR.
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Affiliation(s)
- Walter L Miller
- Department of Pediatrics, Center for Reproductive Sciences, and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Amit V Pandey
- Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland
- Department of BioMedical Research, University of Bern, Bern 3010, Switzerland
| | - Christa E Flück
- Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland
- Department of BioMedical Research, University of Bern, Bern 3010, Switzerland
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Monlong J, Chen X, Barseghyan H, Rowell WJ, Negi S, Nokoff N, Mohnach L, Hirsch J, Finlayson C, Keegan CE, Almalvez M, Berger SI, de Dios I, McNulty B, Robertson A, Miga KH, Speiser PW, Paten B, Vilain E, Délot EC. Long-read sequencing resolves the clinically relevant CYP21A2 locus, supporting a new clinical test for Congenital Adrenal Hyperplasia. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.02.07.25321404. [PMID: 39990550 PMCID: PMC11844570 DOI: 10.1101/2025.02.07.25321404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Congenital Adrenal Hyperplasia (CAH), one of the most common inherited disorders, is caused by defects in adrenal steroidogenesis. It is potentially lethal if untreated and is associated with multiple comorbidities, including fertility issues, obesity, insulin resistance, and dyslipidemia. CAH can result from variants in multiple genes, but the most frequent cause is deletions and conversions in the segmentally duplicated RCCX module, which contains the CYP21A2 gene and a pseudogene. The molecular genetic test to identify pathogenic alleles is cumbersome, incomplete, and available from a limited number of laboratories. It requires testing parents for accurate interpretation, leading to healthcare inequity. Less severe forms are frequently misdiagnosed, and phenotype/genotype correlations incompletely understood. We explored whether emerging technologies could be leveraged to identify all pathogenic alleles of CAH, including phasing in proband-only cases. We targeted long-read sequencing outputs that would be practical in a clinical laboratory setting. Both HiFi-based and nanopore-based whole-genome long-read sequencing datasets could be mined to accurately identify pathogenic single-nucleotide variants, full gene deletions, fusions creating non-functional hybrids between the gene and pseudogene ("30-kb deletion"), as well as count the number of RCCX modules and phase the resulting multimodular haplotypes. On the Hi-Fi data set of 6 samples, the PacBio Paraphase tool was able to distinguish nine different mono-, bi-, and tri-modular haplotypes, as well as the 30-kb and whole gene deletions. To do the same on the ONT-Nanopore dataset, we designed a tool, Parakit, which creates an enriched local pangenome to represent known haplotype assemblies and map ClinVar pathogenic variants and fusions onto them. With few labels in the region, optical genome mapping was not able to reliably resolve module counts or fusions, although designing a tool to mine the dataset specifically for this region may allow doing so in the future. Both sequencing techniques yielded congruent results, matching clinically identified variants, and offered additional information above the clinical test, including phasing, count of RCCX modules, and status of the other module genes, all of which may be of clinical relevance. Thus long-read sequencing could be used to identify variants causing multiple forms of CAH in a single test.
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Concolino P, Falhammar H. Genetics in Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency and Clinical Implications. J Endocr Soc 2025; 9:bvaf018. [PMID: 39911519 PMCID: PMC11795198 DOI: 10.1210/jendso/bvaf018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Indexed: 02/07/2025] Open
Abstract
Of all congenital adrenal hyperplasia (CAH), 95% to 99% is 21-hydroxylase deficiency (21OHD), an autosomal recessive disease. 21OHD is due to an insufficiency of 21-hydroxylase enzyme, which is encoded by the CYP21A2 gene and involved in cortisol and aldosterone production. The clinical presentation differs widely from severe classic to mild nonclassic CAH. 21OHD represents one of the most complex and at the same time intriguing topics in human genetics and its molecular diagnosis involves ongoing challenges. To provide a meticulous presentation of the topic, we searched the past and present literature, including original articles and reviews from PubMed, ScienceDirect, Web of Science, Embase, and Scopus, using search terms for genetics of 21OHD, 21OHD variants, molecular diagnosis of 21OHD, and 21OHD genetic testing. We offer a comprehensive review focusing on recent developments, new concepts, and conclusions.
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Affiliation(s)
- Paola Concolino
- Dipartimento di Scienze di Laboratorio ed Ematologiche, UOC Chimica, Biochimica e Biologia Molecolare Clinica. Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma 00168, Italy
| | - Henrik Falhammar
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-171 76, Sweden
- Department of Endocrinology, Karolinska University Hospital, Stockholm SE-171 76, Sweden
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Körfer D, Grond-Ginsbach C, Peters AS, Burkart S, Hempel M, Schaaf CP, Böckler D, Erhart P. Genetic variants in patients with multiple arterial aneurysms. Langenbecks Arch Surg 2024; 409:304. [PMID: 39382597 PMCID: PMC11464538 DOI: 10.1007/s00423-024-03488-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 09/26/2024] [Indexed: 10/10/2024]
Abstract
PURPOSE The aim of this study was to identify causal genetic variants in patients with multiple arterial aneurysms. METHODS From a total cohort of 3107 patients diagnosed with an arterial aneurysm from 2006 to 2016, patients with known hereditary connective tissue diseases, vasculitis, or other arterial pathologies (n = 918) were excluded. Of the remaining cohort (n = 2189), patients with at least 4 aneurysms at different arterial locations (n = 143) were included. Nine blood samples of respective patients were available and derived from the institutional vascular biomaterial bank, and analyzed by whole exome sequencing (WES). Possible candidate variants were selected based on in silico predictions: (I) Truncating variants or (II) Variants that were classified as likely pathogenic (SIFT score < 0.05 or PolyPhen score > 0.9) and with low (< 0.001) or unknown gnomAD allele frequency. The human genome databases GeneCards and MalaCards were used to correlate the variants with regard to possible associations with vascular diseases. RESULTS A total of 24 variants in 23 different genes associated with vascular diseases were detected in the cohort. One patient with eight aneurysms was heterozygous for a variant in SMAD3, for which pathogenic variants are phenotypically associated with Loeys-Dietz syndrome 3. A heterozygous variant in TNXB was found in a patient with five aneurysms. Homozygous or compound heterozygous pathogenic variants in this gene are associated with Ehlers-Danlos syndrome (classical-like). Another patient with six aneurysms carried two heterozygous TET2 variants together with a heterozygous PPM1D variant. Pathogenic variants in these genes are associated with clonal hematopoiesis of indeterminate potential (CHIP), a known risk factor for cardiovascular disease. CONCLUSION All nine patients in this study carried variants in genes associated with vascular diseases. Current knowledge of the specific variants is insufficient to classify them as pathogenic at the present time, underlining the need for a better understanding of the consequences of genetic variants. WES should be considered for patients with multiple arterial aneurysms to detect germline variants and to improve clinical management for the individual and family members.
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Affiliation(s)
- Daniel Körfer
- Department of Vascular and Endovascular Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany.
| | - Caspar Grond-Ginsbach
- Department of Vascular and Endovascular Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany
| | - Andreas S Peters
- Department of Vascular and Endovascular Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany
- Vascular Biomaterialbank Heidelberg (VBBH), Heidelberg University Hospital, Heidelberg, Germany
| | - Sebastian Burkart
- Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | - Maja Hempel
- Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | | | - Dittmar Böckler
- Department of Vascular and Endovascular Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany
| | - Philipp Erhart
- Department of Vascular and Endovascular Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany
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Pliego-Arreaga R, Cervantes-Montelongo JA, Silva-Martínez GA, Tristán-Flores FE, Pantoja-Hernández MA, Maldonado-Coronado JR. Joint Hypermobility Syndrome and Membrane Proteins: A Comprehensive Review. Biomolecules 2024; 14:472. [PMID: 38672488 PMCID: PMC11048254 DOI: 10.3390/biom14040472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/03/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Ehlers-Danlos syndromes (EDSs) constitute a heterogeneous group of connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Asymptomatic EDSs, joint hypermobility without associated syndromes, EDSs, and hypermobility spectrum disorders are the commonest phenotypes associated with joint hypermobility. Joint hypermobility syndrome (JHS) is a connective tissue disorder characterized by extreme flexibility of the joints, along with pain and other symptoms. JHS can be a sign of a more serious underlying genetic condition, such as EDS, which affects the cartilage, bone, fat, and blood. The exact cause of JHS could be related to genetic changes in the proteins that add flexibility and strength to the joints, ligaments, and tendons, such as collagen. Membrane proteins are a class of proteins embedded in the cell membrane and play a crucial role in cell signaling, transport, and adhesion. Dysregulated membrane proteins have been implicated in a variety of diseases, including cancer, cardiovascular disease, and neurological disorders; recent studies have suggested that membrane proteins may also play a role in the pathogenesis of JHS. This article presents an exploration of the causative factors contributing to musculoskeletal pain in individuals with hypermobility, based on research findings. It aims to provide an understanding of JHS and its association with membrane proteins, addressing the clinical manifestations, pathogenesis, diagnosis, and management of JHS.
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Affiliation(s)
- Raquel Pliego-Arreaga
- Escuela de Medicina, Universidad de Celaya, Celaya 38080, Guanajuato, Mexico; (J.A.C.-M.); (M.A.P.-H.); (J.R.M.-C.)
| | - Juan Antonio Cervantes-Montelongo
- Escuela de Medicina, Universidad de Celaya, Celaya 38080, Guanajuato, Mexico; (J.A.C.-M.); (M.A.P.-H.); (J.R.M.-C.)
- Departamento de Ingeniería Bioquímica, Tecnológico Nacional de México en Celaya, Celaya 38010, Guanajuato, Mexico;
| | | | | | | | - Juan Raúl Maldonado-Coronado
- Escuela de Medicina, Universidad de Celaya, Celaya 38080, Guanajuato, Mexico; (J.A.C.-M.); (M.A.P.-H.); (J.R.M.-C.)
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Zhang R, Cui D, Song C, Ma X, Cai N, Zhang Y, Feng M, Cao Y, Chen L, Qiang R. Evaluating the efficacy of a long-read sequencing-based approach in the clinical diagnosis of neonatal congenital adrenocortical hyperplasia. Clin Chim Acta 2024; 555:117820. [PMID: 38307397 DOI: 10.1016/j.cca.2024.117820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/22/2024] [Accepted: 01/29/2024] [Indexed: 02/04/2024]
Abstract
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders predominantly characterized by impaired corticosteroid synthesis. Clinical phenotypes include hypoadrenocorticism, electrolyte disturbances, abnormal gonadal development, and short stature, of which severe hyponadrenocorticism and salt wasting can be life-threatening. Genetic analysis can help in the clinical diagnosis of CAH. However, the 21-OHD-causing gene CYP21A2 is arranged in tandem with the highly homologous CYP21A1P pseudogene, making it difficult to determine the exact genotypes using the traditional method of multiplex ligation-dependent probe amplification (MLPA) plus Sanger sequencing or next-generation sequencing (NGS). We applied a long-read sequencing-based approach termed comprehensive analysis of CAH (CACAH) to 48 newborns with CAH that were diagnosed by clinical features and the traditional MLPA plus Sanger sequencing method for retrospective analysis, to evaluate its efficacy in the clinical diagnosis of neonatal CAH. Compared with the MLPA plus Sanger sequencing method, CACAH showed 100 % consistency in detecting SNV/indel variants located in exons and exon-intron boundary regions of CAH-related genes. It can directly determine the cis-trans relationship without the need to analyze parental genotypes, which reduces the time to diagnosis. Moreover, CACAH was able to distinguish different CYP21A1P/CYP21A2 and TNXA/TNXB chimeras, and detect additional variants (CYP21A2 variants c.-121C > T, c.*13G > A, c.*52C > T, c.*440C > T, c.*443 T > C, and TNXB variants c.12463 + 2 T > C, c.12204 + 5G > A). We also identified the TNXB variant c.11435_11524 + 30del alone instead of as a part of the TNXA/TNXB-CH-1 chimera in two newborns, which might be introduced by gene conversion. All of these characteristics enabled clinicians to better explain the phenotype of subjects and manage them more effectively. CACAH has a great advantage over the traditional MLPA and Sanger sequencing methods, showing substantial potential in the genetic diagnosis and screening of neonatal CAH.
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Affiliation(s)
- Ruixue Zhang
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Di Cui
- Berry Genomics Corporation, Beijing 102200, China
| | - Chengrong Song
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Xiaoping Ma
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Na Cai
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Yan Zhang
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Mei Feng
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Yanlin Cao
- Berry Genomics Corporation, Beijing 102200, China
| | - Libao Chen
- Berry Genomics Corporation, Beijing 102200, China
| | - Rong Qiang
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China.
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Kamada H, Emura K, Yamamoto R, Kawahara K, Uto S, Minami T, Ito S, Matsumoto KI, Okuda-Ashitaka E. Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers-Danlos syndrome. Sci Rep 2023; 13:18490. [PMID: 37898719 PMCID: PMC10613304 DOI: 10.1038/s41598-023-45638-7] [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: 07/04/2023] [Accepted: 10/21/2023] [Indexed: 10/30/2023] Open
Abstract
Deficiency of an extracellular matrix glycoprotein tenascin-X (TNX) leads to a human heritable disorder Ehlers-Danlos syndrome, and TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. We previously reported that TNX-deficient (Tnxb-/-) mice exhibit mechanical allodynia and hypersensitivity to myelinated A-fibers. Here, we investigated the pain response of Tnxb-/- mice using pharmacological silencing of A-fibers with co-injection of N-(2,6-Dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314), a membrane-impermeable lidocaine analog, plus flagellin, a toll-like receptor 5 (TLR5) ligand. Intraplantar co-injection of QX-314 and flagellin significantly increased the paw withdrawal threshold to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aβ fiber responses), but not 5 Hz (C fiber responses) in wild-type mice. The QX-314 plus flagellin-induced silencing of Aδ- and Aβ-fibers was also observed in Tnxb-/- mice. Co-injection of QX-314 and flagellin significantly inhibited the mechanical allodynia and neuronal activation of the spinal dorsal horn in Tnxb-/- mice. Interestingly, QX-314 alone inhibited the mechanical allodynia in Tnxb-/- mice, and it increased the paw withdrawal threshold to stimuli at frequencies of 250 Hz and 2000 Hz in Tnxb-/- mice, but not in wild-type mice. The inhibition of mechanical allodynia induced by QX-314 alone was blocked by intraplantar injection of a TLR5 antagonist TH1020 in Tnxb-/- mice. These results suggest that mechanical allodynia due to TNX deficiency is caused by the hypersensitivity of Aδ- and Aβ-fibers, and it is induced by constitutive activation of TLR5.
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Affiliation(s)
- Hiroki Kamada
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan
| | - Kousuke Emura
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan
| | - Rikuto Yamamoto
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan
| | - Koichi Kawahara
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan
| | - Sadahito Uto
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan
| | - Toshiaki Minami
- Department of Anesthesiology, Osaka Medical and Pharmaceutical University, Takatsuki, 569-8686, Japan
| | - Seiji Ito
- Department of Anesthesiology, Osaka Medical and Pharmaceutical University, Takatsuki, 569-8686, Japan
| | - Ken-Ichi Matsumoto
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, Izumo, 693-8501, Japan
| | - Emiko Okuda-Ashitaka
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan.
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Mirza N, Upadhyaya S, Mehta S, Malhotra S, Sibal A. Esophageal Stricture and Dermal Pathology Related to Compound Heterozygous Mutations in the TNXB Gene. J Pediatr Genet 2023; 12:224-226. [PMID: 37575646 PMCID: PMC10421679 DOI: 10.1055/s-0041-1724048] [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: 10/17/2020] [Accepted: 01/10/2021] [Indexed: 10/22/2022]
Abstract
The Ehlers-Danlos' syndrome (EDS) constitutes a group of connective tissue disorders that are clinically and genetically heterogeneous. Mutations in the TNXB gene have been recognized as pathogenic causing classical-like EDS due to tenascin-X deficiency. Here, we have reported a unique case of compound heterozygous mutation in TNXB gene leading to esophageal stricture and scarred skin in a 7-year-old boy who presented to us with impacted foreign body in esophagus. The child was also having tendency to atrophic skin scarring secondary to trivial trauma.
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Affiliation(s)
- Nida Mirza
- Indraprastha Apollo Hospital, Delhi, India
| | | | - Sagar Mehta
- Department of Pediatric Gastroenterology, Indraprastha Apollo Hospital, New Delhi
| | - Smita Malhotra
- Department of Pediatric Gastroenterology, Indraprastha Apollo Hospital, New Delhi
| | - Anupam Sibal
- Department of Pediatric Gastroenterology, Indraprastha Apollo Hospital, New Delhi
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Yamaguchi T, Yamada K, Nagai S, Nishikubo T, Koitabashi N, Minami-Hori M, Matsushima M, Shibata Y, Ishiguro H, Sanai H, Fujikawa T, Takiguchi Y, Matsumoto KI, Kosho T. Clinical and molecular delineation of classical-like Ehlers-Danlos syndrome through a comprehensive next-generation sequencing-based screening system. Front Genet 2023; 14:1234804. [PMID: 37712068 PMCID: PMC10498456 DOI: 10.3389/fgene.2023.1234804] [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] [Received: 06/05/2023] [Accepted: 07/24/2023] [Indexed: 09/16/2023] Open
Abstract
Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in TNXB. Thus far, 50 patients from 43 families with biallelic TNXB variants have been identified. Accurate detection of TNXB variants is challenging because of the presence of the pseudogene TNXA, which can undergo non-allelic homologous recombination. Therefore, we designed a genetic screening system that is performed using similar operations to other next-generation sequencing (NGS) panel analyses and can be applied to accurately detect TNXB variants and the recombination of TNXA-derived sequences into TNXB. Using this system, we identified biallelic TNXB variants in nine unrelated clEDS patients. TNXA-derived variations were found in >75% of the current cohort, comparable to previous reports. The current cohort generally exhibited similar clinical features to patients in previous reports, but had a higher frequency of gastrointestinal complications (e.g., perforation, diverticulitis, gastrointestinal bleeding, intestinal obstruction, rectal/anal prolapse, and gallstones). This report is the first to apply an NGS-based screening for TNXB variants and represents the third largest cohort of clEDS, highlighting the importance of increasing awareness of the risk of gastrointestinal complications.
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Affiliation(s)
- Tomomi Yamaguchi
- Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan
- Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan
- Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto, Japan
| | - Kazuo Yamada
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, Izumo, Japan
- Department of Legal Medicine, Faculty of Medicine, Shimane University, Izumo, Japan
| | - So Nagai
- Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan
- Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto, Japan
- Problem-Solving Oriented Training Program for Advanced Medical Personnel: NGSD (Next-Generation Super Doctor) Project, Matsumoto, Japan
| | - Toshiya Nishikubo
- Division of Neonatal Intensive Care, Nara Medical University, Nara, Japan
| | - Norimichi Koitabashi
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | | | - Masaaki Matsushima
- Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- Division of Clinical Genetics, Hokkaido University Hospital, Sapporo, Japan
| | - Yuka Shibata
- Division of Clinical Genetics, Hokkaido University Hospital, Sapporo, Japan
| | - Hiroki Ishiguro
- Department of Clinical Genetics, Graduate School of Medicine, University of Yamanashi, Chuo, Japan
| | - Hiromi Sanai
- Department of Obstetrics and Gynecology, Yamaguchi Prefectural Grand Medical Center, Yamaguchi, Japan
- Department of Medical Genetics, Yamaguchi Prefectural Grand Medical Center, Yamaguchi, Japan
| | - Tomomi Fujikawa
- Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuri Takiguchi
- Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ken-Ichi Matsumoto
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, Izumo, Japan
| | - Tomoki Kosho
- Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan
- Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan
- Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto, Japan
- Research Center for Supports to Advanced Science, Shinshu University, Matsumoto, Japan
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11
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Doherty EL, Aw WY, Warren EC, Hockenberry M, Whitworth CP, Krohn G, Howell S, Diekman BO, Legant WR, Nia HT, Hickey AJ, Polacheck WJ. Patient-derived extracellular matrix demonstrates role of COL3A1 in blood vessel mechanics. Acta Biomater 2023; 166:346-359. [PMID: 37187299 PMCID: PMC10330735 DOI: 10.1016/j.actbio.2023.05.015] [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: 12/16/2022] [Revised: 05/05/2023] [Accepted: 05/09/2023] [Indexed: 05/17/2023]
Abstract
Vascular Ehlers-Danlos Syndrome (vEDS) is a rare autosomal dominant disease caused by mutations in the COL3A1 gene, which renders patients susceptible to aneurysm and arterial dissection and rupture. To determine the role of COL3A1 variants in the biochemical and biophysical properties of human arterial ECM, we developed a method for synthesizing ECM directly from vEDS donor fibroblasts. We found that the protein content of the ECM generated from vEDS donor fibroblasts differed significantly from ECM from healthy donors, including upregulation of collagen subtypes and other proteins related to ECM structural integrity. We further found that ECM generated from a donor with a glycine substitution mutation was characterized by increased glycosaminoglycan content and unique viscoelastic mechanical properties, including increased time constant for stress relaxation, resulting in a decrease in migratory speed of human aortic endothelial cells when seeded on the ECM. Collectively, these results demonstrate that vEDS patient-derived fibroblasts harboring COL3A1 mutations synthesize ECM that differs in composition, structure, and mechanical properties from healthy donors. These results further suggest that ECM mechanical properties could serve as a prognostic indicator for patients with vEDS, and the insights provided by the approach demonstrate the broader utility of cell-derived ECM in disease modeling. STATEMENT OF SIGNIFICANCE: The role of collagen III ECM mechanics remains unclear, despite reported roles in diseases including fibrosis and cancer. Here, we generate fibrous, collagen-rich ECM from primary donor cells from patients with vascular Ehlers-Danlos syndrome (vEDS), a disease caused by mutations in the gene that encodes collagen III. We observe that ECM grown from vEDS patients is characterized by unique mechanical signatures, including altered viscoelastic properties. By quantifying the structural, biochemical, and mechanical properties of patient-derived ECM, we identify potential drug targets for vEDS, while defining a role for collagen III in ECM mechanics more broadly. Furthermore, the structure/function relationships of collagen III in ECM assembly and mechanics will inform the design of substrates for tissue engineering and regenerative medicine.
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Affiliation(s)
- Elizabeth L Doherty
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill and Raleigh, NC, USA; UNC Catalyst for Rare Diseases, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Wen Yih Aw
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill and Raleigh, NC, USA; UNC Catalyst for Rare Diseases, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Emily C Warren
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill and Raleigh, NC, USA
| | - Max Hockenberry
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Chloe P Whitworth
- Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Grace Krohn
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill and Raleigh, NC, USA
| | - Stefanie Howell
- UNC Catalyst for Rare Diseases, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Brian O Diekman
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill and Raleigh, NC, USA
| | - Wesley R Legant
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill and Raleigh, NC, USA; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Hadi Tavakoli Nia
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Anthony J Hickey
- UNC Catalyst for Rare Diseases, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - William J Polacheck
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill and Raleigh, NC, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA; McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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12
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Sumioka T, Matsumoto KI, Reinach PS, Saika S. Tenascins and osteopontin in biological response in cornea. Ocul Surf 2023; 29:131-149. [PMID: 37209968 DOI: 10.1016/j.jtos.2023.05.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/01/2023] [Accepted: 05/16/2023] [Indexed: 05/22/2023]
Abstract
The structural composition, integrity and regular curvature of the cornea contribute to the maintenance of its transparency and vision. Disruption of its integrity caused by injury results in scarring, inflammation and neovascularization followed by losses in transparency. These sight compromising effects is caused by dysfunctional corneal resident cell responses induced by the wound healing process. Upregulation of growth factors/cytokines and neuropeptides affect development of aberrant behavior. These factors trigger keratocytes to first transform into activated fibroblasts and then to myofibroblasts. Myofibroblasts express extracellular matrix components for tissue repair and contract the tissue to facilitate wound closure. Proper remodeling following primary repair is critical for restoration of transparency and visual function. Extracellular matrix components contributing to the healing process are divided into two groups; a group of classical tissue structural components and matrix macromolecules that modulate cell behaviors/activities besides being integrated into the matrix structure. The latter components are designated as matricellular proteins. Their functionality is elicited through mechanisms which modulate the scaffold integrity, cell behaviors, activation/inactivation of either growth factors or cytoplasmic signaling regulation. We discuss here the functional roles of matricellular proteins in mediating injury-induced corneal tissue repair. The roles are described of major matricellular proteins, which include tenascin C, tenascin X and osteopontin. Focus is directed towards dealing with their roles in modulating individual activities of wound healing-related growth factors, e. g., transforming growth factor β (TGF β). Modulation of matricellular protein functions could encompass a potential novel strategy to improve the outcome of injury-induced corneal wound healing.
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Affiliation(s)
- Takayoshi Sumioka
- Department of Ophthalmology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, 641-0012, Japan.
| | - Ken-Ichi Matsumoto
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, 89-1 Enya-cho, Izumo, 693-8501, Japan
| | - Peter Sol Reinach
- Department of Biological. Sciences SUNY Optometry, New York, NY, 10036, USA
| | - Shizuya Saika
- Department of Ophthalmology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, 641-0012, Japan
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13
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Zhu F, Li Y, Wang Y, Yao Y, Zeng R. The same heterozygous Col4A4 mutation triggered different renal pathological changes in Chinese family members. Front Genet 2023; 14:1180149. [PMID: 37323683 PMCID: PMC10265269 DOI: 10.3389/fgene.2023.1180149] [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: 03/07/2023] [Accepted: 05/18/2023] [Indexed: 06/17/2023] Open
Abstract
Background: Mutations in the collagen components of the glomerular basement membrane (GBM) often lead to hereditary glomerulonephritis. Previous studies have identified that autosomal dominant mutations of Col4A3, Col4A4 or Col4A5 are associated with thin basement membrane nephropathy (TBMN), Alport syndrome and other hereditary kidney diseases. However, the genetic mutations underlying other glomerulonephritis types have not been elucidated. Methods: In this study, we investigated a Chinese family with hereditary nephritis using the methods of genetic sequencing and renal biopsy. Genomic DNA was extracted from peripheral blood of the proband and her sister, and subsequently was performed genetic sequencing. They were found to have the similar mutation sites. Other family members were then validated using Sanger sequencing. The proband and her sister underwent renal puncture biopsies, and experienced pathologists performed PAS, Masson, immunofluorescence, and immunoelectron microscopic staining of the kidney tissue sections. Results: Through genetic sequencing analysis, we detected a novel heterozygous frameshift mutation c.1826delC in the COL4A4 (NM_000092.4) gene coding region, and 1 hybrid missense variation c.86G>A (p. R29Q) was also detected in the TNXB (NM_019105.6) gene coding region in several members of this Chinese family. Interestingly, we found that the same mutations caused different clinical features and distinct pathological changes in individual family members, which confirmed that pathological and genetic testing are crucial for the diagnosis and treatment of hereditary kidney diseases. Conclusion: In this study, we found a novel heterozygous mutation in Col4A4 and co-mutations of the TNXB gene in this Chinese family. Our study indicated that the same Col4A4 mutated variants produced different pathological and clinical changes in different family members. This discovery may provide novel insights into the study of hereditary kidney disease. In addition, new genetic biology techniques and renal biopsy of individual family members are essential.
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Affiliation(s)
- Fengming Zhu
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yueqiang Li
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuxi Wang
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Yao
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Zeng
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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14
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Courseault J, Kingry C, Morrison V, Edstrom C, Morrell K, Jaubert L, Elia V, Bix G. Folate-dependent hypermobility syndrome: A proposed mechanism and diagnosis. Heliyon 2023; 9:e15387. [PMID: 37095957 PMCID: PMC10122021 DOI: 10.1016/j.heliyon.2023.e15387] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 04/04/2023] [Accepted: 04/05/2023] [Indexed: 04/26/2023] Open
Abstract
Hypermobility involves excessive flexibility and systemic manifestations of connective tissue fragility. We propose a folate-dependent hypermobility syndrome model based on clinical observations, and through a review of existing literature, we raise the possibility that hypermobility presentation may be dependent on folate status. In our model, decreased methylenetetrahydrofolate reductase (MTHFR) activity disrupts the regulation of the ECM-specific proteinase matrix metalloproteinase 2 (MMP-2), leading to high levels of MMP-2 and elevated MMP-2-mediated cleavage of the proteoglycan decorin. Cleavage of decorin leads ultimately to extracellular matrix (ECM) disorganization and increased fibrosis. This review aims to describe relationships between folate metabolism and key proteins in the ECM that can further explain the signs and symptoms associated with hypermobility, along with possible treatment with 5-methyltetrahydrofolate supplementation.
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Affiliation(s)
- Jacques Courseault
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
- Corresponding
| | - Catherine Kingry
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
| | - Vivianne Morrison
- Tulane University School of Medicine, Departments of Neurosurgery and Neurology, Clinical Neuroscience Research Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
| | - Christiania Edstrom
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
| | - Kelli Morrell
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
| | - Lisa Jaubert
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
| | - Victoria Elia
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
| | - Gregory Bix
- Tulane University School of Medicine, Departments of Neurosurgery and Neurology, Clinical Neuroscience Research Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
- Corresponding
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15
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Okuda-Ashitaka E, Matsumoto KI. Tenascin-X as a causal gene for classical-like Ehlers-Danlos syndrome. Front Genet 2023; 14:1107787. [PMID: 37007968 PMCID: PMC10050494 DOI: 10.3389/fgene.2023.1107787] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 03/06/2023] [Indexed: 03/17/2023] Open
Abstract
Tenascin-X (TNX) is an extracellular matrix glycoprotein for which a deficiency results in a recessive form of classical-like Ehlers-Danlos syndrome (clEDS), a heritable connective tissue disorder with hyperextensible skin without atrophic scarring, joint hypermobility, and easy bruising. Notably, patients with clEDS also suffer from not only chronic joint pain and chronic myalgia but also neurological abnormalities such as peripheral paresthesia and axonal polyneuropathy with high frequency. By using TNX-deficient (Tnxb−/−) mice, well-known as a model animal of clEDS, we recently showed that Tnxb−/− mice exhibit hypersensitivity to chemical stimuli and the development of mechanical allodynia due to the hypersensitization of myelinated A-fibers and activation of the spinal dorsal horn. Pain also occurs in other types of EDS. First, we review the underlying molecular mechanisms of pain in EDS, especially that in clEDS. In addition, the roles of TNX as a tumor suppressor protein in cancer progression have been reported. Recent in silico large-scale database analyses have shown that TNX is downregulated in various tumor tissues and that high expression of TNX in tumor cells has a good prognosis. We describe what is so far known about TNX as a tumor suppressor protein. Furthermore, some patients with clEDS show delayed wound healing. Tnxb−/− mice also exhibit impairment of epithelial wound healing in corneas. TNX is also involved in liver fibrosis. We address the molecular mechanism for the induction of COL1A1 by the expression of both a peptide derived from the fibrinogen-related domain of TNX and integrin α11.
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Affiliation(s)
- Emiko Okuda-Ashitaka
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, Japan
- *Correspondence: Emiko Okuda-Ashitaka, ; Ken-ichi Matsumoto,
| | - Ken-ichi Matsumoto
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, Izumo, Japan
- *Correspondence: Emiko Okuda-Ashitaka, ; Ken-ichi Matsumoto,
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16
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Fanis P, Skordis N, Phylactou LA, Neocleous V. Salt-wasting congenital adrenal hyperplasia phenotype as a result of the TNXA/TNXB chimera 1 (CAH-X CH-1) and the pathogenic IVS2-13A/C > G in CYP21A2 gene. Hormones (Athens) 2023; 22:71-77. [PMID: 36264454 PMCID: PMC10011304 DOI: 10.1007/s42000-022-00410-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 10/07/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Genetic diversity of mutations in the CYP21A2 gene is the main cause of the monogenic congenital adrenal hyperplasia (CAH) disorder. On chromosome 6p21.3, the CYP21A2 gene is partially overlapped by the TNXB gene, the two residing in tandem with their highly homologous corresponding pseudogenes (CYP21A1P and TNXA), which leads to recurrent homologous recombination. METHODS AND RESULTS In the present study, the genetic status of an ethnic Greek-Cypriot family, with a female neonate that was originally classified as male and manifested the salt-wasting (SW) form, is presented. Genetic defects in the CYP21A2 and TNXB genes were investigated by Sanger sequencing multiplex ligation-dependent probe amplification (MLPA) and a real-time PCR assay. The neonate carried in compound heterozygosity the TNXA/TNXB chimeric gene complex (termed CAH-X CH-1) that results in a contiguous CYP21A2 and TNXB deletion and in her second allele the pathogenic IVS2-13A/C > G (c.655A/C > G) in CYP21A2. CONCLUSIONS The classic SW-CAH due to 21-hydroxylase (21-OH) deficiency may result from various complex etiological mechanisms and, as such, can involve the formation of monoallelic TNXA/TNXB chimeras found in trans with other CYP21A2 pathogenic variants. This is a rare case of CAH due to 21-hydroxylase deficiency, which elucidates the role of the complex RCCX CNV structure in the development of the disease. Identification of the correct CAH genotypes for a given phenotype is of considerable value in assisting clinicians in prenatal diagnosis, appropriate treatment, and genetic counseling.
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Affiliation(s)
- Pavlos Fanis
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Nicos Skordis
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
- Division of Pediatric Endocrinology, Paedi Center for Specialized Pediatrics, Nicosia, Cyprus
- Medical School, University of Nicosia, Nicosia, Cyprus
| | - Leonidas A Phylactou
- Department of Molecular Genetics, Function and Therapy, 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
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17
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Ivo CR, Fitas AL, Madureira I, Diamantino C, Gomes S, Gonçalves J, Lopes L. Congenital adrenal hyperplasia with a CYP21A2 deletion overlapping the tenascin-X gene: an atypical presentation. J Pediatr Endocrinol Metab 2023; 36:81-85. [PMID: 36259452 DOI: 10.1515/jpem-2022-0396] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/02/2022] [Indexed: 01/11/2023]
Abstract
OBJECTIVES Congenital Adrenal Hyperplasia (CAH) is a group of genetic diseases characterized by impaired cortisol biosynthesis. 95% of CAH cases result from mutation in the CYP21A2 gene encoding 21-hydroxilase. TNX-B gene partially overlaps CYP21A2 and encodes a matrix protein called Tenascin-X (TNX). Complete tenascin deficiency causes Enlers-Danlos syndrome (EDS). A mono allelic variant called CAH-X CH-1 was recently described, resulting from a CYP21A2 complete deletion that extends into the TNXB. This haploinsufficiency of TNX may be associated with a mild hypermobility form of EDS, as well as other connective tissue comorbidities such as hernia, cardiac defects and chronic arthralgia. CASE PRESENTATION We report four patients heterozygous for a CAH-X CH-1 allele that do not present clinical manifestations of the EDS. CONCLUSIONS All CAH patients, carriers of these TNXA/TNXB chimeras, should be evaluated for clinical manifestations related to connective tissue hypermobility, cardiac abnormalities and other EDS features, allowing for better clinical surveillance management.
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Affiliation(s)
| | - Ana Laura Fitas
- Unidade de Endocrinologia Pediátrica, Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central (CHULC), Lisboa, Portugal
| | - Inês Madureira
- Unidade de Reumatologia Pediátrica, Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central (CHULC), Lisboa, Portugal
| | - Catarina Diamantino
- Unidade de Endocrinologia Pediátrica, Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central (CHULC), Lisboa, Portugal
| | - Susana Gomes
- Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal
| | - João Gonçalves
- Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal
| | - Lurdes Lopes
- Unidade de Endocrinologia Pediátrica, Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central (CHULC), Lisboa, Portugal
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18
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Lao Q, Zhou K, Parker M, Faucz FR, Merke DP. Pseudogene TNXA Variants May Interfere with the Genetic Testing of CAH-X. Genes (Basel) 2023; 14:genes14020265. [PMID: 36833192 PMCID: PMC9956258 DOI: 10.3390/genes14020265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/13/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
CAH-X is a hypermobility-type Ehlers-Danlos syndrome connective tissue dysplasia affecting approximately 15% of patients with 21-hydroxylase deficiency (21-OHD) congenital adrenal hyperplasia (CAH) due to contiguous deletion of CYP21A2 and TNXB genes. The two most common genetic causes of CAH-X are CYP21A1P-TNXA/TNXB chimeras with pseudogene TNXA substitution for TNXB exons 35-44 (CAH-X CH-1) and TNXB exons 40-44 (CAH-X CH-2). A total of 45 subjects (40 families) from a cohort of 278 subjects (135 families of 21-OHD and 11 families of other conditions) were found to have excessive TNXB exon 40 copy number as measured by digital PCR. Here, we report that 42 subjects (37 families) had at least one copy of a TNXA variant allele carrying a TNXB exon 40 sequence, whose overall allele frequency was 10.3% (48/467). Most of the TNXA variant alleles were in cis with either a normal (22/48) or an In2G (12/48) CYP21A2 allele. There is potential interference with CAH-X molecular genetic testing based on copy number assessment, such as with digital PCR and multiplex ligation-dependent probe amplification, since this TNXA variant allele might mask a real copy number loss in TNXB exon 40. This interference most likely happens amongst genotypes of CAH-X CH-2 with an in trans normal or In2G CYP21A2 allele.
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Affiliation(s)
- Qizong Lao
- National Institutes of Health Clinical Center, Bethesda, MD 20892, USA
- Correspondence: ; Tel.: +1-301-451-7168
| | - Kiet Zhou
- National Institutes of Health Clinical Center, Bethesda, MD 20892, USA
| | - Megan Parker
- National Institutes of Health Clinical Center, Bethesda, MD 20892, USA
| | - Fabio R. Faucz
- The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Deborah P. Merke
- National Institutes of Health Clinical Center, Bethesda, MD 20892, USA
- The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
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19
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Miller WL, White PC. History of Adrenal Research: From Ancient Anatomy to Contemporary Molecular Biology. Endocr Rev 2023; 44:70-116. [PMID: 35947694 PMCID: PMC9835964 DOI: 10.1210/endrev/bnac019] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Indexed: 01/20/2023]
Abstract
The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders.
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Affiliation(s)
- Walter L Miller
- Department of Pediatrics, Center for Reproductive Sciences, and Institute for Human Genetics, University of California, San Francisco, CA, USA
| | - Perrin C White
- Division of Pediatric Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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20
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Fajardo-Jiménez MJ, Tejada-Moreno JA, Mejía-García A, Villegas-Lanau A, Zapata-Builes W, Restrepo JE, Cuartas GP, Hernandez JC. Ehlers-Danlos: A Literature Review and Case Report in a Colombian Woman with Multiple Comorbidities. Genes (Basel) 2022; 13:2118. [PMID: 36421793 PMCID: PMC9689997 DOI: 10.3390/genes13112118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/20/2022] [Accepted: 10/25/2022] [Indexed: 09/26/2023] Open
Abstract
Ehlers-Danlos syndromes (EDS) are a heterogeneous group of genetically transmitted connective tissue disorders that directly affect collagen synthesis, with a broad range of symptoms. Case presentation: This study presents a clinical case of a Colombian woman with myopathic EDS and multiple comorbidities taking 40 years of medical history to make the right diagnosis. This article also presents a review of the current literature on EDS, not only to remind the syndrome but also to help the clinician correctly identify symptoms of this diverse syndrome. Conclusion: A multidisciplinary approach to the diagnosis of the patient, including clinical and molecular analysis, and neuropsychological and psychological assessment, is important to improve the treatment choice and the outcome prediction of the patients.
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Affiliation(s)
| | | | - Alejandro Mejía-García
- Grupo Genética Molecular GENMOL, Universidad de Antioquia UdeA, Medellín 050010, Colombia
| | - Andrés Villegas-Lanau
- Grupo Neurociencias de Antioquia GNA, Universidad de Antioquia UdeA, Medellín 050010, Colombia
| | - Wildeman Zapata-Builes
- Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín 050012, Colombia
| | - Jorge E. Restrepo
- Grupo OBSERVATOS, Facultad de Educación y Ciencias Sociales, Tecnológico de Antioquia—Institución Universitaria, Medellín 050034, Colombia
| | - Gina P. Cuartas
- Grupo Neurociencia y Cognición, Facultad de Psicología, Universidad Cooperativa de Colombia, Medellín 050012, Colombia
| | - Juan C. Hernandez
- Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín 050012, Colombia
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Carvalho HC, Machado NCSS, Yáñez-Silva A, Rocabado M, Júnior ARDP, Alves LP, Ribeiro W, Lazo-Osório RA. Autonomic nerve regulation in joint hypermobility patients with myofascial trigger points by Musculoskeletal Interfiber Counterirritant Stimulation (MICS). Med Eng Phys 2022; 109:103903. [DOI: 10.1016/j.medengphy.2022.103903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 09/14/2022] [Accepted: 10/04/2022] [Indexed: 11/11/2022]
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22
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Li Z, Cong X, Kong W. Matricellular proteins: Potential biomarkers and mechanistic factors in aortic aneurysms. J Mol Cell Cardiol 2022; 169:41-56. [DOI: 10.1016/j.yjmcc.2022.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 03/30/2022] [Accepted: 05/03/2022] [Indexed: 10/18/2022]
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Prevalence of CAH-X Syndrome in Italian Patients with Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency. J Clin Med 2022; 11:jcm11133818. [PMID: 35807105 PMCID: PMC9267771 DOI: 10.3390/jcm11133818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/23/2022] [Accepted: 06/28/2022] [Indexed: 11/17/2022] Open
Abstract
21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia (CAH), is associated with pathogenic variants in CYP21A2 gene. The clinical form of the disease ranges from classic or severe to non-classic (NC) or mild late onset. The CYP21A2 gene is located on the long arm of chromosome 6, within the RCCX region, one of the most complex loci in the human genome. The 3′untranslated sequence of CYP21A2 exon 10 overlap the last exon of TNXB gene (these genes lie on the opposite strands of DNA and have the opposite transcriptional direction) that encodes an extracellular matrix glycoprotein tenascin-X (TNX). A recombination event between TNXB and its pseudogene TNXA causes a 30 kb deletion producing a chimeric TNXA/TNXB gene (CAH-X chimera) where both CYP21A2 and TNXB genes are impaired. This genetic condition characterizes a subset of patients with 21OHD who display the hypermobility phenotype of Ehlers–Danlos syndrome (hEDS) (CAH-X Syndrome). The aim of this study was to assess the prevalence of CAH-X syndrome in an Italian cohort of patients with 21OHD. At this purpose, 196 probands were recruited. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were used to identify the CAH-X genotype. Twenty-one individuals showed the heterozygous continuous deletion involving the CYP21A2 and part of the TNXB gene. EDS-related clinical manifestations were identified in most patients carrying the CAH-X chimera. A CAH-X prevalence of 10.7% was estimated in our population.
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Abstract
The term CAH-X was coined to describe a subset of patients with 21-hydroxylase deficiency displaying a phenotype compatible with the hypermobility type of Ehlers Danlos syndrome. The genetic defect is due to the monoallelic presence of a CYP21A2 deletion extending into the gene encoding tenascin X (TNXB), a connective tissue extracellular matrix protein. The result is a chimeric TNXA/TNXB gene causing tenascin-X haploinsufficiency. The prevalence of CAH-X was estimated to be around 14-15% in large cohorts of patients with 21-hydroxylase deficiency. However, population studies are still scarce and the clinical picture of the syndrome has yet to be fully defined. In this review, we discuss the current knowledge regarding the genetic and clinical profile of the CAH-X syndrome.
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25
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Liang G, Wang S, Shao J, Jin Y, Xu L, Yan Y, Günther S, Wang L, Offermanns S. Tenascin-X Mediates Flow-Induced Suppression of EndMT and Atherosclerosis. Circ Res 2022; 130:1647-1659. [PMID: 35443807 DOI: 10.1161/circresaha.121.320694] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Endothelial-to-mesenchymal transition (EndMT) has been identified as a critical driver of vascular inflammation and atherosclerosis, and TGF-β (transforming growth factor β) is a key mediator of EndMT. Both EndMT and atherosclerosis are promoted by disturbed flow, whereas unidirectional laminar flow limits EndMT and is atheroprotective. How EndMT and endothelial TGF-β signaling are regulated by different flow patterns is, however, still poorly understood. METHODS Flow chamber experiments in vitro and endothelium-specific knockout mice were used to study the role of tenascin-X in the regulation of EndMT and atherosclerosis as well as the underlying mechanisms. RESULTS In human endothelial cells as well as in human and mouse aortae, unidirectional laminar flow but not disturbed flow strongly increased endothelial expression of the extracellular matrix protein TN-X (tenascin-X) in a KLF4 (Krüppel-like factor 4) dependent manner. Mice with endothelium-specific loss of TN-X (EC-Tnxb-KO) showed increased endothelial TGF-β signaling as well as increased endothelial expression of EndMT and inflammatory marker genes. When EC-Tnxb-KO mice were subjected to partial carotid artery ligation, we observed increased vascular remodeling. EC-Tnxb-KO mice crossed to low-density lipoprotein receptor-deficient mice showed advanced atherosclerotic lesions after being fed a high-fat diet. Treatment of EC-Tnxb-KO mice with an anti-TGF-beta antibody or additional endothelial loss of TGF-beta receptors 1 and 2 normalized endothelial TGF-beta signaling and prevented EndMT. In in vitro studies, we found that TN-X through its fibrinogen-like domain directly interacts with TGF-β and thereby interferes with its binding to the TGF-β receptor. CONCLUSIONS In summary, we show that TN-X is a central mediator of flow-induced inhibition of EndMT, endothelial inflammation and atherogenesis, which functions by binding to and by blocking the activity of TGF-β. Our data identify a novel mechanism of flow-dependent regulation of vascular TGF-β, which holds promise for generating new strategies to prevent vascular inflammation and atherosclerosis.
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Affiliation(s)
- Guozheng Liang
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Germany (G.L., J.S., Y.J., L.W., S.O.)
| | - ShengPeng Wang
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (S.W., L.X.)
| | - Jingchen Shao
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Germany (G.L., J.S., Y.J., L.W., S.O.)
| | - YoungJune Jin
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Germany (G.L., J.S., Y.J., L.W., S.O.)
| | - Liran Xu
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (S.W., L.X.)
| | - Yang Yan
- Department of Cardiovascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, China (Y.Y.)
| | - Stefan Günther
- Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Germany (S.G.)
| | - Lei Wang
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Germany (G.L., J.S., Y.J., L.W., S.O.)
| | - Stefan Offermanns
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Germany (G.L., J.S., Y.J., L.W., S.O.).,Center for Molecular Medicine, Goethe University Frankfurt, Germany (S.O.).,Cardiopulmonary Institute (CPI), Frankfurt/Bad Nauheim, Germany (S.O.).,German Center for Cardiovascular Research (DZHK), Rhine-Main site, Frankfurt and Bad Nauheim, Germany (S.O.)
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26
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Yoshida KI, Midwood KS, Orend G. Editorial: Tenascins - Key Players in Tissue Homeostasis and Defense. Front Immunol 2022; 12:834353. [PMID: 35095934 PMCID: PMC8790525 DOI: 10.3389/fimmu.2021.834353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 12/20/2021] [Indexed: 11/16/2022] Open
Affiliation(s)
- Kyoko Imanaka Yoshida
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Kim S Midwood
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Gertraud Orend
- University Strasbourg, INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), 1 Place de l'Hopital, Strasbourg, France
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27
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Santoreneos R, Vakulin C, Ellul M, Rawlings L, Hardy T, Poplawski N. Recurrent pneumothorax in a case of tenascin-X deficient Ehlers-Danlos syndrome: Broadening the phenotypic spectrum. Am J Med Genet A 2022; 188:1583-1588. [PMID: 35128805 PMCID: PMC9303620 DOI: 10.1002/ajmg.a.62674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/05/2021] [Accepted: 01/13/2022] [Indexed: 11/10/2022]
Abstract
The genomic region surrounding the Tenascin‐XB gene (TNXB) is a complex and duplicated region, with several pseudogenes that predispose to high rates of homologous recombination. Classical‐like Ehlers–Danlos syndrome (clEDS) is the result of tenascin‐X deficiency due to biallelic loss of function variants in the TNXB gene. Here we present a patient with clEDS and spontaneous pneumothorax, a feature not previously reported to be associated with this condition. Two inherited pathogenic/likely pathogenic variants were identified; a previously reported deletion resulting in a TNXA/TNXB chimeric gene and a novel frameshift variant. The Tenascin‐XB gene is well described in the literature to be associated with collagen metabolism, stabilization of the fibrillar‐collagen matrix and is expressed abundantly in the extracellular matrix. We propose that tenascin‐X deficiency is directly related to pneumothorax predisposition. This case expands the phenotypic spectrum of clEDS and highlights the challenges with molecular analysis and diagnosis
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Affiliation(s)
- Renee Santoreneos
- Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Cassandra Vakulin
- Department of Genetics & Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia
| | - Melissa Ellul
- Department of Genetics & Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia
| | - Lesley Rawlings
- Department of Genetics & Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia
| | - Tristan Hardy
- Department of Genetics & Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia
| | - Nicola Poplawski
- Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.,Department of Genetics & Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia.,Faculty of Health and Medical Sciences, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
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28
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The Ehlers–Danlos Syndromes against the Backdrop of Inborn Errors of Metabolism. Genes (Basel) 2022; 13:genes13020265. [PMID: 35205310 PMCID: PMC8872221 DOI: 10.3390/genes13020265] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 01/26/2022] [Indexed: 02/04/2023] Open
Abstract
The Ehlers–Danlos syndromes are a group of multisystemic heritable connective tissue disorders with clinical presentations that range from multiple congenital malformations, over adolescent-onset debilitating or even life-threatening complications of connective tissue fragility, to mild conditions that remain undiagnosed in adulthood. To date, thirteen different EDS types have been recognized, stemming from genetic defects in 20 different genes. While initial biochemical and molecular analyses mainly discovered defects in genes coding for the fibrillar collagens type I, III and V or their modifying enzymes, recent discoveries have linked EDS to defects in non-collagenous matrix glycoproteins, in proteoglycan biosynthesis and in the complement pathway. This genetic heterogeneity explains the important clinical heterogeneity among and within the different EDS types. Generalized joint hypermobility and skin hyperextensibility with cutaneous fragility, atrophic scarring and easy bruising are defining manifestations of EDS; however, other signs and symptoms of connective tissue fragility, such as complications of vascular and internal organ fragility, orocraniofacial abnormalities, neuromuscular involvement and ophthalmological complications are variably present in the different types of EDS. These features may help to differentiate between the different EDS types but also evoke a wide differential diagnosis, including different inborn errors of metabolism. In this narrative review, we will discuss the clinical presentation of EDS within the context of inborn errors of metabolism, give a brief overview of their underlying genetic defects and pathophysiological mechanisms and provide a guide for the diagnostic approach.
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29
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Marino R, Moresco A, Perez Garrido N, Ramirez P, Belgorosky A. Congenital Adrenal Hyperplasia and Ehlers-Danlos Syndrome. Front Endocrinol (Lausanne) 2022; 13:803226. [PMID: 35282436 PMCID: PMC8913572 DOI: 10.3389/fendo.2022.803226] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/31/2022] [Indexed: 11/13/2022] Open
Abstract
Congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency is an autosomal recessive disorder. The 21-hydroxylase enzyme P450c21 is encoded by the CYP21A2 gene located on chromosome 6p21.33 within the HLA major histocompatibility complex. This locus also contains the CYP21A1P, a non-functional pseudogene, that is highly homologous to the CYP21A2 gene. Other duplicated genes are C4A and C4B, that encode two isoforms of complement factor C4, the RP1 gene that encodes a serine/threonine protein kinase, and the TNXB gene that, encodes the extracellular matrix glycoprotein tenascin-X (TNX). TNX plays a role in collagen deposition by dermal fibroblasts and is expressed in the dermis of the skin and the connective tissue of the heart and skeletal muscle. During meiosis, misalignment may occur producing large gene deletions or gene conversion events resulting in chimeric genes. Chimeric recombination may occur between TNXB and TNXA. Three TNXA/TNXB chimeras have been described that differ in the junction site (CH1 to CH3) and result in a contiguous CYP21A2 and TNXB gene deletion, causing CAH-X syndrome. TNXB deficiency is associated with Ehlers Danlos syndrome (EDS). EDS comprises a clinically and genetically heterogeneous group of connective tissue disorders. As molecular analysis of the TNXB gene is challenging, the TNX-deficient type EDS is probably underdiagnosed. In this minireview, we will address the different strategies of molecular analysis of the TNXB-gene, as well as copy number variations and genetic status of TNXB in different cohorts. Furthermore, clinical features of EDS and clinical recommendations for long-term follow-up are discussed.
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Affiliation(s)
- Roxana Marino
- Molecular Biology Laboratory, Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Angélica Moresco
- Genetics Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Natalia Perez Garrido
- Molecular Biology Laboratory, Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Pablo Ramirez
- Molecular Biology Laboratory, Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Alicia Belgorosky
- Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- *Correspondence: Alicia Belgorosky,
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30
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Halper J. Basic Components of Connective Tissues and Extracellular Matrix: Fibronectin, Fibrinogen, Laminin, Elastin, Fibrillins, Fibulins, Matrilins, Tenascins and Thrombospondins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:105-126. [PMID: 34807416 DOI: 10.1007/978-3-030-80614-9_4] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Collagens are the most abundant components of the extracellular matrix (ECM) and many types of soft tissues. Elastin is another major component of certain soft tissues, such as arterial walls and ligaments. It is an insoluble polymer of the monomeric soluble precursor tropoelastin, and the main component of elastic fibers in matrix tissue where it provides elastic recoil and resilience to a variety of connective tissues, e.g., aorta and ligaments. Elastic fibers regulate activity of transforming growth factors β (TGFβ) through their association with fibrillin microfibrils. Elastin also plays a role in cell adhesion, cell migration, and has the ability to participate in cell signaling. Mutations in the elastin gene lead to cutis laxa. Many other molecules, though lower in quantity, function as essential, structural and/or functional components of the extracellular matrix in soft tissues. Some of these are reviewed in this chapter. Besides their basic structure, biochemistry and physiology, their roles in disorders of soft tissues are discussed only briefly as most chapters in this volume deal with relevant individual compounds. Fibronectin with its multidomain structure plays a role of "master organizer" in matrix assembly as it forms a bridge between cell surface receptors, e.g., integrins, and compounds such collagen, proteoglycans and other focal adhesion molecules. It also plays an essential role in the assembly of fibrillin-1 into a structured network. Though the primary role of fibrinogen is in clot formation, after conversion to fibrin by thrombin it also binds to a variety of compounds, particularly to various growth factors, and as such, fibrinogen is a player in cardiovascular and extracellular matrix physiology. Laminins contribute to the structure of the ECM and modulate cellular functions such as adhesion, differentiation, migration, stability of phenotype, and resistance towards apoptosis. Fibrillins represent the predominant core of microfibrils in elastic as well as non-elastic extracellular matrixes, and interact closely with tropoelastin and integrins. Not only do microfibrils provide structural integrity of specific organ systems, but they also provide basis for elastogenesis in elastic tissues. Fibrillin is important for the assembly of elastin into elastic fibers. Mutations in the fibrillin-1 gene are closely associated with Marfan syndrome. Latent TGFβ binding proteins (LTBPs) are included here as their structure is similar to fibrillins. Several categories of ECM components described after fibrillins are sub-classified as matricellular proteins, i.e., they are secreted into ECM, but do not provide structure. Rather they interact with cell membrane receptors, collagens, proteases, hormones and growth factors, communicating and directing cell-ECM traffic. Fibulins are tightly connected with basement membranes, elastic fibers and other components of extracellular matrix and participate in formation of elastic fibers. Matrilins have been emerging as a new group of supporting actors, and their role in connective tissue physiology and pathophysiology has not been fully characterized. Tenascins are ECM polymorphic glycoproteins found in many connective tissues in the body. Their expression is regulated by mechanical stress both during development and in adulthood. Tenascins mediate both inflammatory and fibrotic processes to enable effective tissue repair and play roles in pathogenesis of Ehlers-Danlos, heart disease, and regeneration and recovery of musculo-tendinous tissue. One of the roles of thrombospondin 1 is activation of TGFβ. Increased expression of thrombospondin and TGFβ activity was observed in fibrotic skin disorders such as keloids and scleroderma. Cartilage oligomeric matrix protein (COMP) or thrombospondin-5 is primarily present in the cartilage. High levels of COMP are present in fibrotic scars and systemic sclerosis of the skin, and in tendon, especially with physical activity, loading and post-injury. It plays a role in vascular wall remodeling and has been found in atherosclerotic plaques as well.
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Affiliation(s)
- Jaroslava Halper
- Department of Pathology, College of Veterinary Medicine, and Department of Basic Sciences, AU/UGA Medical Partnership, The University of Georgia, Athens, GA, USA.
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31
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Micale L, Fusco C, Castori M. Ehlers-Danlos Syndromes, Joint Hypermobility and Hypermobility Spectrum Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:207-233. [PMID: 34807421 DOI: 10.1007/978-3-030-80614-9_9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Ehlers-Danlos syndrome is an umbrella term for a clinically and genetically heterogeneous group of hereditary soft connective tissue disorders mainly featuring abnormal cutaneous texture (doughy/velvety, soft, thin, and/or variably hyperextensible skin), easy bruising, and joint hypermobility. Currently, musculoskeletal manifestations related to joint hypermobility are perceived as the most prevalent determinants of the quality of life of affected individuals. The 2017 International Classification of Ehlers-Danlos syndromes and related disorders identifies 13 clinical types due to deleterious variants in 19 different genes. Recent publications point out the possibility of a wider spectrum of conditions that may be considered members of the Ehlers-Danlos syndrome community. Most Ehlers-Danlos syndromes are due to inherited abnormalities affecting the biogenesis of fibrillar collagens and other components of the extracellular matrix. The introduction of next-generation sequencing technologies in the diagnostic setting fastened patients' classification and improved our knowledge on the phenotypic variability of many Ehlers-Danlos syndromes. This is impacting significantly patients' management and family counseling. At the same time, most individuals presenting with joint hypermobility and associated musculoskeletal manifestations still remain without a firm diagnosis, due to a too vague clinical presentation and/or the lack of an identifiable molecular biomarker. These individuals are currently defined with the term "hypermobility spectrum disorders". Hence, in parallel with a continuous update of the International Classification of Ehlers-Danlos syndromes, the scientific community is investing efforts in offering a more efficient framework for classifying and, hopefully, managing individuals with joint hypermobility.
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Affiliation(s)
- Lucia Micale
- Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Carmela Fusco
- Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Marco Castori
- Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
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32
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Al-Harbi TM, Al-Rammah H, Al-Zahrani N, Liu Y, Sleiman PMA, Dridi W, Hakonarson H. Rare neurological manifestations in a Saudi Arabian patient with Ehlers-Danlos syndrome and a novel homozygous variant in the TNXB gene. Am J Med Genet A 2021; 188:618-623. [PMID: 34636138 DOI: 10.1002/ajmg.a.62539] [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: 11/10/2020] [Revised: 09/14/2021] [Accepted: 09/18/2021] [Indexed: 11/08/2022]
Abstract
We report a 38-year-old Saudi male with Ehlers-Danlos Syndrome (EDS). The patient presented with rare and unusual neurological manifestations, including but not limited to ophthalmoplegia and myopathic pattern on his electromyography. In addition to hand weakness, there was skin hyperextensibility, joint hyperflexibility, and frontal baldness. Next-generation sequencing was performed on target exon sequences, using whole exome sequencing and Burrows-Wheeler Aligner for alignment/base calling. Genome Analysis Toolkit and reference genome Homo sapiens (UCSC hg19) were used for sequence processing and analysis. Variant classification was done according to standard international recommendations. A novel homozygous variant, NM_019105.6: c.8488C>T p.(Gln2830*), was detected in the TNXB gene. This variant is not reported in the literature nor dbSNP or gnomAD databases. Additionally, this variant is predicted to create a premature stop codon and produce a truncated protein or nonsense-mediated mRNA decay. Hence, it is classified as a likely pathogenic variant. The same point variant was found in a heterozygous state in the patient's father and sister. Both presented with milder symptoms associated with Ehlers-Danlos syndromes and heritable connective tissue disorders. Therefore, the patient was diagnosed as a tenascin-X (TNX) deficient type of EDS known as classical-like Ehlers-Danlos syndrome. TNX deficient patients may present with clinical and electrophysiological manifestations that are unusual in EDS like frontal baldness, ophthalmoplegia, and myotonia, which mimic myotonic dystrophy type I. Clinicians should be aware of the potential overlap of symptoms among these two diseases to ensure correct diagnosis is made.
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Affiliation(s)
- Talal M Al-Harbi
- Neurology Department, Neuroscience Centre, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Haya Al-Rammah
- Genetic Unit, Pathology and Laboratory Medicine Department, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Naif Al-Zahrani
- Neurology Department, Neuroscience Centre, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Yichuan Liu
- Center for Applied Genomics (CAG), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Patrick M A Sleiman
- Center for Applied Genomics (CAG), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Walid Dridi
- Genetic Unit, Pathology and Laboratory Medicine Department, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Hakon Hakonarson
- Center for Applied Genomics (CAG), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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33
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Caliogna L, Guerrieri V, Annunziata S, Bina V, Brancato AM, Castelli A, Jannelli E, Ivone A, Grassi FA, Mosconi M, Pasta G. Biomarkers for Ehlers-Danlos Syndromes: There Is a Role? Int J Mol Sci 2021; 22:10149. [PMID: 34576312 PMCID: PMC8469247 DOI: 10.3390/ijms221810149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/16/2021] [Accepted: 09/17/2021] [Indexed: 02/05/2023] Open
Abstract
Ehlers-Danlos syndromes (EDS) are an inherited heterogeneous group of connective tissue disorders characterized by an abnormal collagen synthesis affecting skin, ligaments, joints, blood vessels, and other organs. It is one of the oldest known causes of bruising and bleeding, and it was described first by Hippocrates in 400 BC. In the last years, multiple gene variants involved in the pathogenesis of specific EDS subtypes have been identified; moreover, new clinical diagnostic criteria have been established. New classification models have also been studied in order to differentiate overlapping conditions. Moreover, EDS shares many characteristics with other similar disorders. Although distinguishing between these seemingly identical conditions is difficult, it is essential in ensuring proper patient care. Currently, there are many genetic and molecular studies underway to clarify the etiology of some variants of EDS. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. In this review, we focused on the study of two of the most common forms of EDS-classic and hypermobile-by trying to identify possible biomarkers that could be of great help to confirm patients' diagnosis and their follow up.
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Affiliation(s)
- Laura Caliogna
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Viviana Guerrieri
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Salvatore Annunziata
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Valentina Bina
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy;
| | - Alice Maria Brancato
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Alberto Castelli
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Eugenio Jannelli
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Alessandro Ivone
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Federico Alberto Grassi
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Mario Mosconi
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Gianluigi Pasta
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
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Colman M, Syx D, De Wandele I, Dhooge T, Symoens S, Malfait F. Clinical and molecular characteristics of 168 probands and 65 relatives with a clinical presentation of classical Ehlers-Danlos syndrome. Hum Mutat 2021; 42:1294-1306. [PMID: 34265140 DOI: 10.1002/humu.24258] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/21/2021] [Accepted: 07/12/2021] [Indexed: 12/24/2022]
Abstract
Classical Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder mainly caused by pathogenic variants in COL5A1 or COL5A2, encoding type V collagen. Its diagnosis, based on clinical criteria and molecular confirmation, can be challenging. We report the molecular and clinical characteristics of 168 probands (72 clinically evaluated at our center) and 65 relatives with a clinical presentation of cEDS. Type V collagen defects were found in 145 probands, 121 (83.5%) were located in COL5A1 and 24 (16.5%) in COL5A2. Although 85.6% of molecularly confirmed patients presented the two major clinical criteria (generalized joint hypermobility, hyperextensible skin with atrophic scarring), significant inter- and intrafamilial phenotypic variability was noted. COL5A2 variants often caused a more severe phenotype. Vascular complications were rare in individuals with type V collagen defects (1.4%). Among the 72 probands clinically evaluated in our center, the mutation detection rate was 82.0%. The majority (68.1%) harbored COL5A1/COL5A2 defects. Yet, 13.9% harbored a defect in another gene (COL1A1, PLOD1, TNXB, AEBP1) highlighting important clinical overlap and the need for molecular confirmation of the diagnosis as this has implications regarding follow-up and genetic counseling. Eighteen percent of the 72 probands remained molecularly unexplained and a COL5A1 variant of unknown significance was identified in 6.9%.
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Affiliation(s)
- Marlies Colman
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Delfien Syx
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Inge De Wandele
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Tibbe Dhooge
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Sofie Symoens
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Fransiska Malfait
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
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35
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Scicluna K, Formosa MM, Farrugia R, Borg I. Hypermobile Ehlers-Danlos syndrome: A review and a critical appraisal of published genetic research to date. Clin Genet 2021; 101:20-31. [PMID: 34219226 DOI: 10.1111/cge.14026] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/08/2021] [Accepted: 07/02/2021] [Indexed: 12/15/2022]
Abstract
The Ehlers-Danlos syndromes (EDS) are a collection of rare hereditary connective tissue disorders with heterogeneous phenotypes, usually diagnosed following clinical examination and confirmatory genetic testing. Diagnosis of the commonest subtype, hypermobile Ehlers-Danlos Syndrome (hEDS), relies solely on a clinical diagnosis since its molecular aetiology remains unknown. We performed an up-to-date literature search and selected 11 out of 304 publications according to a set of established criteria. Studies reporting variants affecting collagen proteins were found to be hindered by cohort misclassification and subsequent lack of reproducibility of these genetic findings. The role of the described variants affecting Tenascin-X and LZTS1 is yet to be demonstrated in the majority of hEDS cases, while the functional implication of associated signaling pathways and genes requires further elucidation. The available literature on the genetics of hEDS is scant, dispersed and conflicting due to out-dated nosology terminology. Recent literature has suggested the role of several promising candidate mechanisms which may be linked to the underlying molecular aetiology. Knowledge of the molecular genetic basis of hEDS is expected to increase in the near future through the mainstream use of high-throughput sequencing combined with the updated classification of EDS, and the upcoming Hypermobile Ehlers-Danlos Genetic Evaluation (HEDGE) study.
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Affiliation(s)
- Kirsty Scicluna
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
| | - Melissa M Formosa
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta.,Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
| | - Rosienne Farrugia
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta.,Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
| | - Isabella Borg
- Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta.,Medical Genetics Unit, Department of Pathology, Mater Dei Hospital, Msida, Malta.,Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
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Marino R, Garrido NP, Ramirez P, Notaristéfano G, Moresco A, Touzon MS, Vaiani E, Finkielstain G, Obregón MG, Balbi V, Soria I, Belgorosky A. Ehlers-Danlos Syndrome: Molecular and Clinical Characterization of TNXA/TNXB Chimeras in Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 2021; 106:e2789-e2802. [PMID: 33482002 DOI: 10.1210/clinem/dgab033] [Citation(s) in RCA: 9] [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: 09/16/2020] [Indexed: 12/25/2022]
Abstract
CONTEXT The syndrome CAH-X is due to a contiguous gene deletion of CYP21A2 and TNXB resulting in TNXA/TNXB chimeras. OBJECTIVE To analyze TNXB gene status and to clinically evaluate the Ehlers-Danlos syndrome phenotype in a large cohort of Argentine congenital adrenal hyperplasia (CAH) patients to assess the prevalence of this condition in our population. METHODS TNXB gene analysis was performed in 66 nonrelated CAH patients that were carriers of the CYP21A2 gene deletion. A molecular strategy based on multiplex ligation-dependent probe amplification and Sanger sequencing analysis was developed allowing for the detection of different, previously described TNXA/TNXB chimeras, named CH1, CH2, and CH3. The main outcome measures were TNXB status of CAH patients that were carriers of the CYP21A2 deletion in the homozygous or heterozygous state. RESULTS TNXA/TNXB CH1 was found in 41%, CH2 in 29%, and CH3 in 1% of nonrelated alleles carrying the CYP21A2 deletion. Thus, overall 71% of alleles were found to carry a contiguous gene deletion. Sixty-seven percent of patients analyzed had a monoallelic form and 6% a biallelic form. All patients with the biallelic form had severe skin hyperextensibility and generalized joint hypermobility. CONCLUSION Based on the high frequency of TNXB alterations found in CYP21A2 deletion carrier alleles, we recommend evaluating TNXB status in these patients, and assessing connective tissue dysplasia, including cardiologic alterations in positive cases. The number of patients undergoing cardiological evaluation should be expanded to determine the incidence of structural and functional abnormalities in this cohort.
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Affiliation(s)
- Roxana Marino
- Molecular Biology Laboratory, Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Natalia Perez Garrido
- Molecular Biology Laboratory, Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Pablo Ramirez
- Molecular Biology Laboratory, Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Guillermo Notaristéfano
- Molecular Biology Laboratory, Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Angélica Moresco
- Genetic Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Maria Sol Touzon
- Molecular Biology Laboratory, Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Elisa Vaiani
- Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Gabriela Finkielstain
- Centro de Investigaciones Endocrinológicas "Dr César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Endocrinology Service, Buenos Aires. Currently: Takeda Pharma, Argentina
| | - María Gabriela Obregón
- Genetic Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Viviana Balbi
- Endocrinology Service, Hospital de Niños Sor Maria Ludovica, La Plata, Argentina
| | - Ianina Soria
- Endocrinology Service, Hospital de la Madre y el Niño, La Rioja, Argentina
| | - Alicia Belgorosky
- Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Argentina
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Resequencing of candidate genes for Keratoconus reveals a role for Ehlers-Danlos Syndrome genes. Eur J Hum Genet 2021; 29:1745-1755. [PMID: 33737726 DOI: 10.1038/s41431-021-00849-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 01/22/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023] Open
Abstract
The involvement of genetic factors in the pathogenesis of KC has long been recognized but the identification of variants affecting the underlying protein functions has been challenging. In this study, we selected 34 candidate genes for KC based on previous whole-exome sequencing (WES) and the literature, and resequenced them in 745 KC patients and 810 ethnically matched controls from Belgium, France and Italy. Data analysis was performed using the single variant association test as well as gene-based mutation burden and variance components tests. In our study, we detected enrichment of genetic variation across multiple gene-based tests for the genes COL2A1, COL5A1, TNXB, and ZNF469. The top hit in the single variant association test was obtained for a common variant in the COL12A1 gene. These associations were consistently found across independent subpopulations. Interestingly, COL5A1, TNXB, ZNF469 and COL12A1 are all known Ehlers-Danlos Syndrome (EDS) genes. Though the co-occurrence of KC and EDS has been reported previously, this study is the first to demonstrate a consistent role of genetic variants in EDS genes in the etiology of KC. In conclusion, our data show a shared genetic etiology between KC and EDS, and clearly confirm the currently disputed role of ZNF469 in disease susceptibility for KC.
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Gensemer C, Burks R, Kautz S, Judge DP, Lavallee M, Norris RA. Hypermobile Ehlers-Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes. Dev Dyn 2021; 250:318-344. [PMID: 32629534 PMCID: PMC7785693 DOI: 10.1002/dvdy.220] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 06/24/2020] [Accepted: 06/28/2020] [Indexed: 12/14/2022] Open
Abstract
The Ehlers-Danlos syndromes (EDS) are a group of heritable, connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. There is phenotypic and genetic variation among the 13 subtypes. The initial genetic findings on EDS were related to alterations in fibrillar collagen, but the elucidation of the molecular basis of many of the subtypes revealed several genes not involved in collagen biosynthesis or structure. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. hEDS is the most common type of EDS and involves generalized joint hypermobility, musculoskeletal manifestations, and mild skin involvement along with the presence of several comorbid conditions. Variability in the spectrum and severity of symptoms and progression of patient phenotype likely depend on age, gender, lifestyle, and expression domains of the EDS genes during development and postnatal life. In this review, we summarize the current molecular, genetic, epidemiologic, and pathogenetic findings related to EDS with a focus on the hypermobile type.
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Affiliation(s)
- Cortney Gensemer
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina
| | - Randall Burks
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina
| | - Steven Kautz
- Department of Health Sciences and Research, Medical University of South Carolina, Charleston, South Carolina
| | - Daniel P. Judge
- Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina
| | - Mark Lavallee
- Department of Family Medicine, Wellspan Health, York, Pennsylvania
| | - Russell A. Norris
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina
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Tuna F, Doğanlar ZB, Özdemir H, Demirbag Kabayel D, Doğanlar O. Ehlers-Danlos syndrome-related genes and serum strontium, zinc, and lithium levels in generalized joint hypermobility: a case-control study. Connect Tissue Res 2021; 62:215-225. [PMID: 31594391 DOI: 10.1080/03008207.2019.1675648] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Aim of the study: Generalized joint hypermobility (GJH) is a common feature of almost all Ehlers-Danlos syndrome (EDS) types; however, its genetic basis remains unclear. Therefore, it is crucial to distinguish the genetic basis of GJH from other connective tissue disorders, including the different subtypes of EDS. The aim of this study was to determine the blood EDS-related gene expressions and serum element levels in GJH and reveal their predictive characteristics and correlations with the Beighton score. Materials and Methods: A total of 39 women aged 18-23 years with GJH and 38 age- and sex-matched controls were included in the study. Inductively coupled plasma mass spectrometry was used to analyze the serum levels of zinc (Zn), strontium (Sr), and lithium (Li). The relative expression levels of the EDS-related genes were determined using quantitative real-time polymerase chain reaction (PCR). Results: Our results showed that women with GJH possessed significantly lower Li and higher Zn and Sr levels than the controls. In addition, the gene expressions of TNXB and SLC39A13 were significantly higher, whereas those of COL1A1, COL1A2, COL5A1, FKBP14, and DSE were lower in the GJH group. Pearson correlation analyses revealed a strong negative correlation between the Beighton score and B4GALT7, FKBP14, COL1A1, and Li. However, a significant positive correlation was noted between the Beighton score and SLC39A13, TNXB, Zn, Sr, and B3GALT6. Conclusion: Our findings provide valuable basal levels for conducting gene function analysis of joint hypermobility-related connective tissue disorders.
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Affiliation(s)
- Filiz Tuna
- Department of Physical Medicine and Rehabilitation, Trakya University Faculty of Medicine , Edirne, Turkey
| | - Zeynep Banu Doğanlar
- Department of Medical Biology, Trakya Universtiy Faculty of Medicine , Edirne, Turkey
| | - Hande Özdemir
- Department of Physical Medicine and Rehabilitation, Trakya University Faculty of Medicine , Edirne, Turkey
| | - Derya Demirbag Kabayel
- Department of Physical Medicine and Rehabilitation, Trakya University Faculty of Medicine , Edirne, Turkey
| | - Oğuzhan Doğanlar
- Department of Medical Biology, Trakya Universtiy Faculty of Medicine , Edirne, Turkey
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40
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Affiliation(s)
- Walter L. Miller
- Department of Pediatrics, Center for Reproductive Sciences, and Institute of Human Genetics, University of California, San Francisco, CA, United States
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41
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Carrozza C, Foca L, De Paolis E, Concolino P. Genes and Pseudogenes: Complexity of the RCCX Locus and Disease. Front Endocrinol (Lausanne) 2021; 12:709758. [PMID: 34394006 PMCID: PMC8362596 DOI: 10.3389/fendo.2021.709758] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/19/2021] [Indexed: 11/13/2022] Open
Abstract
Copy Number Variations (CNVs) account for a large proportion of human genome and are a primary contributor to human phenotypic variation, in addition to being the molecular basis of a wide spectrum of disease. Multiallelic CNVs represent a considerable fraction of large CNVs and are strictly related to segmental duplications according to their prevalent duplicate alleles. RCCX CNV is a complex, multiallelic and tandem CNV located in the major histocompatibility complex (MHC) class III region. RCCX structure is typically defined by the copy number of a DNA segment containing a series of genes - the serine/threonine kinase 19 (STK19), the complement 4 (C4), the steroid 21-hydroxylase (CYP21), and the tenascin-X (TNX) - lie close to each other. In the Caucasian population, the most common RCCX haplotype (69%) consists of two segments containing the genes STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB, with a telomere-to-centromere orientation. Nonallelic homologous recombination (NAHR) plays a key role into the RCCX genetic diversity: unequal crossover facilitates large structural rearrangements and copy number changes, whereas gene conversion mediates relatively short sequence transfers. The results of these events increased the RCCX genetic diversity and are responsible of specific human diseases. This review provides an overview on RCCX complexity pointing out the molecular bases of Congenital Adrenal Hyperplasia (CAH) due to CYP21A2 deficiency, CAH-X Syndrome and disorders related to CNV of complement component C4.
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Affiliation(s)
- Cinzia Carrozza
- Dipartimento di Scienze di Laboratorio e Infettivologiche, UOC Chimica, Biochimica e Biologia Molecolare Clinica, Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Roma, Italy
- Dipartimento di Scienze Biotecnologiche di base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Laura Foca
- Dipartimento di Scienze di Laboratorio e Infettivologiche, UOC Chimica, Biochimica e Biologia Molecolare Clinica, Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Roma, Italy
| | - Elisa De Paolis
- Dipartimento di Scienze di Laboratorio e Infettivologiche, UOC Chimica, Biochimica e Biologia Molecolare Clinica, Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Roma, Italy
| | - Paola Concolino
- Dipartimento di Scienze di Laboratorio e Infettivologiche, UOC Chimica, Biochimica e Biologia Molecolare Clinica, Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Roma, Italy
- *Correspondence: Paola Concolino,
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Ishiguro H, Yagasaki H, Horiuchi Y. Ehlers-Danlos Syndrome in the Field of Psychiatry: A Review. Front Psychiatry 2021; 12:803898. [PMID: 35087434 PMCID: PMC8787077 DOI: 10.3389/fpsyt.2021.803898] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/16/2021] [Indexed: 12/27/2022] Open
Abstract
Ehlers-Danlos syndrome (EDS) comprises a series of rare hereditary connective tissue diseases characterized by joint hypermobility, joint dislocation, and hyperextensibility of the skin, as well as cardiovascular involvement. EDS is often associated with chronic widespread physical pain, which can lead to psychological pain. Poor awareness and limited diagnosis of EDS and related symptoms result in decreased self-esteem and confusion regarding physical sensation. Furthermore, EDS imposes substantial psychological burden on patients due to exercise restriction, scars, keloids, and subcutaneous fat accumulation on the extremities, which leads to parental overprotection and bullying experiences from other children at school age. Recent large-scale studies have suggested that patients with EDS have a higher risk of mood disorders than the general population. Other cohort studies indicated high prevalence of anorexia nervosa, addiction, obsessive compulsive disorder, and anxiety disorder were found in patients with EDS. Case reports instead indicated that some psychiatric disorders were secondary symptoms due to physical problems from EDS. Therefore, psychiatrists must be more knowledgeable and proactive about EDS in their practice. We review the previous case reports and literature for patients with EDS, along with our own case of complicated psychiatric problems, which are strongly related to early stressful situations through childhood and adolescence. This is to aid general psychiatrists in the discussion of appropriate medical management in such infrequent, yet challenging conditions.
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Affiliation(s)
- Hiroki Ishiguro
- Center of Genetic Medicine, Hospital, University of Yamanashi, Kofu, Japan.,Cancer Counseling and Support Center, Hospital, University of Yamanashi, Kofu, Japan.,Department of Neuropsychiatry, Graduate School of Medicine, University of Yamanashi, Kofu, Japan
| | - Hideaki Yagasaki
- Center of Genetic Medicine, Hospital, University of Yamanashi, Kofu, Japan
| | - Yasue Horiuchi
- Center of Genetic Medicine, Hospital, University of Yamanashi, Kofu, Japan.,Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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43
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Lao Q, Mallappa A, Rueda Faucz F, Joyal E, Veeraraghavan P, Chen W, Merke DP. A TNXB splice donor site variant as a cause of hypermobility type Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia. Mol Genet Genomic Med 2020; 9:e1556. [PMID: 33332743 PMCID: PMC8077117 DOI: 10.1002/mgg3.1556] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 09/18/2020] [Accepted: 10/29/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disease of steroidogenesis that affects 1 in 15,000. Approximately, 10% of the CAH population also suffer from CAH-X, a connective tissue dysplasia consistent with hypermobility type Ehlers-Danlos syndrome (EDS). Most patients with CAH-X carry a contiguous gene deletion involving CYP21A2 encoding 21-hydroxylase and TNXB encoding tenascin-X (TNX), but some are of unknown etiology. METHODS We conducted clinical evaluation and medical history review of EDS-related manifestations in subjects from two unrelated CAH families who carry a heterozygous TNXB c.12463+2T>C variant that alters the splice donor site of intron 42. A next generation sequencing (NGS) based EDS panel composed of 45 genes was performed for index patients from each family. TNX expression in patient skin biopsy tissues and dermal fibroblasts was assessed by qRT-PCR and Sanger sequencing. RESULTS All three evaluated CAH patients carrying the TNXB splice site variant had moderate EDS manifestations. An NGS panel excluded involvement of other known EDS-related variants. RNA assay on skin biopsies and dermal fibroblasts did not detect splicing errors in TNX mRNA; however, the removal of intron 42 was less efficient in the allele harboring the splice site variant as evidenced by the existence of a premature TNX RNA form, leading to an allele specific decrease in TNX mRNA. CONCLUSIONS Carrying a TNXB c.12463+2T>C variant at the intron 42 splice donor site causes an allele specific decrease in TNX expression, which can be associated with moderate EDS in CAH patients.
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Affiliation(s)
- Qizong Lao
- National Institutes of Health Clinical Center, Bethesda, MD, USA
| | - Ashwini Mallappa
- National Institutes of Health Clinical Center, Bethesda, MD, USA
| | - Fabio Rueda Faucz
- The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Elizabeth Joyal
- National Institutes of Health Clinical Center, Bethesda, MD, USA
| | | | | | - Deborah P Merke
- National Institutes of Health Clinical Center, Bethesda, MD, USA.,The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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Matsumoto KI, Aoki H. The Roles of Tenascins in Cardiovascular, Inflammatory, and Heritable Connective Tissue Diseases. Front Immunol 2020; 11:609752. [PMID: 33335533 PMCID: PMC7736112 DOI: 10.3389/fimmu.2020.609752] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 11/03/2020] [Indexed: 12/12/2022] Open
Abstract
Tenascins are a family of multifunctional extracellular matrix (ECM) glycoproteins with time- and tissue specific expression patterns during development, tissue homeostasis, and diseases. There are four family members (tenascin-C, -R, -X, -W) in vertebrates. Among them, tenascin-X (TNX) and tenascin-C (TNC) play important roles in human pathologies. TNX is expressed widely in loose connective tissues. TNX contributes to the stability and maintenance of the collagen network, and its absence causes classical-like Ehlers-Danlos syndrome (clEDS), a heritable connective tissue disorder. In contrast, TNC is specifically and transiently expressed upon pathological conditions such as inflammation, fibrosis, and cancer. There is growing evidence that TNC is involved in inflammatory processes with proinflammatory or anti-inflammatory activity in a context-dependent manner. In this review, we summarize the roles of these two tenascins, TNX and TNC, in cardiovascular and inflammatory diseases and in clEDS, and we discuss the functional consequences of the expression of these tenascins for tissue homeostasis.
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Affiliation(s)
- Ken-Ichi Matsumoto
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University, Izumo, Japan
| | - Hiroki Aoki
- Cardiovascular Research Institute, Kurume University, Kurume, Japan
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Brisset M, Metay C, Carlier RY, Badosa C, Marques C, Schalkwijk J, vanVlijmen-Willems I, Jimenez-Mallebrera C, Keren B, Jobic V, Laforêt P, Malfatti E. Biallelic mutations in Tenascin-X cause classical-like Ehlers-Danlos syndrome with slowly progressive muscular weakness. Neuromuscul Disord 2020; 30:833-838. [PMID: 32988710 DOI: 10.1016/j.nmd.2020.09.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 09/01/2020] [Accepted: 09/02/2020] [Indexed: 11/19/2022]
Abstract
Tenascin-X, is an extracellular matrix glycoprotein expressed in skin, muscle, tendons, and blood vessels with an anti-adhesive function. Biallelic Tenascin-X mutations cause classical-like Ehlers-Danlos syndrome. We report a 46-year-old woman with slowly progressive weakness of the lower limbs and myalgia from age 28 years. In the past she had Raynaud's phenomenon, multiple sprains and joint dislocations, conjunctival haemorrhages and a colonic perforation during colonoscopy. Neurologic examination showed moderate asymmetric proximal and axial muscular weakness, distal amyotrophy of 4 limbs, moderate skin hyperextensibility, and hypermobility of distal joints of fingers. Whole body Magnetic Resonance Imaging showed symmetric fatty infiltration of thigh and leg muscles, with predominant atrophy of thighs. Next Generation Sequencing revealed two pathogenic TNXB variants, g.32024681C>G, c.7826-1G>C, and g.32016181dup, c.9998dupA, p.(Asn3333Lysfs*35). Western Blot and immunofluorescence studies confirmed a marked Tenascin-X reduction in both patient's serum and muscle. Here we further detail the clinical and genetic spectrum of a patient with classical-like Ehlers-Danlos syndrome and prominent muscle involvement.
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Affiliation(s)
- Marion Brisset
- APHP, Department of Neurology, Raymond Poincaré Hospital, Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, 104 Bld Raymond Poincaré, 92380 Garches, France
| | - Corinne Metay
- APHP, Centre de Génétique Moléculaire et Chromosomique, Service de Biochimie Métabolique, U.F de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Groupe Hospitalier La Pitié-Salpêtrière Charles Foix, Paris, France
| | - Robert-Yves Carlier
- APHP, Medical imaging Department, Raymond Poincaré teaching Hospital, Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, GHU PIFO, 104 Bld Raymond Poincaré, 92380 Garches, France
| | - Carmen Badosa
- Department of Dermatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Caterina Marques
- Department of Dermatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Joost Schalkwijk
- Neuromuscular Unit, Neuropaediatrics Department, Institut de Recerca Sant Joan de Déu Hospital Sant Joan de Deu, Barcelona Spain
| | - Ivonne vanVlijmen-Willems
- Neuromuscular Unit, Neuropaediatrics Department, Institut de Recerca Sant Joan de Déu Hospital Sant Joan de Deu, Barcelona Spain
| | - Cecilia Jimenez-Mallebrera
- Neuromuscular Unit, Neuropaediatrics Department, Institut de Recerca Sant Joan de Déu Hospital Sant Joan de Deu, Barcelona Spain; U703 Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Spain; Department of Genetics, Microbiology and Statistics, University of Barcelona, Spain
| | - Boris Keren
- AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Unité fonctionnelle de cytogénétique, Paris, France
| | - Valérie Jobic
- APHP, Centre de Génétique Moléculaire et Chromosomique, Service de Biochimie Métabolique, U.F de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Groupe Hospitalier La Pitié-Salpêtrière Charles Foix, Paris, France
| | - Pascal Laforêt
- APHP, Department of Neurology, Raymond Poincaré Hospital, Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, 104 Bld Raymond Poincaré, 92380 Garches, France; Service de Neurologie, U1179 UVSQ-INSERM Handicap Neuromusculaire : Physiologie, Biothérapie et Pharmacologie appliquées, UFR Simone Veil-Santé, Université Versailles Saint Quentin en Yvelines, Pôle neuro-locomoteur, Hôpital Raymond Poincaré, 104 boulevard Raymond Poincaré, 92380 Paris-Saclay, France
| | - Edoardo Malfatti
- APHP, Department of Neurology, Raymond Poincaré Hospital, Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, 104 Bld Raymond Poincaré, 92380 Garches, France; Service de Neurologie, U1179 UVSQ-INSERM Handicap Neuromusculaire : Physiologie, Biothérapie et Pharmacologie appliquées, UFR Simone Veil-Santé, Université Versailles Saint Quentin en Yvelines, Pôle neuro-locomoteur, Hôpital Raymond Poincaré, 104 boulevard Raymond Poincaré, 92380 Paris-Saclay, France.
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Ritelli M, Venturini M, Cinquina V, Chiarelli N, Colombi M. Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives. Orphanet J Rare Dis 2020; 15:197. [PMID: 32736638 PMCID: PMC7393722 DOI: 10.1186/s13023-020-01470-0] [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: 04/24/2020] [Accepted: 07/21/2020] [Indexed: 12/17/2022] Open
Abstract
Background The Ehlers-Danlos syndromes (EDS) are rare connective tissue disorders consisting of 13 subtypes with overlapping features including joint hypermobility, skin and generalized connective tissue fragility. Classical EDS (cEDS) is principally caused by heterozygous COL5A1 or COL5A2 variants and rarely by the COL1A1 p.(Arg312Cys) substitution. Current major criteria are (1) skin hyperextensibility plus atrophic scars and (2) generalized joint hypermobility (gJHM). Minor criteria include additional mucocutaneous signs, epicanthal folds, gJHM complications, and an affected first-degree relative. Minimal criteria prompting molecular testing are major criterion 1 plus either major criterion 2 or 3 minor criteria. In addition to these features, the clinical picture also involves multiple organ systems, but large-scale cohort studies are still missing. This study aimed to investigate the multisystemic involvement and natural history of cEDS through a cross-sectional study on a cohort of 75 molecularly confirmed patients evaluated from 2010 to 2019 in a tertiary referral center. The diagnostic criteria, additional mucocutaneous, osteoarticular, musculoskeletal, cardiovascular, gastrointestinal, uro-gynecological, neuropsychiatric, and atopic issues, and facial/ocular features were ascertained, and feature rates compared by sex and age. Results Our study confirms that cEDS is mainly characterized by cutaneous and articular involvement, though none of their hallmarks was represented in all cases and suggests a milder multisystemic involvement and a more favorable natural history compared to other EDS subtypes. Abnormal scarring was the most frequent and characteristic sign, skin hyperextensibility and gJHM were less common, all without any sex and age bias; joint instability complications were more recurrent in adults. Some orthopedic features showed a high prevalence, whereas the other issues related to the investigated organ systems were less recurrent with few exceptions and age-related differences. Conclusions Our findings define the diagnostic relevance of cutaneous and articular features and additional clinical signs associated to cEDS. Furthermore, our data suggest an update of the current EDS nosology concerning scarring that should be considered separately from skin hyperextensibility and that the clinical diagnosis of cEDS may be enhanced by the accurate evaluation of orthopedic manifestations at all ages, faciocutaneous indicators in children, and some acquired traits related to joint instability complications, premature skin aging, and patterning of abnormal scarring in older individuals.
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Affiliation(s)
- Marco Ritelli
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, I-25123, Brescia, Italy
| | - Marina Venturini
- Division of Dermatology, Department of Clinical and Experimental Sciences, Spedali Civili University Hospital, Brescia, Italy
| | - Valeria Cinquina
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, I-25123, Brescia, Italy
| | - Nicola Chiarelli
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, I-25123, Brescia, Italy
| | - Marina Colombi
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, I-25123, Brescia, Italy.
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Malfait F, Castori M, Francomano CA, Giunta C, Kosho T, Byers PH. The Ehlers-Danlos syndromes. Nat Rev Dis Primers 2020; 6:64. [PMID: 32732924 DOI: 10.1038/s41572-020-0194-9] [Citation(s) in RCA: 177] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/15/2020] [Indexed: 12/16/2022]
Abstract
The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue, with common features including joint hypermobility, soft and hyperextensible skin, abnormal wound healing and easy bruising. Fourteen different types of EDS are recognized, of which the molecular cause is known for 13 types. These types are caused by variants in 20 different genes, the majority of which encode the fibrillar collagen types I, III and V, modifying or processing enzymes for those proteins, and enzymes that can modify glycosaminoglycan chains of proteoglycans. For the hypermobile type of EDS, the molecular underpinnings remain unknown. As connective tissue is ubiquitously distributed throughout the body, manifestations of the different types of EDS are present, to varying degrees, in virtually every organ system. This can make these disorders particularly challenging to diagnose and manage. Management consists of a care team responsible for surveillance of major and organ-specific complications (for example, arterial aneurysm and dissection), integrated physical medicine and rehabilitation. No specific medical or genetic therapies are available for any type of EDS.
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Affiliation(s)
- Fransiska Malfait
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
| | - Marco Castori
- Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
| | - Clair A Francomano
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Cecilia Giunta
- Connective Tissue Unit, Division of Metabolism and Children's Research Centre, University Children's Hospital, Zurich, Switzerland
| | - Tomoki Kosho
- Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Peter H Byers
- Department of Pathology and Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA
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Ritelli M, Cinquina V, Venturini M, Colombi M. Identification of the novel COL5A1 c.3369_3431dup, p.(Glu1124_Gly1144dup) variant in a patient with incomplete classical Ehlers-Danlos syndrome: The importance of phenotype-guided genetic testing. Mol Genet Genomic Med 2020; 8:e1422. [PMID: 32720758 PMCID: PMC7549590 DOI: 10.1002/mgg3.1422] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/02/2020] [Accepted: 07/02/2020] [Indexed: 01/08/2023] Open
Abstract
Background Classical Ehlers–Danlos syndrome (cEDS) is a connective tissue disorder mainly caused by heterozygous COL5A1 or COL5A2 variants encoding type V collagen and rarely by the p.(Arg312Cys) missense substitution in COL1A1 encoding type I collagen. The current EDS nosology specifies that minimal suggestive criteria are marked skin hyperextensibility plus atrophic scarring together with either generalized joint hypermobility or at least three minor criteria comprising additional cutaneous and articular signs. To reach a final diagnosis, molecular testing is required. Herein, we report on a 3‐year‐old female who came to our attention with an inconclusive next generation sequencing (NGS) panel comprising all cEDS‐associated genes. Methods Despite the patient did not formally fulfill the nosological criteria because the skin was only slightly hyperextensible, we made a cEDS diagnosis, mainly for the presence of typical atrophic scars. We investigated COL5A1 intragenic deletions/duplications by Multiplex Ligation‐dependent Probe Amplification (MLPA), excluded the recessive classical‐like EDS type 2 by AEBP1 Sanger analysis, and retested COL5A1 with the Sanger method. Results Molecular analyses revealed the novel COL5A1 c.3369_3431dup p.(Glu1124_Gly1144dup) intermediate‐sized duplication with a predicted dominant negative effect that was missed both by NGS and MLPA. Conclusions This report highlights that some cEDS patients might not display overt skin hyperextensibility and the importance of clinical expertise to make such a diagnosis in patients with an incomplete presentation. Our results also exemplify that NGS is not a fool‐proof technology and that Sanger sequencing achieves the diagnostic goal when there is a sufficiently clear phenotypic indication.
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Affiliation(s)
- Marco Ritelli
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Valeria Cinquina
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Marina Venturini
- Division of Dermatology, Department of Clinical and Experimental Sciences, Spedali Civili University Hospital, Brescia, Italy
| | - Marina Colombi
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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Gao Y, Lu L, Yu B, Mao J, Wang X, Nie M, Wu X. The Prevalence of the Chimeric TNXA/TNXB Gene and Clinical Symptoms of Ehlers-Danlos Syndrome with 21-Hydroxylase Deficiency. J Clin Endocrinol Metab 2020; 105:5820120. [PMID: 32291442 DOI: 10.1210/clinem/dgaa199] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 04/13/2020] [Indexed: 11/19/2022]
Abstract
PURPOSE Defects in both CYP21A2 and TNXB genes can cause congenital adrenal hyperplasia combined with hypermobility-type Ehlers-Danlos syndrome (EDS), which has recently been named CAH-X syndrome. The purpose of this study is to assess the prevalence of the chimeric TNXA/TNXB gene and clinical symptoms in a Chinese cohort with 21-hydroxylase deficiency (21-OHD). METHODS A total of 424 patients with 21-OHD who were genetically diagnosed were recruited for this study. Multiplex ligation-dependent probe amplification and sequencing were used to identify the CAH-X genotype. Clinical features of joints, skin, and other systems were evaluated in 125 patients. RESULTS Ninety-four of the 424 patients had a deletion on at least 1 allele of CYP21A2 and 59 of them harbored the heterozygotic TNXA/TNXB chimera. Frequencies of CAH-X CH-1, CH-2, and CH-3 were 8.2%, 3.1%, and 2.6%, respectively. The incidences of clinical features of EDS were 71.0% and 26.6% in patients with the chimeric TNXA/TNXB genes or without (P < .001). There were statistically significant differences in manifestations among articular (P < .001 in generalized hypermobility) and dermatologic features (P < .001 in hyperextensible skin, P = .015 in velvety skin and P = .033 in poor wound healing). The prevalence of generalized hypermobility was more common in CAH-X CH-2 or CH-3 than CH-1 patients (60% vs 20%, P = .028). CONCLUSIONS In summary, about 14% of patients with 21-OHD may have chimeric TNXA/TNXB gene mutations in our study and most of them showed EDS-related clinical symptoms. The correlation between CAH-X genotypes and clinical features in connective tissue, like joint or skin, needs to be further investigated.
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Affiliation(s)
- Yinjie Gao
- NHC key laboratory of Endocrinology, Peking Union Medical College Hospital; Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Lin Lu
- NHC key laboratory of Endocrinology, Peking Union Medical College Hospital; Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | | | - Jiangfeng Mao
- NHC key laboratory of Endocrinology, Peking Union Medical College Hospital; Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xi Wang
- NHC key laboratory of Endocrinology, Peking Union Medical College Hospital; Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Min Nie
- NHC key laboratory of Endocrinology, Peking Union Medical College Hospital; Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xueyan Wu
- NHC key laboratory of Endocrinology, Peking Union Medical College Hospital; Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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Chen Cardenas SM, El-Kaissi S, Jarad O, Liaqat M, Korbonits M, Hamrahian AH. Unusual Combination of MEN-1 and the Contiguous Gene Deletion Syndrome of CAH and Ehlers-Danlos Syndrome (CAH-X). J Endocr Soc 2020; 4:bvaa077. [PMID: 32715272 PMCID: PMC7371387 DOI: 10.1210/jendso/bvaa077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Indexed: 11/19/2022] Open
Abstract
The contiguous gene deletion syndrome of congenital adrenal hyperplasia and Ehlers-Danlos syndrome, named CAH-X, is a rare entity that occurs because of a deletion of a chromosomal area containing 2 neighboring genes, TNXB and CYP21A. Here, we describe a patient from a consanguineous family in which coincidentally MEN-1 syndrome is associated with CAH-X, causing particular challenges explaining the phenotypic features of the patient. A 33-year-old man with salt-wasting congenital adrenal hyperplasia and classic-like Ehlers-Danlos syndrome presented with an adrenal crisis with a history of recurrent hypoglycemia, abdominal pain, and vomiting. He was found to have primary hyperparathyroidism, hyperprolactinemia, and pancreatic neuroendocrine tumors, as well as primary hypogonadism, large adrenal myelolipomas, and low bone mineral density. A bladder diverticulum was incidentally found. Genetic analysis revealed a heterozygous previously well-described MEN1 mutation (c.784-9G > A), a homozygous complete deletion of CYP21A2 (c.1-?_1488+? del), as well as a large deletion of the neighboring TNXB gene (c.11381-?_11524+?). The deletion includes the complete CYP21A2 gene and exons 35 through 44 of the TNXB gene. CGH array found 12% homozygosity over the whole genome. This rare case illustrates a complex clinical scenario with some initial diagnostic challenges.
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Affiliation(s)
- Stanley M Chen Cardenas
- Division of Endocrinology, Diabetes, and Metabolism. The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Samer El-Kaissi
- Department of Endocrinology, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE
| | - Ola Jarad
- Department of Endocrinology, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE
| | - Muneezeh Liaqat
- Pathology and Laboratory Medicine Institute, Cleveland Clinic Abu Dhabi and National Reference Laboratory, Abu Dhabi, UAE
| | - Márta Korbonits
- Department of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Amir H Hamrahian
- Division of Endocrinology, Diabetes, and Metabolism. The Johns Hopkins University School of Medicine, Baltimore, Maryland
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