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Thomas HR, Yoder BK, Alexander MS, Parant JM. Engineering precision zebrafish alleles of human disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.05.18.654701. [PMID: 40475461 PMCID: PMC12139734 DOI: 10.1101/2025.05.18.654701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/18/2025]
Abstract
Animal models of human diseases are an essential component of understanding disease pathogenesis and serve as preclinical models for therapeutic evaluation. Recently human patient genome sequencing has defined unique patient variants that result in disease states with different phenotypes than those observed with null alleles. The UAB Center for Precision Animal Modeling (CPAM) serves to analyze patient variant pathogenicity and disease mechanisms through the generation of animal models. We have optimized a zebrafish gene editing platform to successfully generate 11 patient variants (first round: NF1 R1276Q, NF1 G484R, VMA21 G55V, SPOP D144N, SGO1 K23E, Pex10 H310D, and FKRP C318Y; second round: NF1 R681*, NF1 M992del, P53 R175H, and PKD2 L656W) and 1 research allele (p53 K120R). We used CRISPR/Cas9 guide directed cleavage along with single-stranded oligodeoxynucleotide (ssODNs) repair templates to generate these models. We evaluated multiple oligo orientations and sizes, but did not find a unified consensus orientation or size that significantly impacted efficiency, emphasizing the need to empirically evaluate multiple variations for the best homology directed repair (HDR) rate. We determined PCR amplicon Next Generation Sequencing (NGS) evaluation of HDR efficiency at the F0 embryo level is best for determining the ideal guide and oligo combination. Further NGS evaluation of DNA from progeny from F0s (germline derived), not F0 biopsy DNA, is essential to identify germline transmitting founders. Surprisingly we find that most founders exhibit a jackpot effect in the germ line but not in the somatic tissue. We found NGS superior to using ICE (Inference of CRISPR Edits) for determining HDR frequency. When applicable, allelic-specific PCR or allelic specific restriction digestion can be used to genotype mutation carrying F1 generation animals, however we demonstrated that false positives occur. Further, we successfully used high resolution melting curve analysis (HRMA) to differentiate and identify F1 animals with patient variants.
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Affiliation(s)
- Holly R. Thomas
- Department of Cell, Developmental and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, AL, USA
| | - Bradley K. Yoder
- Department of Cell, Developmental and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, AL, USA
| | - Matthew S. Alexander
- Department of Pediatrics, Division of Neurology at University of Alabama at Birmingham Heersink School of Medicine and Children’s of Alabama, AL, USA
| | - John M. Parant
- Department of Cell, Developmental and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, AL, USA
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2
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Ankathatti Narayanaswamy I, Kattepur AK, Raju K, Perumal V, Ramalingam R, Raavi V. Shugoshin 1 expression in various cancers: a potential target for therapy. Clin Transl Oncol 2025; 27:1953-1966. [PMID: 39476301 DOI: 10.1007/s12094-024-03749-1] [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: 08/19/2024] [Accepted: 09/25/2024] [Indexed: 04/27/2025]
Abstract
Shugoshin 1 (SGO1) is one of the Shugoshin (guardian spirit) family proteins, which is reported to be majorly involved in the protection of centromeres and proper segregation of chromosomes during cell division. Recent studies found that the altered expression of SGO1 is associated with various cancers and genetic disorders, and suggested as a target for therapy. In the present study, we have reviewed the available literature on SGO1 gene and protein expression in various cancer-cell lines, animal models and cancer patients, and targeting SGO1 with siRNA/shRNA. A significant increase in the expression of SGO1 mRNA and protein levels were observed in prostate, renal, lung, breast, neuroblastoma, leukemia, hepatocellular, and colon cancer-cell lines and the levels were associated with increased cellular proliferation, invasion, and metastasis. The altered SGO1 levels were observed in SGO1 knockout/haploinsufficient mice compared to wild type and the levels were associated with increased chromosome instability and tumorigenesis. Consistent with cell lines, higher SGO1 expression was also observed in tumor tissues of cancer patients compared to adjacent normal tissue and the levels were positively correlated with tumor stage, grade, size, and hormonal status. Higher SGO1 expression was related to resistance to chemotherapeutic agents and the knockdown of SGO1 increased sensitivity to those agents. Furthermore, targeting SGO1 with siRNA/shRNA reduced the expression of SGO1 and proliferation, and induced apoptosis of cancer cells. Overall, the SGO1 expression levels were significantly higher in various cancers, and targeting SGO1 with siRNA and shRNA reduced the levels of SGO1, proliferation and metastasis of cancers.
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Affiliation(s)
- Indumathi Ankathatti Narayanaswamy
- Department of Cell Biology and Molecular Genetics, Sri Devaraj Urs Academy of Higher Education and Research (Deemed to be University), Kolar, Karnataka, 563 103, India
| | - Abhay Kumaraswamy Kattepur
- Department of Surgical Oncology, R L Jalappa Institute of Oncology, Sri Devaraj Urs Academy of Higher Education and Research (Deemed to be University), Kolar, Karnataka, 563 103, India
| | - Kalyani Raju
- Department of Pathology, Sri Devaraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research (Deemed to be University), Kolar, 563 103, Karnataka, India
| | - Venkatachalam Perumal
- Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai, Tamil Nadu, 600 116, India
| | - Ravi Ramalingam
- Department of Medicine, Cardiology Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7882, San Antonio, TX, 78229, USA
| | - Venkateswarlu Raavi
- Department of Cell Biology and Molecular Genetics, Sri Devaraj Urs Academy of Higher Education and Research (Deemed to be University), Kolar, Karnataka, 563 103, India.
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Ahuja K, Pathania S, Baron N, Khlevner J, Bialer M, Mait‐Kaufman J. Chronic atrial and intestinal dysrhythmia: A rare genetic disorder of intestinal pseudo-obstruction. JPGN REPORTS 2025; 6:162-165. [PMID: 40386336 PMCID: PMC12078061 DOI: 10.1002/jpr3.12158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 09/06/2024] [Accepted: 09/12/2024] [Indexed: 05/20/2025]
Abstract
Pediatric intestinal pseudo-obstruction (PIPO) is a rare and severe disorder of gastrointestinal (GI) motility; patients with PIPO display signs and symptoms of intestinal obstruction in the absence of occluding lesions. Chronic atrial and intestinal dysrhythmia (CAID) syndrome is an exceedingly rare autosomal recessive disorder caused by mutations in the SGO1 gene; SGO1 mutations disrupt the cohesin complex, a protein involved in chromosome organization during cell division and hence, DNA stability. CAID leads to both GI and cardiac dysfunction. This case report highlights an exceptional instance of early-onset pediatric CAID marked by recurrent pseudo-obstruction and, notably, developmental delay, which has not been previously described. The case emphasizes the importance of genetic evaluation in pediatric patients with unexplained pseudo-obstruction, and the importance of multidisciplinary management.
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Affiliation(s)
- Kanya Ahuja
- Pediatric Gastroenterology, Liver Disease and NutritionCohen Children's Medical CenterNew YorkNew YorkUSA
- Pediatric Gastroenterology, Hepatology and NutritionCharleston Area Medical Center/West Virginia University‐CharlestonCharlestonWest VirginiaUSA
| | - Shivany Pathania
- General PediatricsCohen Children's Medical CenterNew YorkNew YorkUSA
| | - Nicole Baron
- Division of Pediatric Gastroenterology, Hepatology and NutritionColumbia University Irving Medical CenterNew YorkNew YorkUSA
| | - Julie Khlevner
- Division of Pediatric Gastroenterology, Hepatology and NutritionColumbia University Irving Medical CenterNew YorkNew YorkUSA
| | - Martin Bialer
- Division of Medical GeneticsCohen Children's Medical CenterNew YorkNew YorkUSA
| | - Jennifer Mait‐Kaufman
- Pediatric Gastroenterology, Liver Disease and NutritionCohen Children's Medical CenterNew YorkNew YorkUSA
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Di Nardo M, Musio A. Cohesin - bridging the gap among gene transcription, genome stability, and human diseases. FEBS Lett 2025; 599:190-208. [PMID: 38852996 DOI: 10.1002/1873-3468.14949] [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: 02/19/2024] [Revised: 04/15/2024] [Accepted: 05/08/2024] [Indexed: 06/11/2024]
Abstract
The intricate landscape of cellular processes governing gene transcription, chromatin organization, and genome stability is a fascinating field of study. A key player in maintaining this delicate equilibrium is the cohesin complex, a molecular machine with multifaceted roles. This review presents an in-depth exploration of these intricate connections and their significant impact on various human diseases.
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Affiliation(s)
- Maddalena Di Nardo
- Institute for Biomedical Technologies (ITB), National Research Council (CNR), Pisa, Italy
| | - Antonio Musio
- Institute for Biomedical Technologies (ITB), National Research Council (CNR), Pisa, Italy
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Yadav A, Garg AK, Veerwal H, Bhatia P, Bhattacharya A, Sharma V. When gut meets the heart: Chronic atrial and intestinal dysrhythmia presenting as chronic intestinal pseudo-obstruction, an uncommon cohesinopathy. Indian J Gastroenterol 2024; 43:1223-1225. [PMID: 38305838 DOI: 10.1007/s12664-024-01521-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Affiliation(s)
- Abhishek Yadav
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Amit Kumar Garg
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Hardik Veerwal
- Department of Nuclear Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Prateek Bhatia
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Anish Bhattacharya
- Department of Nuclear Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Vishal Sharma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India.
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Guo S, Zha L. Pathogenesis and Clinical Characteristics of Hereditary Arrhythmia Diseases. Genes (Basel) 2024; 15:1368. [PMID: 39596569 PMCID: PMC11593610 DOI: 10.3390/genes15111368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 10/19/2024] [Accepted: 10/22/2024] [Indexed: 11/28/2024] Open
Abstract
Hereditary arrhythmias, as a class of cardiac electrophysiologic abnormalities caused mainly by genetic mutations, have gradually become one of the most important causes of sudden cardiac death in recent years. With the continuous development of genetics and molecular biology techniques, the study of inherited arrhythmias has made remarkable progress in the past few decades. More and more disease-causing genes are being identified, and there have been advances in the application of genetic testing for disease screening in individuals with disease and their family members. Determining more refined disease prevention strategies and therapeutic regimens that are tailored to the genetic characteristics and molecular pathogenesis of different groups or individuals forms the basis of individualized treatment. Understanding advances in the study of inherited arrhythmias provides important clues to better understand their pathogenesis and clinical features. This article provides a review of the pathophysiologic alterations caused by genetic variants and their relationship to disease phenotypes, including mainly cardiac ion channelopathies and cardiac conduction disorders.
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Affiliation(s)
- Shuang Guo
- Department of Vascular Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China;
| | - Lingfeng Zha
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Chevalier NR, Zig L, Gomis A, Amedzrovi Agbesi RJ, El Merhie A, Pontoizeau L, Le Parco I, Rouach N, Arnoux I, de Santa Barbara P, Faure S. Calcium wave dynamics in the embryonic mouse gut mesenchyme: impact on smooth muscle differentiation. Commun Biol 2024; 7:1277. [PMID: 39375515 PMCID: PMC11458798 DOI: 10.1038/s42003-024-06976-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 09/26/2024] [Indexed: 10/09/2024] Open
Abstract
Intestinal smooth muscle differentiation is a complex physico-biological process involving several different pathways. Here, we investigate the properties of Ca2+ waves in the developing intestinal mesenchyme using GCamp6f expressing mouse embryos and investigate their relationship with smooth muscle differentiation. We find that Ca2+ waves are absent in the pre-differentiation mesenchyme and start propagating immediately following α-SMA expression. Ca2+ waves are abrogated by CaV1.2 and gap-junction blockers, but are independent of the Rho pathway. The myosine light-chain kinase inhibitor ML-7 strongly disorganized or abolished Ca2+ waves, showing that perturbation of the contractile machinery at the myosine level also affected the upstream Ca2+ handling chain. Inhibiting Ca2+ waves and contractility with CaV1.2 blockers did not perturb circular smooth muscle differentiation at early stages. At later stages, CaV1.2 blockers abolished intestinal elongation and differentiation of the longitudinal smooth muscle, leading instead to the emergence of KIT-expressing interstitial cells of Cajal at the gut periphery. CaV1.2 blockers also drove apoptosis of already differentiated, CaV1.2-expressing smooth muscle and enteric neural cells. We provide fundamental new data on Ca2+ waves in the developing murine gut and their relation to myogenesis in this organ.
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Affiliation(s)
- Nicolas R Chevalier
- Laboratoire Matière et Systèmes Complexes, Université Paris Cité, CNRS UMR 7057, 10 rue Alice Domon et Léonie Duquet, 75013, Paris, France.
| | - Léna Zig
- Laboratoire Matière et Systèmes Complexes, Université Paris Cité, CNRS UMR 7057, 10 rue Alice Domon et Léonie Duquet, 75013, Paris, France
| | - Anthony Gomis
- Laboratoire Matière et Systèmes Complexes, Université Paris Cité, CNRS UMR 7057, 10 rue Alice Domon et Léonie Duquet, 75013, Paris, France
| | - Richard J Amedzrovi Agbesi
- Laboratoire Matière et Systèmes Complexes, Université Paris Cité, CNRS UMR 7057, 10 rue Alice Domon et Léonie Duquet, 75013, Paris, France
| | - Amira El Merhie
- Laboratoire Matière et Systèmes Complexes, Université Paris Cité, CNRS UMR 7057, 10 rue Alice Domon et Léonie Duquet, 75013, Paris, France
| | | | - Isabelle Le Parco
- Université Paris Cité, CNRS, Institut Jacques Monod, 75013, Paris, France
| | - Nathalie Rouach
- Neuroglial Interactions in Cerebral Physiology and Pathologies, Center for Interdisciplinary Research in Biology, Collège de France, CNRS, INSERM, Labex Memolife, Université PSL, Paris, France
| | - Isabelle Arnoux
- Neuroglial Interactions in Cerebral Physiology and Pathologies, Center for Interdisciplinary Research in Biology, Collège de France, CNRS, INSERM, Labex Memolife, Université PSL, Paris, France
| | | | - Sandrine Faure
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
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Bildstein T, Charbit-Henrion F, Azabdaftari A, Cerf-Bensussan N, Uhlig HH. Cellular and molecular basis of proximal small intestine disorders. Nat Rev Gastroenterol Hepatol 2024; 21:687-709. [PMID: 39117867 DOI: 10.1038/s41575-024-00962-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/28/2024] [Indexed: 08/10/2024]
Abstract
The proximal part of the small intestine, including duodenum and jejunum, is not only dedicated to nutrient digestion and absorption but is also a highly regulated immune site exposed to environmental factors. Host-protective responses against pathogens and tolerance to food antigens are essential functions in the small intestine. The cellular ecology and molecular pathways to maintain those functions are complex. Maladaptation is highlighted by common immune-mediated diseases such as coeliac disease, environmental enteric dysfunction or duodenal Crohn's disease. An expanding spectrum of more than 100 rare monogenic disorders inform on causative molecular mechanisms of nutrient absorption, epithelial homeostasis and barrier function, as well as inflammatory immune responses and immune regulation. Here, after summarizing the architectural and cellular traits that underlie the functions of the proximal intestine, we discuss how the integration of tissue immunopathology and molecular mechanisms can contribute towards our understanding of disease and guide diagnosis. We propose an integrated mechanism-based taxonomy and discuss the latest experimental approaches to gain new mechanistic insight into these disorders with large disease burden worldwide as well as implications for therapeutic interventions.
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Affiliation(s)
- Tania Bildstein
- Great Ormond Street Hospital for Children, Department of Paediatric Gastroenterology, London, UK
| | - Fabienne Charbit-Henrion
- Department of Genomic Medicine for Rare Diseases, Necker-Enfants Malades Hospital, APHP, University of Paris-Cité, Paris, France
- INSERM UMR1163, Intestinal Immunity, Institut Imagine, Paris, France
| | - Aline Azabdaftari
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Oxford, UK
| | | | - Holm H Uhlig
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Oxford, UK.
- Department of Paediatrics, University of Oxford, Oxford, UK.
- National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre, Oxford, UK.
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9
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Basilisco G, Marchi M, Coletta M. Chronic intestinal pseudo-obstruction in adults: A practical guide to identify patient subgroups that are suitable for more specific treatments. Neurogastroenterol Motil 2024; 36:e14715. [PMID: 37994282 DOI: 10.1111/nmo.14715] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 11/06/2023] [Accepted: 11/10/2023] [Indexed: 11/24/2023]
Abstract
Chronic intestinal pseudo-obstruction is a rare and heterogeneous syndrome characterized by recurrent symptoms of intestinal obstruction with radiological features of dilated small or large intestine with air/fluid levels in the absence of any mechanical occlusive lesion. Several diseases may be associated with chronic intestinal pseudo-obstruction and in these cases, the prognosis and treatment are related to the underlying disease. Also, in its "primary or idiopathic" form, two subgroups of patients should be determined as they require a more specific therapeutic approach: patients whose chronic intestinal pseudo-obstruction is due to sporadic autoimmune/inflammatory mechanisms and patients whose neuromuscular changes are genetically determined. In a context of a widely heterogeneous adult population presenting chronic intestinal pseudo-obstruction, this review aims to summarize a practical diagnostic workup for identifying definite subgroups of patients who might benefit from more specific treatments, based on the etiology of their underlying condition.
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Affiliation(s)
- Guido Basilisco
- Gastroenterology and Endoscopic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Margherita Marchi
- Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy
| | - Marina Coletta
- Gastroenterology and Endoscopic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Chanpong A, Alves MM, Bonora E, De Giorgio R, Thapar N. Evaluating the molecular and genetic mechanisms underlying gut motility disorders. Expert Rev Gastroenterol Hepatol 2023; 17:1301-1312. [PMID: 38117595 DOI: 10.1080/17474124.2023.2296558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 12/14/2023] [Indexed: 12/22/2023]
Abstract
INTRODUCTION Gastrointestinal (GI) motility disorders comprise a wide range of different diseases affecting the structural or functional integrity of the GI neuromusculature. Their clinical presentation and burden of disease depends on the predominant location and extent of gut involvement as well as the component of the gut neuromusculature affected. AREAS COVERED A comprehensive literature review was conducted using the PubMed and Medline databases to identify articles related to GI motility and functional disorders, published between 2016 and 2023. In this article, we highlight the current knowledge of molecular and genetic mechanisms underlying GI dysmotility, including disorders of gut-brain interaction, which involve both GI motor and sensory disturbance. EXPERT OPINION Although the pathophysiology and molecular mechanisms underlying many such disorders remain unclear, recent advances in the assessment of intestinal tissue samples, genetic testing with the application of 'omics' technologies and the use of animal models will provide better insights into disease pathogenesis as well as opportunities to improve therapy.
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Affiliation(s)
- Atchariya Chanpong
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK
| | - Maria M Alves
- Department of Clinical Genetics, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Elena Bonora
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna, Bologna, Italy
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, AOUB, Bologna, Italy
| | - Roberto De Giorgio
- Department of Translational Sciences, University of Ferrara, Ferrara, Italy
| | - Nikhil Thapar
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
- Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Australia
- School of Medicine, University of Queensland, Brisbane, Australia
- Woolworths Centre for Child Nutrition Research, Queensland University of Technology, Brisbane, Australia
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Viti F, De Giorgio R, Ceccherini I, Ahluwalia A, Alves MM, Baldo C, Baldussi G, Bonora E, Borrelli O, Dall'Oglio L, De Coppi P, De Filippo C, de Santa Barbara P, Diamanti A, Di Lorenzo C, Di Maulo R, Galeone A, Gandullia P, Hashmi SK, Lacaille F, Lancon L, Leone S, Mahé MM, Molnar MJ, Palmitelli A, Perin S, Prato AP, Thapar N, Vassalli M, Heuckeroth RO. Multi-disciplinary Insights from the First European Forum on Visceral Myopathy 2022 Meeting. Dig Dis Sci 2023; 68:3857-3871. [PMID: 37650948 PMCID: PMC10517037 DOI: 10.1007/s10620-023-08066-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 07/28/2023] [Indexed: 09/01/2023]
Abstract
Visceral myopathy is a rare, life-threatening disease linked to identified genetic mutations in 60% of cases. Mostly due to the dearth of knowledge regarding its pathogenesis, effective treatments are lacking. The disease is most commonly diagnosed in children with recurrent or persistent disabling episodes of functional intestinal obstruction, which can be life threatening, often requiring long-term parenteral or specialized enteral nutritional support. Although these interventions are undisputedly life-saving as they allow affected individuals to avoid malnutrition and related complications, they also seriously compromise their quality of life and can carry the risk of sepsis and thrombosis. Animal models for visceral myopathy, which could be crucial for advancing the scientific knowledge of this condition, are scarce. Clearly, a collaborative network is needed to develop research plans to clarify genotype-phenotype correlations and unravel molecular mechanisms to provide targeted therapeutic strategies. This paper represents a summary report of the first 'European Forum on Visceral Myopathy'. This forum was attended by an international interdisciplinary working group that met to better understand visceral myopathy and foster interaction among scientists actively involved in the field and clinicians who specialize in care of people with visceral myopathy.
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Affiliation(s)
- Federica Viti
- Institute of Biophysics, National Research Council, Via De Marini, 6, 16149, Genoa, Italy.
| | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | | | - Arti Ahluwalia
- Centro di Ricerca 'E. Piaggio' and Department of Information Engineering, University of Pisa, Pisa, Italy
| | - Maria M Alves
- Department of Clinical Genetics, Erasmus University Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Chiara Baldo
- IRCCS Istituto Giannina Gaslini Pediatric Hospital, Genoa, Italy
| | - Giannina Baldussi
- 'Uniti per la P.I.P.O.' Patient Advocacy Organization, Brescia, Italy
| | - Elena Bonora
- Unit of Medical Genetics, Department of Medical and Surgical Sciences, University of Bologna, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Osvaldo Borrelli
- Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Luigi Dall'Oglio
- Digestive Surgery and Endoscopy, Bambino Gesù Children's Research Hospital IRCCS, Rome, Italy
| | - Paolo De Coppi
- Pediatric Surgery, Great Ormond Street Hospital for Children, London, UK
| | - Carlotta De Filippo
- Institute of Agricultural Biology and Biotechnology of the National Research Council, Pisa, Italy
| | - Pascal de Santa Barbara
- Physiology and Experimental Medicine of the Heart and Muscles (PhyMedExp), University of Montpellier, INSERM, CNRS, Montpellier, France
| | | | - Carlo Di Lorenzo
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA
| | | | | | - Paolo Gandullia
- IRCCS Istituto Giannina Gaslini Pediatric Hospital, Genoa, Italy
| | - Sohaib K Hashmi
- Department of Pediatrics, The Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center, Philadelphia, PA, USA
| | - Florence Lacaille
- Pediatric Gastroenterology-Hepatology-Nutrition, Necker-Enfants Malades Hospital, Paris, France
| | - Laurence Lancon
- 'Association des POIC' Patient Advocacy Organization, Marseille, France
| | - Salvatore Leone
- AMICI ETS, Associazione Nazionale per le Malattie Infiammatorie Croniche dell'Intestino, Milan, Italy
| | - Maxime M Mahé
- Nantes Université, INSERM, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, Nantes, France
| | | | | | - Silvia Perin
- Unit of Pediatric Surgery, Department of Women and Child Health, University of Padua, Padua, Italy
| | - Alessio Pini Prato
- Unit of Pediatric Surgery, 'St. Antonio e Biagio e Cesare Arrigo' Hospital, Alessandria, Italy
| | - Nikhil Thapar
- Stem Cell and Regenerative Medicine, GOS Institute of Child Health, University College London, London, UK
- Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Australia
- School of Medicine, University of Queensland, Brisbane, Australia
- Woolworths Centre for Child Nutrition Research, Queensland University of Technology, Brisbane, Australia
| | - Massimo Vassalli
- James Watt School of Engineering, University of Glasgow, Glasgow, UK
| | - Robert O Heuckeroth
- Department of Pediatrics, The Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center, Philadelphia, PA, USA
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Bianco F, Lattanzio G, Lorenzini L, Mazzoni M, Clavenzani P, Calzà L, Giardino L, Sternini C, Costanzini A, Bonora E, De Giorgio R. Enteric Neuromyopathies: Highlights on Genetic Mechanisms Underlying Chronic Intestinal Pseudo-Obstruction. Biomolecules 2022; 12:biom12121849. [PMID: 36551277 PMCID: PMC9776039 DOI: 10.3390/biom12121849] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/04/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Severe gut motility disorders are characterized by the ineffective propulsion of intestinal contents. As a result, the patients develop disabling/distressful symptoms, such as nausea and vomiting along with altered bowel habits up to radiologically demonstrable intestinal sub-obstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is a typical clinical phenotype of severe gut dysmotility. This syndrome occurs due to changes altering the morpho-functional integrity of the intrinsic (enteric) innervation and extrinsic nerve supply (hence neuropathy), the interstitial cells of Cajal (ICC) (mesenchymopathy), and smooth muscle cells (myopathy). In the last years, several genes have been identified in different subsets of CIPO patients. The focus of this review is to cover the most recent update on enteric dysmotility related to CIPO, highlighting (a) forms with predominant underlying neuropathy, (b) forms with predominant myopathy, and (c) mitochondrial disorders with a clear gut dysfunction as part of their clinical phenotype. We will provide a thorough description of the genes that have been proven through recent evidence to cause neuro-(ICC)-myopathies leading to abnormal gut contractility patterns in CIPO. The discovery of susceptibility genes for this severe condition may pave the way for developing target therapies for enteric neuro-(ICC)-myopathies underlying CIPO and other forms of gut dysmotility.
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Affiliation(s)
- Francesca Bianco
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Giulia Lattanzio
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Luca Lorenzini
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Maurizio Mazzoni
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Paolo Clavenzani
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Laura Calzà
- IRET Foundation, 40064 Ozzano Emilia, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Luciana Giardino
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
- IRET Foundation, 40064 Ozzano Emilia, Italy
| | - Catia Sternini
- UCLA/DDRC, Division of Digestive Diseases, Departments Medicine and Neurobiology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90001, USA
| | - Anna Costanzini
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Elena Bonora
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
- Correspondence: (E.B.); (R.D.G.); Tel.: +39-051-2094761 (E.B.); +39-0532-236631 (R.D.G.)
| | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
- Correspondence: (E.B.); (R.D.G.); Tel.: +39-051-2094761 (E.B.); +39-0532-236631 (R.D.G.)
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13
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Schmidt J, Dreha-Kulaczewski S, Zafeiriou MP, Schreiber MK, Wilken B, Funke R, Neuhofer CM, Altmüller J, Thiele H, Nürnberg P, Biskup S, Li Y, Zimmermann WH, Kaulfuß S, Yigit G, Wollnik B. Somatic mosaicism in STAG2-associated cohesinopathies: Expansion of the genotypic and phenotypic spectrum. Front Cell Dev Biol 2022; 10:1025332. [PMID: 36467423 PMCID: PMC9710855 DOI: 10.3389/fcell.2022.1025332] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 10/26/2022] [Indexed: 08/25/2024] Open
Abstract
STAG2 is a component of the large, evolutionarily highly conserved cohesin complex, which has been linked to various cellular processes like genome organization, DNA replication, gene expression, heterochromatin formation, sister chromatid cohesion, and DNA repair. A wide spectrum of germline variants in genes encoding subunits or regulators of the cohesin complex have previously been identified to cause distinct but phenotypically overlapping multisystem developmental disorders belonging to the group of cohesinopathies. Pathogenic variants in STAG2 have rarely been implicated in an X-linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphic features. Here, we describe for the first time a mosaic STAG2 variant in an individual with developmental delay, microcephaly, and hemihypotrophy of the right side. We characterized the grade of mosaicism by deep sequencing analysis on DNA extracted from EDTA blood, urine and buccal swabs. Furthermore, we report an additional female with a novel de novo splice variant in STAG2. Interestingly, both individuals show supernumerary nipples, a feature that has not been reported associated to STAG2 before. Remarkably, additional analysis of STAG2 transcripts in both individuals showed only wildtype transcripts, even after blockage of nonsense-mediated decay using puromycin in blood lymphocytes. As the phenotype of STAG2-associated cohesinopathies is dominated by global developmental delay, severe microcephaly, and brain abnormalities, we investigated the expression of STAG2 and other related components of the cohesin complex during Bioengineered Neuronal Organoids (BENOs) generation by RNA sequencing. Interestingly, we observed a prominent expression of STAG2, especially between culture days 0 and 15, indicating an essential function of STAG2 in early brain development. In summary, we expand the genotypic and phenotypic spectrum of STAG2-associated cohesinopathies and show that BENOs represent a promising model to gain further insights into the critical role of STAG2 in the complex process of nervous system development.
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Affiliation(s)
- Julia Schmidt
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
| | - Steffi Dreha-Kulaczewski
- Department of Pediatics and Adolescent Medicine, University Medical Center Göttingen, Göttingen, Germany
| | - Maria-Patapia Zafeiriou
- Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany
- Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany
| | - Marie-Kristin Schreiber
- Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany
- Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany
| | - Bernd Wilken
- Department of Pediatric Neurology, Klinikum Kassel, Kassel, Germany
| | - Rudolf Funke
- Department of Pediatric Neurology, Klinikum Kassel, Kassel, Germany
| | - Christiane M Neuhofer
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
- Institute of Neurogenomics, Helmholtz Zentrum Munich, Munich, Germany
- Department of Neurology, Friedrich-Baur-Institute, LMU Hospital, Ludwig Maximilians University, Munich, Germany
| | - Janine Altmüller
- Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
- Berlin Institute of Health at Charité, Core Facility Genomics, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Holger Thiele
- Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
| | - Peter Nürnberg
- Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
| | - Saskia Biskup
- CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany
| | - Yun Li
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
| | - Wolfram Hubertus Zimmermann
- Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany
- Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany
| | - Silke Kaulfuß
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
| | - Gökhan Yigit
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany
| | - Bernd Wollnik
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany
- Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany
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14
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Wilde AAM, Semsarian C, Márquez MF, Shamloo AS, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace 2022; 24:1307-1367. [PMID: 35373836 PMCID: PMC9435643 DOI: 10.1093/europace/euac030] [Citation(s) in RCA: 190] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Affiliation(s)
- Arthur A M Wilde
- Heart Centre, Department of Cardiology, Amsterdam Universitair Medische
Centra, Amsterdam, location AMC, The Netherlands
| | - Christopher Semsarian
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute,
University of Sydney, Sydney, Australia
| | - Manlio F Márquez
- Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de
México, Mexico
- Member of the Latin American Heart Rhythm Society (LAHRS)
| | | | - Michael J Ackerman
- Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine,
and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm
Services and Pediatric Cardiology; Windland Smith Rice Genetic Heart Rhythm Clinic and
Windland Smith Rice Sudden Death Genomics Laboratory, Mayo
Clinic, Rochester, MN, USA
| | - Euan A Ashley
- Department of Cardiovascular Medicine, Stanford University,
Stanford, California, USA
| | - Eduardo Back Sternick
- Arrhythmia and Electrophysiology Unit, Biocor Institute,
Minas Gerais, Brazil; and
Member of the Latin American Heart Rhythm Society (LAHRS)
| | - Héctor Barajas-Martinez
- Cardiovascular Research, Lankenau Institute of Medical
Research, Wynnewood, PA, USA; and Member of the Latin American Heart Rhythm Society (LAHRS)
| | - Elijah R Behr
- Cardiovascular Clinical Academic Group, Institute of Molecular and Clinical
Sciences, St. George’s, University of London; St. George’s University Hospitals NHS
Foundation Trust, London, UK; Mayo Clinic Healthcare, London
| | - Connie R Bezzina
- Amsterdam UMC Heart Center, Department of Experimental
Cardiology, Amsterdam, The
Netherlands
| | - Jeroen Breckpot
- Center for Human Genetics, University Hospitals Leuven,
Leuven, Belgium
| | - Philippe Charron
- Sorbonne Université, APHP, Centre de Référence des Maladies Cardiaques
Héréditaires, ICAN, Inserm UMR1166, Hôpital
Pitié-Salpêtrière, Paris, France
| | | | - Lia Crotti
- Center for Cardiac Arrhythmias of Genetic Origin,
Istituto Auxologico Italiano, IRCCS, Milan, Italy
- Cardiomyopathy Unit and Cardiac Rehabilitation Unit, San Luca Hospital,
Istituto Auxologico Italiano, IRCCS, Milan,
Italy
- Department of Medicine and Surgery, University of
Milano-Bicocca, Milan, Italy
| | - Michael H Gollob
- Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology,
University of Toronto, Toronto, ON, Canada
| | - Steven Lubitz
- Cardiac Arrhythmia Service, Massachusetts General Hospital and Harvard
Medical School, Boston, MA, USA
| | - Naomasa Makita
- National Cerebral and Cardiovascular Center, Research
Institute, Suita, Japan
| | - Seiko Ohno
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular
Center, Suita, Japan
| | - Martín Ortiz-Genga
- Clinical Department, Health in Code, A
Coruña, Spain; and Member of the Latin
American Heart Rhythm Society (LAHRS)
| | - Luciana Sacilotto
- Arrhythmia Unit, Instituto do Coracao, Hospital das Clinicas HCFMUSP,
Faculdade de Medicina, Universidade de Sao Paulo, Sao
Paulo, Brazil; and Member of the Latin
American Heart Rhythm Society (LAHRS)
| | - Eric Schulze-Bahr
- Institute for Genetics of Heart Diseases, University Hospital
Münster, Münster, Germany
| | - Wataru Shimizu
- Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon
Medical School, Bunkyo-ku, Tokyo, Japan
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Division of Cardiology, Department of
Medicine, University of Washington, Seattle, WA,
USA
| | - Rafik Tadros
- Cardiovascular Genetics Center, Department of Medicine, Montreal Heart
Institute, Université de Montréal, Montreal,
Canada
| | - James S Ware
- National Heart and Lung Institute and MRC London Institute of Medical
Sciences, Imperial College London, London,
UK
- Royal Brompton & Harefield Hospitals, Guy’s
and St. Thomas’ NHS Foundation Trust, London, UK
| | - David S Winlaw
- Cincinnati Children's Hospital Medical Centre, University of
Cincinnati, Cincinnati, OH, USA
| | - Elizabeth S Kaufman
- Metrohealth Medical Center, Case Western Reserve University,
Cleveland, OH, USA
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15
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Kamel SM, Broekman S, Tessadori F, van Wijk E, Bakkers J. The zebrafish cohesin protein Sgo1 is required for cardiac function and eye development. Dev Dyn 2022; 251:1357-1367. [PMID: 35275424 PMCID: PMC9545960 DOI: 10.1002/dvdy.468] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/02/2022] [Accepted: 03/05/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Cohesinopathies is a term that refers to/covers rare genetic diseases caused by mutations in the cohesin complex proteins. The cohesin complex is a multiprotein complex that facilitates different aspects of cell division, gene transcription, DNA damage repair, and chromosome architecture. Shugoshin proteins prevent the cohesin complex from premature dissociation from chromatids during cell division. Patients with a homozygous missense mutation in SGO1, which encodes for Shugoshin1, have problems with normal pacing of the heart and gut. RESULTS To study the role of shugoshin during embryo development, we mutated the zebrafish sgo1 gene. Homozygous sgo1 mutant embryos display various phenotypes related to different organs, including a reduced heart rate accompanied by reduced cardiac function. In addition, sgo1 mutants are vision-impaired as a consequence of structurally defective and partially non-functional photoreceptor cells. Furthermore, the sgo1 mutants display reduced food intake and early lethality. CONCLUSION We have generated a zebrafish model of Sgo1 that showed its importance during organ development and function.
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Affiliation(s)
- Sarah M. Kamel
- Hubrecht Institute‐KNAW, University Medical Centre UtrechtUtrechtThe Netherlands
| | - Sanne Broekman
- Department of OtorhinolaryngologyRadboud University Medical CenterNijmegenThe Netherlands
- Donders Institute for Brain, Cognition and BehaviorRadboud University Medical CenterNijmegenThe Netherlands
| | - Federico Tessadori
- Hubrecht Institute‐KNAW, University Medical Centre UtrechtUtrechtThe Netherlands
| | - Erwin van Wijk
- Department of OtorhinolaryngologyRadboud University Medical CenterNijmegenThe Netherlands
- Donders Institute for Brain, Cognition and BehaviorRadboud University Medical CenterNijmegenThe Netherlands
| | - Jeroen Bakkers
- Hubrecht Institute‐KNAW, University Medical Centre UtrechtUtrechtThe Netherlands
- Department of Medical Physiology, Division of Heart & LungsUniversity Medical Center UtrechtUtrechtThe Netherlands
- Department of Pediatric Cardiology, Division of PediatricsUniversity Medical Center UtrechtUtrechtThe Netherlands
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16
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Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick Eduardo B, Barajas‐Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz‐Genga M, Sacilotto L, Schulze‐Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, Aiba T, Bollmann A, Choi J, Dalal A, Darrieux F, Giudicessi J, Guerchicoff M, Hong K, Krahn AD, Mac Intyre C, Mackall JA, Mont L, Napolitano C, Ochoa Juan P, Peichl P, Pereira AC, Schwartz PJ, Skinner J, Stellbrink C, Tfelt‐Hansen J, Deneke T. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. J Arrhythm 2022; 38:491-553. [PMID: 35936045 PMCID: PMC9347209 DOI: 10.1002/joa3.12717] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Arthur A. M. Wilde
- Heart Centre, Department of Cardiology, Amsterdam Universitair Medische CentraAmsterdamThe Netherlands
| | - Christopher Semsarian
- Agnes Ginges Centre for Molecular Cardiology at Centenary InstituteUniversity of SydneySydneyAustralia
| | - Manlio F. Márquez
- Instituto Nacional de Cardiología Ignacio ChávezCiudad de MéxicoMexico
| | | | - Michael J. Ackerman
- Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology; Windland Smith Rice Genetic Heart Rhythm Clinic and Windland Smith Rice Sudden Death Genomics Laboratory, Mayo ClinicRochesterMNUSA
| | - Euan A. Ashley
- Department of Cardiovascular MedicineStanford UniversityStanfordCAUSA
| | | | | | - Elijah R. Behr
- Cardiovascular Clinical Academic Group, Institute of Molecular and Clinical Sciences, St. George’sUniversity of London; St. George’s University Hospitals NHS Foundation TrustLondonUKMayo Clinic HealthcareLondon
| | - Connie R. Bezzina
- Amsterdam UMC Heart Center, Department of Experimental CardiologyAmsterdamThe Netherlands
| | - Jeroen Breckpot
- Center for Human GeneticsUniversity Hospitals LeuvenLeuvenBelgium
| | | | | | - Lia Crotti
- Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano, IRCCSMilanItaly
- Cardiomyopathy Unit and Cardiac Rehabilitation Unit, San Luca Hospital, Istituto Auxologico Italiano, IRCCSMilanItaly
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMilanItaly
| | - Michael H. Gollob
- Inherited Arrhythmia and Cardiomyopathy Program, Division of CardiologyUniversity of TorontoTorontoONCanada
| | - Steven Lubitz
- Cardiac Arrhythmia ServiceMassachusetts General Hospital and Harvard Medical SchoolBostonMAUSA
| | - Naomasa Makita
- National Cerebral and Cardiovascular CenterResearch InstituteSuitaJapan
| | - Seiko Ohno
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular CenterSuitaJapan
| | | | - Luciana Sacilotto
- Arrhythmia Unit, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao PauloBrazil
| | - Eric Schulze‐Bahr
- Institute for Genetics of Heart DiseasesUniversity Hospital MünsterMünsterGermany
| | - Wataru Shimizu
- Department of Cardiovascular MedicineGraduate School of MedicineTokyoJapan
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Division of Cardiology, Department of MedicineUniversity of WashingtonSeattleWAUSA
| | - Rafik Tadros
- Cardiovascular Genetics Center, Department of Medicine, Montreal Heart InstituteUniversité de MontréalMontrealCanada
| | - James S. Ware
- National Heart and Lung Institute and MRC London Institute of Medical SciencesImperial College LondonLondonUK
- Royal Brompton & Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation TrustLondonUK
| | - David S. Winlaw
- Cincinnati Children's Hospital Medical CentreUniversity of CincinnatiCincinnatiOHUSA
| | | | - Takeshi Aiba
- Department of Clinical Laboratory Medicine and Genetics, National Cerebral and Cardiovascular Center, SuitaOsakaJapan
| | - Andreas Bollmann
- Department of ElectrophysiologyHeart Center Leipzig at University of LeipzigLeipzigGermany
- Leipzig Heart InstituteLeipzigGermany
| | - Jong‐Il Choi
- Division of Cardiology, Department of Internal Medicine, Korea University Anam HospitalKorea University College of MedicineSeoulRepublic of Korea
| | - Aarti Dalal
- Department of Pediatrics, Division of CardiologyVanderbilt University School of MedicineNashvilleTNUSA
| | - Francisco Darrieux
- Arrhythmia Unit, Instituto do Coração, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São PauloSão PauloBrazil
| | - John Giudicessi
- Department of Cardiovascular Medicine (Divisions of Heart Rhythm Services and Circulatory Failure and the Windland Smith Rice Genetic Heart Rhythm Clinic), Mayo ClinicRochesterMNUSA
| | - Mariana Guerchicoff
- Division of Pediatric Arrhythmia and Electrophysiology, Italian Hospital of Buenos AiresBuenos AiresArgentina
| | - Kui Hong
- Department of Cardiovascular MedicineThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Andrew D. Krahn
- Division of CardiologyUniversity of British ColumbiaVancouverCanada
| | - Ciorsti Mac Intyre
- Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo ClinicRochesterMNUSA
| | - Judith A. Mackall
- Center for Cardiac Electrophysiology and Pacing, University Hospitals Cleveland Medical CenterCase Western Reserve University School of MedicineClevelandOHUSA
| | - Lluís Mont
- Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS). Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), MadridSpain
| | - Carlo Napolitano
- Molecular Cardiology, Istituti Clinici Scientifici Maugeri, IRCCSPaviaItaly
- Department of Molecular MedicineUniversity of PaviaPaviaItaly
| | - Pablo Ochoa Juan
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), MadridSpain
- Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de HierroMadridSpain
- Centro de Investigacion Biomedica en Red en Enfermedades Cariovasculares (CIBERCV), MadridSpain
| | - Petr Peichl
- Department of CardiologyInstitute for Clinical and Experimental MedicinePragueCzech Republic
| | - Alexandre C. Pereira
- Laboratory of Genetics and Molecular Cardiology, Heart InstituteUniversity of São Paulo Medical SchoolSão PauloBrazil
- Hipercol Brasil ProgramSão PauloBrazil
| | - Peter J. Schwartz
- Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano, IRCCSMilanItaly
| | - Jon Skinner
- Sydney Childrens Hospital NetworkUniversity of SydneySydneyAustralia
| | - Christoph Stellbrink
- Department of Cardiology and Intensive Care MedicineUniversity Hospital Campus Klinikum BielefeldBielefeldGermany
| | - Jacob Tfelt‐Hansen
- The Department of Cardiology, the Heart Centre, Copenhagen University Hospital, Rigshopitalet, Copenhagen, Denmark; Section of genetics, Department of Forensic Medicine, Faculty of Medical SciencesUniversity of CopenhagenDenmark
| | - Thomas Deneke
- Heart Center Bad NeustadtBad Neustadt a.d. SaaleGermany
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17
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Bonora E, Bianco F, Giorgio RD. Comment to the Description of a Novel Cohesinopathy in Chronic Intestinal Pseudo Obstruction. J Neurogastroenterol Motil 2022; 28:501-502. [PMID: 35799243 PMCID: PMC9274473 DOI: 10.5056/jnm22017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Affiliation(s)
- Elena Bonora
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Italy
| | - Francesca Bianco
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Italy
- Department of Veterinary Medical Sciences, University of Bologna, Italy
| | - Roberto De Giorgio
- Department of Translational Medicine, St. Anna Hospital, University of Ferrara, Italy
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18
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Zada A, Kuil LE, de Graaf BM, Kakiailatu N, Windster JD, Brooks AS, van Slegtenhorst M, de Koning B, Wijnen RMH, Melotte V, Hofstra RMW, Brosens E, Alves MM. TFAP2B Haploinsufficiency Impacts Gastrointestinal Function and Leads to Pediatric Intestinal Pseudo-obstruction. Front Cell Dev Biol 2022; 10:901824. [PMID: 35874825 PMCID: PMC9304996 DOI: 10.3389/fcell.2022.901824] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/14/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Pediatric Intestinal Pseudo-obstruction (PIPO) is a congenital enteric disorder characterized by severe gastrointestinal (GI) dysmotility, without mechanical obstruction. Although several genes have been described to cause this disease, most patients do not receive a genetic diagnosis. Here, we aim to identify the genetic cause of PIPO in a patient diagnosed with severe intestinal dysmotility shortly after birth. Methods: Whole exome sequencing (WES) was performed in the patient and unaffected parents, in a diagnostic setting. After identification of the potential disease-causing variant, its functional consequences were determined in vitro and in vivo. For this, expression constructs with and without the causing variant, were overexpressed in HEK293 cells. To investigate the role of the candidate gene in GI development and function, a zebrafish model was generated where its expression was disrupted using CRISPR/Cas9 editing. Results: WES analysis identified a de novo heterozygous deletion in TFAP2B (NM_003221.4:c.602-5_606delTCTAGTTCCA), classified as a variant of unknown significance. In vitro studies showed that this deletion affects RNA splicing and results in loss of exon 4, leading to the appearance of a premature stop codon and absence of TFAP2B protein. Disruption of tfap2b in zebrafish led to decreased enteric neuronal numbers and delayed transit time. However, no defects in neuronal differentiation were detected. tfap2b crispants also showed decreased levels of ednrbb mRNA, a downstream target of tfap2b. Conclusion: We showed that TFAP2B haploinsufficiency leads to reduced neuronal numbers and GI dysmotility, suggesting for the first time, that this gene is involved in PIPO pathogenesis.
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Affiliation(s)
- Almira Zada
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
- *Correspondence: Almira Zada, ; Maria M. Alves,
| | - Laura E. Kuil
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Bianca M. de Graaf
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Naomi Kakiailatu
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Jonathan D. Windster
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
- Department of Pediatric Surgery, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Alice S. Brooks
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Marjon van Slegtenhorst
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Barbara de Koning
- Department of Pediatric Gastroenterology, Erasmus University Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - René M. H. Wijnen
- Department of Pediatric Surgery, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Veerle Melotte
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Robert M. W. Hofstra
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Erwin Brosens
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Maria M. Alves
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
- *Correspondence: Almira Zada, ; Maria M. Alves,
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19
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Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, Aiba T, Bollmann A, Choi JI, Dalal A, Darrieux F, Giudicessi J, Guerchicoff M, Hong K, Krahn AD, MacIntyre C, Mackall JA, Mont L, Napolitano C, Ochoa JP, Peichl P, Pereira AC, Schwartz PJ, Skinner J, Stellbrink C, Tfelt-Hansen J, Deneke T. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases. Heart Rhythm 2022; 19:e1-e60. [PMID: 35390533 DOI: 10.1016/j.hrthm.2022.03.1225] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 12/12/2022]
Affiliation(s)
- Arthur A M Wilde
- Heart Centre, Department of Cardiology, Amsterdam Universitair Medische Centra, Amsterdam, location AMC, The Netherlands.
| | - Christopher Semsarian
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, University of Sydney, Sydney, Australia.
| | - Manlio F Márquez
- Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de México, Mexico; and Member of the Latin American Heart Rhythm Society (LAHRS).
| | | | - Michael J Ackerman
- Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology; Windland Smith Rice Genetic Heart Rhythm Clinic and Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA
| | - Euan A Ashley
- Department of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
| | - Eduardo Back Sternick
- Arrhythmia and Electrophysiology Unit, Biocor Institute, Minas Gerais, Brazil; and Member of the Latin American Heart Rhythm Society (LAHRS)
| | | | - Elijah R Behr
- Cardiovascular Clinical Academic Group, Institute of Molecular and Clinical Sciences, St. George's, University of London; St. George's University Hospitals NHS Foundation Trust, London, UK; Mayo Clinic Healthcare, London
| | - Connie R Bezzina
- Amsterdam UMC Heart Center, Department of Experimental Cardiology, Amsterdam, The Netherlands
| | - Jeroen Breckpot
- Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium
| | - Philippe Charron
- Sorbonne Université, APHP, Centre de Référence des Maladies Cardiaques Héréditaires, ICAN, Inserm UMR1166, Hôpital Pitié-Salpêtrière, Paris, France
| | | | - Lia Crotti
- Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Cardiomyopathy Unit and Cardiac Rehabilitation Unit, San Luca Hospital, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Michael H Gollob
- Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, University of Toronto, Toronto, ON, Canada
| | - Steven Lubitz
- Cardiac Arrhythmia Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Naomasa Makita
- National Cerebral and Cardiovascular Center, Research Institute, Suita, Japan
| | - Seiko Ohno
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Martín Ortiz-Genga
- Clinical Department, Health in Code, A Coruña, Spain; and Member of the Latin American Heart Rhythm Society (LAHRS)
| | - Luciana Sacilotto
- Arrhythmia Unit, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil; and Member of the Latin American Heart Rhythm Society (LAHRS)
| | - Eric Schulze-Bahr
- Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany
| | - Wataru Shimizu
- Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Rafik Tadros
- Cardiovascular Genetics Center, Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Canada
| | - James S Ware
- National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - David S Winlaw
- Cincinnati Children's Hospital Medical Centre, University of Cincinnati, Cincinnati, OH, USA
| | - Elizabeth S Kaufman
- Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH, USA.
| | - Takeshi Aiba
- Department of Clinical Laboratory Medicine and Genetics, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
| | - Andreas Bollmann
- Department of Electrophysiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany; Leipzig Heart Institute, Leipzig Heart Digital, Leipzig, Germany
| | - Jong-Il Choi
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Aarti Dalal
- Department of Pediatrics, Division of Cardiology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Francisco Darrieux
- Arrhythmia Unit, Instituto do Coração, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - John Giudicessi
- Department of Cardiovascular Medicine (Divisions of Heart Rhythm Services and Circulatory Failure and the Windland Smith Rice Genetic Heart Rhythm Clinic), Mayo Clinic, Rochester, MN, USA
| | - Mariana Guerchicoff
- Division of Pediatric Arrhythmia and Electrophysiology, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Kui Hong
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Andrew D Krahn
- Division of Cardiology, University of British Columbia, Vancouver, Canada
| | - Ciorsti MacIntyre
- Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, MN, USA
| | - Judith A Mackall
- Center for Cardiac Electrophysiology and Pacing, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Lluís Mont
- Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Carlo Napolitano
- Molecular Cardiology, Istituti Clinici Scientifici Maugeri, IRCCS, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Juan Pablo Ochoa
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Cariovasculares (CIBERCV), Madrid, Spain
| | - Petr Peichl
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Alexandre C Pereira
- Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo Medical School, São Paulo 05403-000, Brazil; Hipercol Brasil Program, São Paulo, Brazil
| | - Peter J Schwartz
- Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano, IRCCS, Milan, Italy
| | - Jon Skinner
- Sydney Childrens Hospital Network, University of Sydney, Sydney, Australia
| | - Christoph Stellbrink
- Department of Cardiology and Intensive Care Medicine, University Hospital Campus Klinikum Bielefeld, Bielefeld, Germany
| | - Jacob Tfelt-Hansen
- The Department of Cardiology, the Heart Centre, Copenhagen University Hospital, Rigshopitalet, Copenhagen, Denmark; Section of Genetics, Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Denmark
| | - Thomas Deneke
- Heart Center Bad Neustadt, Bad Neustadt a.d. Saale, Germany
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20
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Schuermans N, Hemelsoet D, Terryn W, Steyaert S, Van Coster R, Coucke PJ, Steyaert W, Callewaert B, Bogaert E, Verloo P, Vanlander AV, Debackere E, Ghijsels J, LeBlanc P, Verdin H, Naesens L, Haerynck F, Callens S, Dermaut B, Poppe B. Shortcutting the diagnostic odyssey: the multidisciplinary Program for Undiagnosed Rare Diseases in adults (UD-PrOZA). Orphanet J Rare Dis 2022; 17:210. [PMID: 35606766 PMCID: PMC9128245 DOI: 10.1186/s13023-022-02365-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 05/13/2022] [Indexed: 11/23/2022] Open
Abstract
Background In order to facilitate the diagnostic process for adult patients suffering from a rare disease, the Undiagnosed Disease Program (UD-PrOZA) was founded in 2015 at the Ghent University Hospital in Belgium. In this study we report the five-year results of our multidisciplinary approach in rare disease diagnostics. Methods Patients referred by a healthcare provider, in which an underlying rare disease is likely, qualify for a UD-PrOZA evaluation. UD-PrOZA uses a multidisciplinary clinical approach combined with state-of-the-art genomic technologies in close collaboration with research facilities to diagnose patients. Results Between 2015 and 2020, 692 patients (94% adults) were referred of which 329 (48%) were accepted for evaluation. In 18% (60 of 329) of the cases a definite diagnosis was made. 88% (53 of 60) of the established diagnoses had a genetic origin. 65% (39 of 60) of the genetic diagnoses were made through whole exome sequencing (WES). The mean time interval between symptom-onset and diagnosis was 19 years. Key observations included novel genotype–phenotype correlations, new variants in known disease genes and the identification of three new disease genes. In 13% (7 of 53), identifying the molecular cause was associated with therapeutic recommendations and in 88% (53 of 60), gene specific genetic counseling was made possible. Actionable secondary findings were reported in 7% (12 of 177) of the patients in which WES was performed. Conclusion UD-PrOZA offers an innovative interdisciplinary platform to diagnose rare diseases in adults with previously unexplained medical problems and to facilitate translational research. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02365-y.
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Affiliation(s)
- Nika Schuermans
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. .,Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
| | | | - Wim Terryn
- Department of Nephrology, Jan Yperman Hospital, Ieper, Belgium
| | - Sanne Steyaert
- Department of General Internal Medicine, Ghent University Hospital, Ghent, Belgium
| | - Rudy Van Coster
- Department of Pediatrics, Division of Pediatric Neurology and Metabolic Diseases, Ghent University Hospital, Ghent, Belgium
| | - Paul J Coucke
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Wouter Steyaert
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bert Callewaert
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Elke Bogaert
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Patrick Verloo
- Department of Pediatrics, Division of Pediatric Neurology and Metabolic Diseases, Ghent University Hospital, Ghent, Belgium
| | - Arnaud V Vanlander
- Department of Pediatrics, Division of Pediatric Neurology and Metabolic Diseases, Ghent University Hospital, Ghent, Belgium
| | - Elke Debackere
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Jody Ghijsels
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Pontus LeBlanc
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Hannah Verdin
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Leslie Naesens
- Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium.,Primary Immunodeficiency Research Lab, Center for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Center, Ghent University Hospital, Ghent, Belgium
| | - Filomeen Haerynck
- Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium
| | - Steven Callens
- Department of General Internal Medicine, Ghent University Hospital, Ghent, Belgium
| | - Bart Dermaut
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Bruce Poppe
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
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21
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Carvalhal S, Bader I, Rooimans MA, Oostra AB, Balk JA, Feichtinger RG, Beichler C, Speicher MR, van Hagen JM, Waisfisz Q, van Haelst M, Bruijn M, Tavares A, Mayr JA, Wolthuis RMF, Oliveira RA, de Lange J. Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation. SCIENCE ADVANCES 2022; 8:eabk0114. [PMID: 35044816 PMCID: PMC8769543 DOI: 10.1126/sciadv.abk0114] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 11/24/2021] [Indexed: 05/14/2023]
Abstract
Budding uninhibited by benzimidazoles (BUB1) contributes to multiple mitotic processes. Here, we describe the first two patients with biallelic BUB1 germline mutations, who both display microcephaly, intellectual disability, and several patient-specific features. The identified mutations cause variable degrees of reduced total protein level and kinase activity, leading to distinct mitotic defects. Both patients’ cells show prolonged mitosis duration, chromosome segregation errors, and an overall functional spindle assembly checkpoint. However, while BUB1 levels mostly affect BUBR1 kinetochore recruitment, impaired kinase activity prohibits centromeric recruitment of Aurora B, SGO1, and TOP2A, correlating with anaphase bridges, aneuploidy, and defective sister chromatid cohesion. We do not observe accelerated cohesion fatigue. We hypothesize that unresolved DNA catenanes increase cohesion strength, with concomitant increase in anaphase bridges. In conclusion, BUB1 mutations cause a neurodevelopmental disorder, with clinical and cellular phenotypes that partially resemble previously described syndromes, including autosomal recessive primary microcephaly, mosaic variegated aneuploidy, and cohesinopathies.
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Affiliation(s)
- Sara Carvalhal
- Instituto Gulbenkian de Ciência, R. Q.ta Grande 6, 2780-156 Oeiras, Portugal
- Algarve Biomedical Center Research Institute, Universidade do Algarve, 8005-139 Faro, Portugal
- Centre for Biomedical Research, Universidade do Algarve, 8005-139 Faro, Portugal
| | - Ingrid Bader
- Unit of Clinical Genetics, Paracelsus Medical University, Salzburg, Austria
| | - Martin A. Rooimans
- Cancer Center Amsterdam, Amsterdam University Medical Centers, Oncogenetics Section, De Boelelaan 1118, 1081 HV Amsterdam, Netherlands
| | - Anneke B. Oostra
- Cancer Center Amsterdam, Amsterdam University Medical Centers, Oncogenetics Section, De Boelelaan 1118, 1081 HV Amsterdam, Netherlands
| | - Jesper A. Balk
- Cancer Center Amsterdam, Amsterdam University Medical Centers, Oncogenetics Section, De Boelelaan 1118, 1081 HV Amsterdam, Netherlands
| | - René G. Feichtinger
- Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Christine Beichler
- Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria
| | - Michael R. Speicher
- Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria
| | - Johanna M. van Hagen
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1118, 1081 HV Amsterdam, Netherlands
| | - Quinten Waisfisz
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1118, 1081 HV Amsterdam, Netherlands
| | - Mieke van Haelst
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1118, 1081 HV Amsterdam, Netherlands
| | - Martijn Bruijn
- Northwest Clinics, Wilhelminalaan 12, 1815 JD Alkmaar, Netherlands
| | - Alexandra Tavares
- Instituto Gulbenkian de Ciência, R. Q.ta Grande 6, 2780-156 Oeiras, Portugal
| | - Johannes A. Mayr
- Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Rob M. F. Wolthuis
- Cancer Center Amsterdam, Amsterdam University Medical Centers, Oncogenetics Section, De Boelelaan 1118, 1081 HV Amsterdam, Netherlands
| | - Raquel A. Oliveira
- Instituto Gulbenkian de Ciência, R. Q.ta Grande 6, 2780-156 Oeiras, Portugal
| | - Job de Lange
- Cancer Center Amsterdam, Amsterdam University Medical Centers, Oncogenetics Section, De Boelelaan 1118, 1081 HV Amsterdam, Netherlands
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22
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Silva AC, Matthys OB, Joy DA, Kauss MA, Natarajan V, Lai MH, Turaga D, Blair AP, Alexanian M, Bruneau BG, McDevitt TC. Co-emergence of cardiac and gut tissues promotes cardiomyocyte maturation within human iPSC-derived organoids. Cell Stem Cell 2021; 28:2137-2152.e6. [PMID: 34861147 DOI: 10.1016/j.stem.2021.11.007] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 02/13/2021] [Accepted: 11/12/2021] [Indexed: 01/15/2023]
Abstract
During embryogenesis, paracrine signaling between tissues in close proximity contributes to the determination of their respective cell fate(s) and development into functional organs. Organoids are in vitro models that mimic organ formation and cellular heterogeneity, but lack the paracrine input of surrounding tissues. Here, we describe a human multilineage iPSC-derived organoid that recapitulates cooperative cardiac and gut development and maturation, with extensive cellular and structural complexity in both tissues. We demonstrate that the presence of endoderm tissue (gut/intestine) in the organoids contributed to the development of cardiac tissue features characteristic of stages after heart tube formation, including cardiomyocyte expansion, compartmentalization, enrichment of atrial/nodal cells, myocardial compaction, and fetal-like functional maturation. Overall, this study demonstrates the ability to generate and mature cooperative tissues originating from different germ lineages within a single organoid model, an advance that will further the examination of multi-tissue interactions during development, physiological maturation, and disease.
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Affiliation(s)
- Ana C Silva
- Gladstone Institutes, San Francisco, CA 94158, USA
| | - Oriane B Matthys
- Gladstone Institutes, San Francisco, CA 94158, USA; UC Berkeley-UC San Francisco Graduate Program in Bioengineering, San Francisco, CA 94143, USA
| | - David A Joy
- Gladstone Institutes, San Francisco, CA 94158, USA; UC Berkeley-UC San Francisco Graduate Program in Bioengineering, San Francisco, CA 94143, USA
| | - Mara A Kauss
- Gladstone Institutes, San Francisco, CA 94158, USA; UC San Francisco Graduate Program in Biomedical Sciences, San Francisco, CA 94143, USA
| | | | | | | | | | | | - Benoit G Bruneau
- Gladstone Institutes, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, CA 94143, USA
| | - Todd C McDevitt
- Gladstone Institutes, San Francisco, CA 94158, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA.
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23
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Bianco F, Lattanzio G, Lorenzini L, Diquigiovanni C, Mazzoni M, Clavenzani P, Calzà L, Giardino L, Sternini C, Bonora E, De Giorgio R. Novel understanding on genetic mechanisms of enteric neuropathies leading to severe gut dysmotility. Eur J Histochem 2021; 65. [PMID: 34818877 PMCID: PMC8636838 DOI: 10.4081/ejh.2021.3289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 11/03/2021] [Indexed: 11/24/2022] Open
Abstract
The enteric nervous system (ENS) is the third division of the autonomic nervous system and the largest collection of neurons outside the central nervous system (CNS). The ENS has been referred to as “the brain-in-thegut” or “the second brain of the human body” because of its highly integrated neural circuits controlling a vast repertoire of gut functions, including absorption/secretion, splanchnic blood vessels, some immunological aspects, intestinal epithelial barrier, and gastrointestinal (GI) motility. The latter function is the result of the ENS fine-tuning over smooth musculature, along with the contribution of other key cells, such as enteric glia (astrocyte-like cells supporting and contributing to neuronal activity), interstitial cells of Cajal (the pacemaker cells of the GI tract involved in neuromuscular transmission), and enteroendocrine cells (releasing bioactive substances, which affect gut physiology). Any noxa insult perturbing the ENS complexity may determine a neuropathy with variable degree of neuro-muscular dysfunction. In this review we aim to cover the most recent update on genetic mechanisms leading to enteric neuropathies ranging from Hirschsprung’s disease (characterized by lack of any enteric neurons in the gut wall) up to more generalized form of dysmotility such as chronic intestinal pseudo-obstruction (CIPO) with a significant reduction of enteric neurons. In this line, we will discuss the role of the RAD21 mutation, which we have demonstrated in a family whose affected members exhibited severe GI dysmotility. Other genes contributing to gut motility abnormalities will also be presented. In conclusion, the knowledge on the molecular mechanisms involved in enteric neuropathy may unveil strategies to better manage patients with neurogenic gut dysmotility and pave the way to targeted therapies.
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Affiliation(s)
- Francesca Bianco
- Department of Veterinary Sciences; Department of Medical and Surgical Sciences, University of Bologna.
| | | | | | | | | | | | | | | | - Catia Sternini
- UCLA/DDRC, Division of Digestive Diseases, Departments Medicine and Neurobiology, David Geffen School of Medicine, UCLA, Los Angeles CA.
| | - Elena Bonora
- Department of Medical and Surgical Sciences, University of Bologna.
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24
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Chanpong A, Borrelli O, Thapar N. Hirschsprung disease and Paediatric Intestinal Pseudo-obstruction. Best Pract Res Clin Gastroenterol 2021; 56-57:101765. [PMID: 35331399 DOI: 10.1016/j.bpg.2021.101765] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 01/31/2023]
Abstract
Hirschsprung disease (HSCR) and Paediatric Intestinal Pseudo-obstruction (PIPO) comprise two of the most recognized and severe disorders of gastrointestinal (GI) motility. HSCR is a developmental disorder of the enteric nervous system invariably affecting the large intestine, whereas the majority of PIPO conditions represent congenital disorders of one or more components of the neuromusculature and more diffusely affect the GI tract. Histopathology is deemed the gold standard for the diagnosis of HSCR and, arguably, of PIPO, but, other diagnostic modalities such as manometric and genetic studies have seen recent advances that may increase their utility. Especially for PIPO, management is multidisciplinary and best performed in specialist referral centres. Surgery remains the only viable treatment for HSCR and appears essential to optimize and sustain feeding and viability of intestinal function in PIPO patients. Novel therapies such as neural stem cell transplants show promise for the future.
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Affiliation(s)
- Atchariya Chanpong
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom; Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, 90110, Thailand; Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, United Kingdom
| | - Osvaldo Borrelli
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
| | - Nikhil Thapar
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, United Kingdom; Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Queensland, 4101, Australia.
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25
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Sane A, Sridhar S, Sanyal K, Ghosh SK. Shugoshin ensures maintenance of the spindle assembly checkpoint response and efficient spindle disassembly. Mol Microbiol 2021; 116:1079-1098. [PMID: 34407255 DOI: 10.1111/mmi.14796] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/07/2021] [Accepted: 08/15/2021] [Indexed: 11/27/2022]
Abstract
Shugoshin proteins are evolutionarily conserved across eukaryotes, with some species-specific cellular functions, ensuring the fidelity of chromosome segregation. They act as adaptors at various subcellular locales to mediate several protein-protein interactions in a spatio-temporal manner. Here, we characterize shugoshin (Sgo1) in the human fungal pathogen Candida albicans. We observe that Sgo1 retains its centromeric localization and performs its conserved functions of regulating the sister chromatid biorientation, centromeric condensin localization, and maintenance of chromosomal passenger complex (CPC). We identify novel roles of Sgo1 as a spindle assembly checkpoint (SAC) component with functions in maintaining a prolonged SAC response by retaining Mad2 and Bub1 at the kinetochores in response to improper kinetochore-microtubule attachments. Strikingly, we discover the in vivo localization of Sgo1 along the length of the mitotic spindle. Our results indicate that Sgo1 performs a hitherto unknown function of facilitating timely disassembly of the mitotic spindle in C. albicans. To summarize, this study unravels a unique functional adaptation of shugoshin in maintaining genomic stability.
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Affiliation(s)
- Aakanksha Sane
- Department of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Powai, India
| | - Shreyas Sridhar
- Molecular Biology & Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.,Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
| | - Kaustuv Sanyal
- Molecular Biology & Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.,Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
| | - Santanu K Ghosh
- Department of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Powai, India
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26
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Venkatesh V, Aneja A, Seetharaman K, Anushree N, Rana SS, Lal SB. A Novel Cohesinopathy Causing Chronic Intestinal Pseudo Obstruction in 2 Siblings and Literature Review. J Neurogastroenterol Motil 2021; 27:436-437. [PMID: 34210909 PMCID: PMC8266498 DOI: 10.5056/jnm20259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/26/2021] [Accepted: 03/08/2021] [Indexed: 01/18/2023] Open
Affiliation(s)
- Vybhav Venkatesh
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Aradhana Aneja
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Keerthivasan Seetharaman
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Neha Anushree
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Surinder S Rana
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sadhna B Lal
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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27
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He L, Wang X, Jin Y, Xu W, Guan Y, Wu J, Han S, Liu G. Identification and validation of the miRNA-mRNA regulatory network in fetoplacental arterial endothelial cells of gestational diabetes mellitus. Bioengineered 2021; 12:3503-3515. [PMID: 34233591 PMCID: PMC8806558 DOI: 10.1080/21655979.2021.1950279] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Gestational diabetes mellitus (GDM) increases the risk of fetal heart malformations, though little is known about the mechanism of hyperglycemia-induced heart malformations. Thus, we aimed to reveal the global landscape of miRNAs and mRNAs in GDM-exposed fetoplacental arterial endothelial cells (dAECs) and establish regulatory networks for exploring the pathophysiological mechanism of fetal heart malformations in maternal hyperglycemia. Gene Expression Omnibus (GEO) datasets were used, and identification of differentially expressed miRNAs (DEMs) and genes (DEGs) in GDM was based on a previous sequencing analysis of dAECs. A miRNA-mRNA network containing 20 DEMs and 65 DEGs was established using DEMs altered in opposite directions to DEGs. In an in vivo study, we established a streptozotocin-induced pregestational diabetes mellitus (PGDM) mouse model and found the fetal cardiac wall thickness in different regions to be dramatically increased in the PGDM grouValidation of DEMs and DEGs in the fetal heart showed significantly upregulated expression of let-7e-5p, miR-139-5p and miR-195-5p and downregulated expression of SGOL1, RRM2, RGS5, CDK1 and CENPA. In summary, we reveal the miRNA-mRNA regulatory network related to fetal cardiac development disorders in offspring, which may shed light on the potential molecular mechanisms of fetal cardiac development disorders during maternal hyperglycemia.
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Affiliation(s)
- Longkai He
- Department of Pediatrics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Xiaotong Wang
- Department of Pediatrics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Ya Jin
- Department of Pediatrics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Weipeng Xu
- Department of Pediatrics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Yi Guan
- Department of Pediatrics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Jingchao Wu
- Department of Pediatrics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Shasha Han
- Department of Pediatrics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Guosheng Liu
- Department of Pediatrics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
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28
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Antony J, Chin CV, Horsfield JA. Cohesin Mutations in Cancer: Emerging Therapeutic Targets. Int J Mol Sci 2021; 22:6788. [PMID: 34202641 PMCID: PMC8269296 DOI: 10.3390/ijms22136788] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/08/2021] [Accepted: 06/18/2021] [Indexed: 12/12/2022] Open
Abstract
The cohesin complex is crucial for mediating sister chromatid cohesion and for hierarchal three-dimensional organization of the genome. Mutations in cohesin genes are present in a range of cancers. Extensive research over the last few years has shown that cohesin mutations are key events that contribute to neoplastic transformation. Cohesin is involved in a range of cellular processes; therefore, the impact of cohesin mutations in cancer is complex and can be cell context dependent. Candidate targets with therapeutic potential in cohesin mutant cells are emerging from functional studies. Here, we review emerging targets and pharmacological agents that have therapeutic potential in cohesin mutant cells.
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Affiliation(s)
- Jisha Antony
- Department of Pathology, Otago Medical School, University of Otago, Dunedin 9016, New Zealand;
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
| | - Chue Vin Chin
- Department of Pathology, Otago Medical School, University of Otago, Dunedin 9016, New Zealand;
| | - Julia A. Horsfield
- Department of Pathology, Otago Medical School, University of Otago, Dunedin 9016, New Zealand;
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
- Genetics Otago Research Centre, University of Otago, Dunedin 9016, New Zealand
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29
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Liu D, Song AT, Qi X, van Vliet PP, Xiao J, Xiong F, Andelfinger G, Nattel S. Cohesin-protein Shugoshin-1 controls cardiac automaticity via HCN4 pacemaker channel. Nat Commun 2021; 12:2551. [PMID: 33953173 PMCID: PMC8100125 DOI: 10.1038/s41467-021-22737-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 03/16/2021] [Indexed: 12/12/2022] Open
Abstract
Endogenous cardiac pacemaker function regulates the rate and rhythm of cardiac contraction. The mutation p.Lys23Glu in the cohesin protein Shugoshin-1 causes severe heart arrhythmias due to sinoatrial node dysfunction and a debilitating gastrointestinal motility disorder, collectively termed the Chronic Atrial and Intestinal Dysrhythmia Syndrome, linking Shugoshin-1 and pacemaker activity. Hyperpolarization-activated, cyclic nucleotide-gated cation channel 4 (HCN4) is the predominant pacemaker ion-channel in the adult heart and carries the majority of the "funny" current, which strongly contributes to diastolic depolarization in pacemaker cells. Here, we study the mechanism by which Shugoshin-1 affects cardiac pacing activity with two cell models: neonatal rat ventricular myocytes and Chronic Atrial and Intestinal Dysrhythmia Syndrome patient-specific human induced pluripotent stem cell derived cardiomyocytes. We find that Shugoshin-1 interacts directly with HCN4 to promote and stabilize cardiac pacing. This interaction enhances funny-current by optimizing HCN4 cell-surface expression and function. The clinical p.Lys23Glu mutation leads to an impairment in the interaction between Shugoshin-1 and HCN4, along with depressed funny-current and dysrhythmic activity in induced pluripotent stem cell derived cardiomyocytes derived from Chronic Atrial and Intestinal Dysrhythmia Syndrome patients. Our work reveals a critical non-canonical, cohesin-independent role for Shugoshin-1 in maintaining cardiac automaticity and identifies potential therapeutic avenues for cardiac pacemaking disorders, in particular Chronic Atrial and Intestinal Dysrhythmia Syndrome.
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Affiliation(s)
- Donghai Liu
- Montreal Heart Institute, Department of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Andrew Taehun Song
- Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada
- Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montréal, QC, Canada
| | - Xiaoyan Qi
- Montreal Heart Institute, Department of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Patrick Piet van Vliet
- Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montréal, QC, Canada
- LIA (International Associated Laboratory) INSERM, Marseille, France
- LIA (International Associated Laboratory) Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
| | - Jiening Xiao
- Montreal Heart Institute, Department of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Feng Xiong
- Montreal Heart Institute, Department of Medicine, Université de Montréal, Montréal, QC, Canada
- Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada
| | - Gregor Andelfinger
- Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montréal, QC, Canada
- Department of Pediatrics, University of Montreal, Montréal, QC, Canada
- Department of Biochemistry, University of Montreal, Montréal, QC, Canada
| | - Stanley Nattel
- Montreal Heart Institute, Department of Medicine, Université de Montréal, Montréal, QC, Canada.
- Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
- Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
- IHU LIRYC Institute, Fondation Bordeaux Université, Bordeaux, France.
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30
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Holland AM, Bon-Frauches AC, Keszthelyi D, Melotte V, Boesmans W. The enteric nervous system in gastrointestinal disease etiology. Cell Mol Life Sci 2021; 78:4713-4733. [PMID: 33770200 PMCID: PMC8195951 DOI: 10.1007/s00018-021-03812-y] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/20/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023]
Abstract
A highly conserved but convoluted network of neurons and glial cells, the enteric nervous system (ENS), is positioned along the wall of the gut to coordinate digestive processes and gastrointestinal homeostasis. Because ENS components are in charge of the autonomous regulation of gut function, it is inevitable that their dysfunction is central to the pathophysiology and symptom generation of gastrointestinal disease. While for neurodevelopmental disorders such as Hirschsprung, ENS pathogenesis appears to be clear-cut, the role for impaired ENS activity in the etiology of other gastrointestinal disorders is less established and is often deemed secondary to other insults like intestinal inflammation. However, mounting experimental evidence in recent years indicates that gastrointestinal homeostasis hinges on multifaceted connections between the ENS, and other cellular networks such as the intestinal epithelium, the immune system, and the intestinal microbiome. Derangement of these interactions could underlie gastrointestinal disease onset and elicit variable degrees of abnormal gut function, pinpointing, perhaps unexpectedly, the ENS as a diligent participant in idiopathic but also in inflammatory and cancerous diseases of the gut. In this review, we discuss the latest evidence on the role of the ENS in the pathogenesis of enteric neuropathies, disorders of gut-brain interaction, inflammatory bowel diseases, and colorectal cancer.
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Affiliation(s)
- Amy Marie Holland
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Ana Carina Bon-Frauches
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Daniel Keszthelyi
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, NUTRIM-School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Veerle Melotte
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Werend Boesmans
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.
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31
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Le TL, Galmiche L, Levy J, Suwannarat P, Hellebrekers DM, Morarach K, Boismoreau F, Theunissen TE, Lefebvre M, Pelet A, Martinovic J, Gelot A, Guimiot F, Calleroz A, Gitiaux C, Hully M, Goulet O, Chardot C, Drunat S, Capri Y, Bole-Feysot C, Nitschké P, Whalen S, Mouthon L, Babcock HE, Hofstra R, de Coo IF, Tabet AC, Molina TJ, Keren B, Brooks A, Smeets HJ, Marklund U, Gordon CT, Lyonnet S, Amiel J, Bondurand N. Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans. J Clin Invest 2021; 131:145837. [PMID: 33497358 DOI: 10.1172/jci145837] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/14/2021] [Indexed: 02/06/2023] Open
Abstract
Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities. The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility.
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Affiliation(s)
- Thuy-Linh Le
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France
| | - Louise Galmiche
- INSERM UMR 1235, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, University of Nantes, Nantes, France.,Pathology Department, Assistance Publique Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, Paris, France
| | - Jonathan Levy
- Genetics Department, Robert Debré Hospital, AP-HP, Paris, France.,Université de Paris, NeuroDiderot, INSERM UMR 1141, Paris, France
| | - Pim Suwannarat
- Department of Genetics, Mid-Atlantic Permanente Medical Group, Suitland, Maryland, USA
| | - Debby Mei Hellebrekers
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands
| | - Khomgrit Morarach
- Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Franck Boismoreau
- Institut de Biologie de l'ENS (IBENS), INSERM, CNRS, École Normale Supérieure, PSL Research University, Paris, France
| | - Tom Ej Theunissen
- Department of Genetics and Cell Biology, Maastricht University, Maastricht, Netherlands
| | - Mathilde Lefebvre
- Fetal Pathology Unit, Armand Trousseau Hospital, AP-HP, Paris, France
| | - Anna Pelet
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France
| | - Jelena Martinovic
- Fetal Pathology Unit, Antoine Béclère Hospital, AP-HP, Paris-Saclay University, Clamart, France
| | - Antoinette Gelot
- Neuropathology, Pathology Department, Armand Trousseau Hospital, AP-HP, Paris, France.,Aix-Marseille University, INMED INSERM UMR1249, Campus de Luminy, Marseille, France
| | - Fabien Guimiot
- Université de Paris, NeuroDiderot, INSERM UMR 1141, Paris, France.,Fetal Pathology Unit, Robert Debré Hospital, AP-HP, Paris, France
| | - Amanda Calleroz
- Pathology and Laboratory Medicine Division, Children's National Hospital, Washington DC, USA
| | - Cyril Gitiaux
- Department of Pediatric Clinical Neurophysiology, Necker-Enfants Malades Hospital, AP-HP, Université de Paris, Paris, France
| | - Marie Hully
- Department of Pediatric Neurology and Rehabilitation, Necker-Enfants Malades Hospital, AP-HP, Université de Paris, Paris, France
| | - Olivier Goulet
- Department of Pediatric Gastroenterology-Hepatology-Nutrition, Necker-Enfants Malades Hospital, AP-HP, Paris, France
| | - Christophe Chardot
- Department of Pediatric Surgery, Necker-Enfants Malades Hospital, AP-HP, Paris, France
| | - Severine Drunat
- Genetics Department, Robert Debré Hospital, AP-HP, Paris, France.,Université de Paris, NeuroDiderot, INSERM UMR 1141, Paris, France
| | - Yline Capri
- Genetics Department, Robert Debré Hospital, AP-HP, Paris, France
| | - Christine Bole-Feysot
- Genomics Core Facility, Imagine Institute-Structure Federative de Recherche Necker, INSERM UMR 1163 and INSERM US24/CNRS UMS 3633, Université de Paris, Paris, France
| | | | - Sandra Whalen
- Clinical Genetics Unit and Reference Center, Anomalies du Développement et Syndromes Malformatifs, AP-HP, Sorbonne University, Armand Trousseau Hospital, Paris, France
| | - Linda Mouthon
- Department of Genetics, La Pitié-Salpêtrière Hospital, AP-HP, Paris, France
| | - Holly E Babcock
- Children's National Hospital, Rare Disease Institute, Washington, DC, USA
| | - Robert Hofstra
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands
| | - Irenaeus Fm de Coo
- Department of Toxicogenomics, Unit Clinical Genomics, Maastricht University, MHeNs School for Mental Health and Neuroscience, Maastricht, Netherlands
| | - Anne-Claude Tabet
- Genetics Department, Robert Debré Hospital, AP-HP, Paris, France.,Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, France
| | - Thierry J Molina
- Pathology Department, Assistance Publique Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, Paris, France.,Université de Paris, Imagine Institute, Laboratory of Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM UMR 1163, Paris, France
| | - Boris Keren
- Department of Genetics, La Pitié-Salpêtrière Hospital, AP-HP, Paris, France
| | - Alice Brooks
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands
| | - Hubert Jm Smeets
- Department of Toxicogenomics, Unit Clinical Genomics, Maastricht University, MHeNs School for Mental Health and Neuroscience, Maastricht, Netherlands
| | - Ulrika Marklund
- Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Christopher T Gordon
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France
| | - Stanislas Lyonnet
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France.,Fédération de Génétique, Necker-Enfants Malades Hospital, AP-HP, Paris, France
| | - Jeanne Amiel
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France.,Fédération de Génétique, Necker-Enfants Malades Hospital, AP-HP, Paris, France
| | - Nadège Bondurand
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France
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32
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Martire D, Garnier S, Sagnol S, Bourret A, Marchal S, Chauvet N, Guérin A, Forgues D, Berrebi D, Chardot C, Bellaiche M, Rendu J, Kalfa N, Faure S, de Santa Barbara P. Phenotypic switch of smooth muscle cells in paediatric chronic intestinal pseudo-obstruction syndrome. J Cell Mol Med 2021; 25:4028-4039. [PMID: 33656779 PMCID: PMC8051695 DOI: 10.1111/jcmm.16367] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 12/31/2020] [Accepted: 01/12/2021] [Indexed: 12/11/2022] Open
Abstract
Smooth Muscle Cells (SMC) are unique amongst all muscle cells in their capacity to modulate their phenotype. Indeed, SMCs do not terminally differentiate but instead harbour a remarkable capacity to dedifferentiate, switching between a quiescent contractile state and a highly proliferative and migratory phenotype, a quality often associated to SMC dysfunction. However, phenotypic plasticity remains poorly examined in the field of gastroenterology in particular in pathologies in which gut motor activity is impaired. Here, we assessed SMC status in biopsies of infants with chronic intestinal pseudo-obstruction (CIPO) syndrome, a life-threatening intestinal motility disorder. We showed that CIPO-SMCs harbour a decreased level of contractile markers. This phenotype is accompanied by an increase in Platelet-Derived Growth Factor Receptor-alpha (PDGFRA) expression. We showed that this modulation occurs without origin-related differences in CIPO circular and longitudinal-derived SMCs. As we characterized PDGFRA as a marker of digestive mesenchymal progenitors during embryogenesis, our results suggest a phenotypic switch of the CIPO-SMC towards an undifferentiated stage. The development of CIPO-SMC culture and the characterization of SMC phenotypic switch should enable us to design therapeutic approaches to promote SMC differentiation in CIPO.
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Affiliation(s)
- Delphine Martire
- PhyMedExp, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Sarah Garnier
- PhyMedExp, Université de Montpellier, CNRS, INSERM, Montpellier, France.,Visceral Paediatric Surgery Unit, CHU de Montpellier, Université de Montpellier, Montpellier, France
| | - Sébastien Sagnol
- PhyMedExp, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Annick Bourret
- PhyMedExp, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Stéphane Marchal
- PhyMedExp, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Norbert Chauvet
- PhyMedExp, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Amandine Guérin
- PhyMedExp, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Dominique Forgues
- Visceral Paediatric Surgery Unit, CHU de Montpellier, Université de Montpellier, Montpellier, France
| | - Dominique Berrebi
- Department of Paediatric Gastroenterology, Assistance Publique Hôpitaux (APHP) Hospital Robert Debré, Paris, France
| | | | - Marc Bellaiche
- Department of Paediatric Gastroenterology, Assistance Publique Hôpitaux (APHP) Hospital Robert Debré, Paris, France
| | - John Rendu
- Centre Hospitalier Universitaire de Grenoble Alpes, Biochimie Génétique et Moléculaire, Grenoble, France
| | - Nicolas Kalfa
- Visceral Paediatric Surgery Unit, CHU de Montpellier, Université de Montpellier, Montpellier, France
| | - Sandrine Faure
- PhyMedExp, Université de Montpellier, CNRS, INSERM, Montpellier, France
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33
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Santos D, Mahtab M, Boavida A, Pisani FM. Role of the DDX11 DNA Helicase in Warsaw Breakage Syndrome Etiology. Int J Mol Sci 2021; 22:2308. [PMID: 33669056 PMCID: PMC7956524 DOI: 10.3390/ijms22052308] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/13/2021] [Accepted: 02/23/2021] [Indexed: 12/23/2022] Open
Abstract
Warsaw breakage syndrome (WABS) is a genetic disorder characterized by sister chromatid cohesion defects, growth retardation, microcephaly, hearing loss and other variable clinical manifestations. WABS is due to biallelic mutations of the gene coding for the super-family 2 DNA helicase DDX11/ChlR1, orthologous to the yeast chromosome loss protein 1 (Chl1). WABS is classified in the group of "cohesinopathies", rare hereditary diseases that are caused by mutations in genes coding for subunits of the cohesin complex or protein factors having regulatory roles in the sister chromatid cohesion process. In fact, among the cohesion regulators, an important player is DDX11, which is believed to be important for the functional coupling of DNA synthesis and cohesion establishment at the replication forks. Here, we will review what is known about the molecular and cellular functions of human DDX11 and its role in WABS etiopathogenesis, even in light of recent findings on the role of cohesin and its regulator network in promoting chromatin loop formation and regulating chromatin spatial organization.
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Affiliation(s)
- Diana Santos
- Istituto di Biochimica e Biologia Cellulare, Consiglio Nazionale delle Ricerche, Via P. Castellino 111, 80131 Naples, Italy; (D.S.); (M.M.); (A.B.)
| | - Mohammad Mahtab
- Istituto di Biochimica e Biologia Cellulare, Consiglio Nazionale delle Ricerche, Via P. Castellino 111, 80131 Naples, Italy; (D.S.); (M.M.); (A.B.)
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy
| | - Ana Boavida
- Istituto di Biochimica e Biologia Cellulare, Consiglio Nazionale delle Ricerche, Via P. Castellino 111, 80131 Naples, Italy; (D.S.); (M.M.); (A.B.)
| | - Francesca M. Pisani
- Istituto di Biochimica e Biologia Cellulare, Consiglio Nazionale delle Ricerche, Via P. Castellino 111, 80131 Naples, Italy; (D.S.); (M.M.); (A.B.)
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Anti-epileptic drug topiramate upregulates TGFβ1 and SOX9 expression in primary embryonic palatal mesenchyme cells: Implications for teratogenicity. PLoS One 2021; 16:e0246989. [PMID: 33577554 PMCID: PMC7880431 DOI: 10.1371/journal.pone.0246989] [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: 09/01/2020] [Accepted: 01/28/2021] [Indexed: 12/27/2022] Open
Abstract
Topiramate is an anti-epileptic drug that is commonly prescribed not just to prevent seizures but also migraine headaches, with over 8 million prescriptions dispensed annually. Topiramate use during pregnancy has been linked to significantly increased risk of babies born with orofacial clefts (OFCs). However, the exact molecular mechanism of topiramate teratogenicity is unknown. In this study, we first used an unbiased antibody array analysis to test the effect of topiramate on human embryonic palatal mesenchyme (HEPM) cells. This analysis identified 40 differentially expressed proteins, showing strong connectivity to known genes associated with orofacial clefts. However, among known OFC genes, only TGFβ1 was significantly upregulated in the antibody array analysis. Next, we validated that topiramate could increase expression of TGFβ1 and of downstream target phospho-SMAD2 in primary mouse embryonic palatal mesenchyme (MEPM) cells. Furthermore, we showed that topiramate treatment of primary MEPM cells increased expression of SOX9. SOX9 overexpression in chondrocytes is known to cause cleft palate in mouse. We propose that topiramate mediates upregulation of TGFβ1 signaling through activation of γ-aminobutyric acid (GABA) receptors in the palate. TGFβ1 and SOX9 play critical roles in orofacial morphogenesis, and their abnormal overexpression provides a plausible etiologic molecular mechanism for the teratogenic effects of topiramate.
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Functioning mechanisms of Shugoshin-1 in centromeric cohesion during mitosis. Essays Biochem 2021; 64:289-297. [PMID: 32451529 DOI: 10.1042/ebc20190077] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/30/2020] [Accepted: 05/05/2020] [Indexed: 12/15/2022]
Abstract
Proper regulation of centromeric cohesion is required for faithful chromosome segregation that prevents chromosomal instability. Extensive studies have identified and established the conserved protein Shugoshin (Sgo1/2) as an essential protector for centromeric cohesion. In this review, we summarize the current understanding of how Shugoshin-1 (Sgo1) protects centromeric cohesion at the molecular level. Targeting of Sgo1 to inner centromeres is required for its proper function of cohesion protection. We therefore discuss about the molecular mechanisms that install Sgo1 onto inner centromeres. At metaphase-to-anaphase transition, Sgo1 at inner centromeres needs to be disabled for the subsequent sister-chromatid segregation. A few recent studies suggest interesting models to explain how it is achieved. These models are discussed as well.
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Zhu CZ, Zhao HW, Lin HW, Wang F, Li YX. Latest developments in chronic intestinal pseudo-obstruction. World J Clin Cases 2020. [DOI: 10.12998/wjcc.v8.i23.5850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
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Zhu CZ, Zhao HW, Lin HW, Wang F, Li YX. Latest developments in chronic intestinal pseudo-obstruction. World J Clin Cases 2020; 8:5852-5865. [PMID: 33344584 PMCID: PMC7723695 DOI: 10.12998/wjcc.v8.i23.5852] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 10/02/2020] [Accepted: 10/19/2020] [Indexed: 02/05/2023] Open
Abstract
Chronic intestinal pseudo-obstruction (CIPO) is a type of intestinal dysfunction presenting as symptoms of intestinal obstruction but without actual mechanical obstruction. An extremely low incidence, non-specific clinical symptoms, strong heterogeneity, and no definitive cause in some patients make CIPO very difficult to diagnose correctly. Imaging and gastrointestinal manometry are commonly used. Most patients have progressive worsening of their symptoms and require intervention, and nutritional assessment and treatment are very important to determine the prognosis. With improvements in surgical techniques, small bowel transplantation is a feasible treatment option for patients with advanced CIPO; however, the long-term prognosis for CIPO patients remains unsatisfactory. Generally, the disease is rare and difficult to diagnose, which leads to clinicians' lack of understanding of the disease and results in a high rate of misdiagnosis. This review describes the characteristics of CIPO and the latest developments in diagnosis and treatment, in detail. The goal of our review is to improve clinicians' understanding of CIPO so that the disease is identified quickly and accurately, and treated as early as possible to improve patients' quality of life.
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Affiliation(s)
- Chang-Zhen Zhu
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Hong-Wei Zhao
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Hong-Wei Lin
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Feng Wang
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yuan-Xin Li
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
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Wang W, Zhou C, Tang H, Yu Y, Zhang Q. Combined Analysis of DNA Methylome and Transcriptome Reveal Novel Candidate Genes Related to Porcine Escherichia coli F4ab/ac-Induced Diarrhea. Front Cell Infect Microbiol 2020; 10:250. [PMID: 32547963 PMCID: PMC7272597 DOI: 10.3389/fcimb.2020.00250] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/29/2020] [Indexed: 12/13/2022] Open
Abstract
Enterotoxigenic Escherichia coli (ETEC) that express F4 (K88) fimbriae are the principal microorganisms responsible for bacterial diarrhea in neonatal and pre-weaning piglets. To better understand the molecular effects of ETEC F4ab/ac infection, we performed a genome-wide comparison of the changes in DNA methylation and gene expression in ETEC F4ab/ac infected porcine intestinal epithelial cells. We characterized the pattern of changes in methylation and found 3297 and 1593 differentially methylated regions in cells infected with F4ab and F4ac, respectively. Moreover, 606 and 780 differentially expressed genes (DEGs) in ETEC F4ab and F4ac infected cells were detected and these genes were highly enriched in immune/defense response related pathways. Integrative analysis identified 27 and 10 genes showing inverse correlations between promoter methylation and expression with ETEC F4ab/ac infection. Altered DNA methylation and expression of various genes suggested their roles and potential functional interactions upon ETEC F4ab/ac infection. Further functional analyses revealed that three DEGs (S100A9, SGO1, and ESPL1) in F4ab infected cells and three DEGs (MAP3K21, PAK6, and MPZL1) in F4ac infected cells are likely involved in the host cells response to ETEC infection. Our data provides further insight into the epigenetic and transcriptomic alterations of ETEC F4ab/ac infected porcine intestinal epithelial cells, and may advance the identification of biomarkers and drug targets for predicting susceptibility to and controlling ETEC F4ab/ac induced diarrhea.
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Affiliation(s)
- Wenwen Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, China
| | - Chuanli Zhou
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Hui Tang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, China
| | - Ying Yu
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Qin Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, China.,College of Animal Science and Technology, China Agricultural University, Beijing, China
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Chronic Atrial Intestinal Dysrhythmia Syndrome Is Associated with Cerebral Small Vessel Disease and Predominantly Cerebellar Microbleeds. Can J Neurol Sci 2020; 47:566-568. [PMID: 32213217 DOI: 10.1017/cjn.2020.57] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Benedict B, van Schie JJM, Oostra AB, Balk JA, Wolthuis RMF, Riele HT, de Lange J. WAPL-Dependent Repair of Damaged DNA Replication Forks Underlies Oncogene-Induced Loss of Sister Chromatid Cohesion. Dev Cell 2020; 52:683-698.e7. [PMID: 32084359 DOI: 10.1016/j.devcel.2020.01.024] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 11/19/2019] [Accepted: 01/22/2020] [Indexed: 12/22/2022]
Abstract
Premature loss of sister chromatid cohesion at metaphase is a diagnostic marker for different cohesinopathies. Here, we report that metaphase spreads of many cancer cell lines also show premature loss of sister chromatid cohesion. Cohesion loss occurs independently of mutations in cohesion factors including SA2, a cohesin subunit frequently inactivated in cancer. In untransformed cells, induction of DNA replication stress by activation of oncogenes or inhibition of DNA replication is sufficient to trigger sister chromatid cohesion loss. Importantly, cell growth under conditions of replication stress requires the cohesin remover WAPL. WAPL promotes rapid RAD51-dependent repair and restart of broken replication forks. We propose that active removal of cohesin allows cancer cells to overcome DNA replication stress. This leads to oncogene-induced cohesion loss from newly synthesized sister chromatids that may contribute to genomic instability and likely represents a targetable cancer cell vulnerability.
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Affiliation(s)
- Bente Benedict
- Netherlands Cancer Institute, Division of Tumor Biology and Immunology, Amsterdam, the Netherlands
| | - Janne J M van Schie
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Anneke B Oostra
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Jesper A Balk
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Rob M F Wolthuis
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
| | - Hein Te Riele
- Netherlands Cancer Institute, Division of Tumor Biology and Immunology, Amsterdam, the Netherlands.
| | - Job de Lange
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
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Faramarz A, Balk JA, van Schie JJM, Oostra AB, Ghandour CA, Rooimans MA, Wolthuis RMF, de Lange J. Non-redundant roles in sister chromatid cohesion of the DNA helicase DDX11 and the SMC3 acetyl transferases ESCO1 and ESCO2. PLoS One 2020; 15:e0220348. [PMID: 31935221 PMCID: PMC6959578 DOI: 10.1371/journal.pone.0220348] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 12/30/2019] [Indexed: 12/30/2022] Open
Abstract
In a process linked to DNA replication, duplicated chromosomes are entrapped in large, circular cohesin complexes and functional sister chromatid cohesion (SCC) is established by acetylation of the SMC3 cohesin subunit. Roberts Syndrome (RBS) and Warsaw Breakage Syndrome (WABS) are rare human developmental syndromes that are characterized by defective SCC. RBS is caused by mutations in the SMC3 acetyltransferase ESCO2, whereas mutations in the DNA helicase DDX11 lead to WABS. We found that WABS-derived cells predominantly rely on ESCO2, not ESCO1, for residual SCC, growth and survival. Reciprocally, RBS-derived cells depend on DDX11 to maintain low levels of SCC. Synthetic lethality between DDX11 and ESCO2 correlated with a prolonged delay in mitosis, and was rescued by knockdown of the cohesin remover WAPL. Rescue experiments using human or mouse cDNAs revealed that DDX11, ESCO1 and ESCO2 act on different but related aspects of SCC establishment. Furthermore, a DNA binding DDX11 mutant failed to correct SCC in WABS cells and DDX11 deficiency reduced replication fork speed. We propose that DDX11, ESCO1 and ESCO2 control different fractions of cohesin that are spatially and mechanistically separated.
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Affiliation(s)
- Atiq Faramarz
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Jesper A. Balk
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Janne J. M. van Schie
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Anneke B. Oostra
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Cherien A. Ghandour
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Martin A. Rooimans
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Rob M. F. Wolthuis
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Job de Lange
- Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
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Abstract
PURPOSE OF REVIEW The purpose of this review is to discuss current knowledge on pediatric intestinal pseudo-obstruction. We will also review new mutations that have been identified through advancement in genetic testing, allowing for a better understanding of the underlying mechanisms of intestinal dysmotility and potential etiologies. RECENT FINDINGS With the advancements in genetic testing, new mutations have been identified in the diagnosis of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), a disorder leading to pediatric pseudo-obstruction. MYLK, LMOD1, MYL9, and MYH11 encode for various proteins within smooth muscle cells; abnormalities within these proteins lead to abnormal intestinal smooth muscle contractions. Chronic intestinal pseudo-obstruction (CIPO) is defined by symptoms of bowel obstruction in the absence of a lumen-occluding lesion. CIPO is a heterogeneous group of disorders caused by abnormalities in the enteric neurons, intestinal smooth muscle, and/or the interstitial cells of Cajal (ICC). Symptoms can be non-specific and etiologies include both primary and secondary causes of CIPO that contribute to the delay in recognizing this condition and making the correct diagnosis. Chronic intestinal pseudo-obstruction has been recognized in both adults and children with fundamental differences in the etiology, symptom onset, clinical features and natural history of this disorder. For this reason, it has been considered a separate entity referred to as pediatric intestinal pseudo-obstruction (PIPO).
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Affiliation(s)
- Heidi E Gamboa
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
| | - Manu Sood
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA
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Pisani FM. Spotlight on Warsaw Breakage Syndrome. APPLICATION OF CLINICAL GENETICS 2019; 12:239-248. [PMID: 31824187 PMCID: PMC6901054 DOI: 10.2147/tacg.s186476] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 11/13/2019] [Indexed: 12/14/2022]
Abstract
Warsaw breakage syndrome (WABS) is a very rare recessive hereditary disease caused by mutations in the gene coding for the DNA helicase DDX11, involved in genome stability maintenance and sister cohesion establishment. Typical clinical features observed in WABS patients include growth retardation, facial dysmorphia, microcephaly, hearing loss due to cochlear malformations and, at cytological level, sister chromatid cohesion defects. Molecular bases of WABS have not yet been elucidated, due to lack of disease animal model systems and limited knowledge of the DDX11 physiological functions. However, WABS is considered to belong to the group of cohesinopathies, genetic disorders due to mutations of subunits or regulators of cohesin, the protein complex responsible for tethering sister chromatids from the time of their synthesis till they separate in mitosis. Recent evidences suggest that cohesin and its regulators have additional key roles in chromatin organization by promoting the formation of chromatin loops. This “non-canonical” function of cohesin is expected to impact gene transcription during cell differentiation and embryonic development and its dis-regulation, caused by mutation/loss of genes encoding cohesin subunits or regulators, could originate the developmental defects observed in cohesinopathies. Ethiopathogenesis of WABS is discussed in line with these recent findings and evidence of a possible role of DDX11 as a cohesin regulator.
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Affiliation(s)
- Francesca M Pisani
- Istituto di Biochimica e Biologia Cellulare, Consiglio Nazionale delle Ricerche, Naples 80131, Italy
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Piché J, Van Vliet PP, Pucéat M, Andelfinger G. The expanding phenotypes of cohesinopathies: one ring to rule them all! Cell Cycle 2019; 18:2828-2848. [PMID: 31516082 PMCID: PMC6791706 DOI: 10.1080/15384101.2019.1658476] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 08/13/2019] [Accepted: 08/17/2019] [Indexed: 12/13/2022] Open
Abstract
Preservation and development of life depend on the adequate segregation of sister chromatids during mitosis and meiosis. This process is ensured by the cohesin multi-subunit complex. Mutations in this complex have been associated with an increasing number of diseases, termed cohesinopathies. The best characterized cohesinopathy is Cornelia de Lange syndrome (CdLS), in which intellectual and growth retardations are the main phenotypic manifestations. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably. Novel roles of the cohesin complex have emerged during the past decades, suggesting that important cell cycle regulators exert important biological effects through non-cohesion-related functions and broadening the potential pathomechanisms involved in cohesinopathies. This review focuses on non-cohesion-related functions of the cohesin complex, gene dosage effect, epigenetic regulation and TGF-β in cohesinopathy context, especially in comparison to Chronic Atrial and Intestinal Dysrhythmia (CAID) syndrome, a very distinct cohesinopathy caused by a homozygous Shugoshin-1 (SGO1) mutation (K23E) and characterized by pacemaker failure in both heart (sick sinus syndrome followed by atrial flutter) and gut (chronic intestinal pseudo-obstruction) with no intellectual or growth delay. We discuss the possible impact of SGO1 alterations in human pathologies and the potential impact of the SGO1 K23E mutation in the sinus node and gut development and functions. We suggest that the human phenotypes observed in CdLS, CAID syndrome and other cohesinopathies can inform future studies into the less well-known non-cohesion-related functions of cohesin complex genes. Abbreviations: AD: Alzheimer Disease; AFF4: AF4/FMR2 Family Member 4; ANKRD11: Ankyrin Repeat Domain 11; APC: Anaphase Promoter Complex; ASD: Atrial Septal Defect; ATRX: ATRX Chromatin Remodeler; ATRX: Alpha Thalassemia X-linked intellectual disability syndrome; BIRC5: Baculoviral IAP Repeat Containing 5; BMP: Bone Morphogenetic Protein; BRD4: Bromodomain Containing 4; BUB1: BUB1 Mitotic Checkpoint Serine/Threonine Kinase; CAID: Chronic Atrial and Intestinal Dysrhythmia; CDK1: Cyclin Dependent Kinase 1; CdLS: Cornelia de Lange Syndrome; CHD: Congenital Heart Disease; CHOPS: Cognitive impairment, coarse facies, Heart defects, Obesity, Pulmonary involvement, Short stature, and skeletal dysplasia; CIPO: Chronic Intestinal Pseudo-Obstruction; c-kit: KIT Proto-Oncogene Receptor Tyrosine Kinase; CoATs: Cohesin Acetyltransferases; CTCF: CCCTC-Binding Factor; DDX11: DEAD/H-Box Helicase 11; ERG: Transcriptional Regulator ERG; ESCO2: Establishment of Sister Chromatid Cohesion N-Acetyltransferase 2; GJC1: Gap Junction Protein Gamma 1; H2A: Histone H2A; H3K4: Histone H3 Lysine 4; H3K9: Histone H3 Lysine 9; HCN4: Hyperpolarization Activated Cyclic Nucleotide Gated Potassium and Sodium Channel 4;p HDAC8: Histone deacetylases 8; HP1: Heterochromatin Protein 1; ICC: Interstitial Cells of Cajal; ICC-MP: Myenteric Plexus Interstitial cells of Cajal; ICC-DMP: Deep Muscular Plexus Interstitial cells of Cajal; If: Pacemaker Funny Current; IP3: Inositol trisphosphate; JNK: C-Jun N-Terminal Kinase; LDS: Loeys-Dietz Syndrome; LOAD: Late-Onset Alzheimer Disease; MAPK: Mitogen-Activated Protein Kinase; MAU: MAU Sister Chromatid Cohesion Factor; MFS: Marfan Syndrome; NIPBL: NIPBL, Cohesin Loading Factor; OCT4: Octamer-Binding Protein 4; P38: P38 MAP Kinase; PDA: Patent Ductus Arteriosus; PDS5: PDS5 Cohesin Associated Factor; P-H3: Phospho Histone H3; PLK1: Polo Like Kinase 1; POPDC1: Popeye Domain Containing 1; POPDC2: Popeye Domain Containing 2; PP2A: Protein Phosphatase 2; RAD21: RAD21 Cohesin Complex Component; RBS: Roberts Syndrome; REC8: REC8 Meiotic Recombination Protein; RNAP2: RNA polymerase II; SAN: Sinoatrial node; SCN5A: Sodium Voltage-Gated Channel Alpha Subunit 5; SEC: Super Elongation Complex; SGO1: Shogoshin-1; SMAD: SMAD Family Member; SMC1A: Structural Maintenance of Chromosomes 1A; SMC3: Structural Maintenance of Chromosomes 3; SNV: Single Nucleotide Variant; SOX2: SRY-Box 2; SOX17: SRY-Box 17; SSS: Sick Sinus Syndrome; STAG2: Cohesin Subunit SA-2; TADs: Topology Associated Domains; TBX: T-box transcription factors; TGF-β: Transforming Growth Factor β; TGFBR: Transforming Growth Factor β receptor; TOF: Tetralogy of Fallot; TREK1: TREK-1 K(+) Channel Subunit; VSD: Ventricular Septal Defect; WABS: Warsaw Breakage Syndrome; WAPL: WAPL Cohesin Release Factor.
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Affiliation(s)
- Jessica Piché
- Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Montréal, QC, Canada
| | - Patrick Piet Van Vliet
- Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Montréal, QC, Canada
- LIA (International Associated Laboratory), CHU Sainte-Justine, Montréal, QC, Canada
- LIA (International Associated Laboratory), INSERM, Marseille, U1251-13885, France
| | - Michel Pucéat
- LIA (International Associated Laboratory), CHU Sainte-Justine, Montréal, QC, Canada
- LIA (International Associated Laboratory), INSERM, Marseille, U1251-13885, France
- INSERM U-1251, MMG,Aix-Marseille University, Marseille, 13885, France
| | - Gregor Andelfinger
- Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Montréal, QC, Canada
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Kruszka P, Berger SI, Casa V, Dekker MR, Gaesser J, Weiss K, Martinez AF, Murdock DR, Louie RJ, Prijoles EJ, Lichty AW, Brouwer OF, Zonneveld-Huijssoon E, Stephan MJ, Hogue J, Hu P, Tanima-Nagai M, Everson JL, Prasad C, Cereda A, Iascone M, Schreiber A, Zurcher V, Corsten-Janssen N, Escobar L, Clegg NJ, Delgado MR, Hajirnis O, Balasubramanian M, Kayserili H, Deardorff M, Poot RA, Wendt KS, Lipinski RJ, Muenke M. Cohesin complex-associated holoprosencephaly. Brain 2019; 142:2631-2643. [PMID: 31334757 PMCID: PMC7245359 DOI: 10.1093/brain/awz210] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/15/2019] [Accepted: 05/22/2019] [Indexed: 12/16/2022] Open
Abstract
Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.
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Affiliation(s)
- Paul Kruszka
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Seth I Berger
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Valentina Casa
- Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands
| | - Mike R Dekker
- Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands
| | - Jenna Gaesser
- Department of Pediatrics, Division of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Karin Weiss
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ariel F Martinez
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - David R Murdock
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Raymond J Louie
- Greenwood Genetic Center, JC Self Research Institute of Human Genetics, Greenwood, SC, USA
| | - Eloise J Prijoles
- Greenwood Genetic Center, JC Self Research Institute of Human Genetics, Greenwood, SC, USA
| | - Angie W Lichty
- Greenwood Genetic Center, JC Self Research Institute of Human Genetics, Greenwood, SC, USA
| | - Oebele F Brouwer
- Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Evelien Zonneveld-Huijssoon
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Mark J Stephan
- Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Jacob Hogue
- Division of Clinical Genetics, Department of Pediatrics, Madigan Army Hospital, Tacoma, WA, USA
| | - Ping Hu
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Momoko Tanima-Nagai
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Joshua L Everson
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
- Molecular and Environmental Toxicology Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Chitra Prasad
- Children’s Health Research Institute, London, ON, Canada
| | - Anna Cereda
- Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Maria Iascone
- Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy
| | | | - Vickie Zurcher
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Nicole Corsten-Janssen
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Luis Escobar
- Peyton Manning Children’s Hospital at St. Vincent, Medical Genetics and Neurodevelopment Center, Indianapolis, IN, USA
| | - Nancy J Clegg
- Texas Scottish Rite Hospital for Children, Dallas, TX, USA
| | - Mauricio R Delgado
- Texas Scottish Rite Hospital for Children, Dallas, TX, USA
- Department of Neurology and Neurotherapeutics UT Southwestern Medical Center Dallas, TX, USA
| | - Omkar Hajirnis
- Pediatric Neurology, Synapses Child Neurology and Development Centre, Thane, Maharashtra, India
| | - Meena Balasubramanian
- Sheffield Clinical Genetics Service, Sheffield Children’s, NHS Foundation Trust, Sheffield, UK
- Academic Unit of Child Health, University of Sheffield, Sheffield, UK
| | - Hülya Kayserili
- Medical Genetics, Medical Faculty, Koç University, Istanbul, Turkey
| | - Matthew Deardorff
- The Division of Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- The Department of Pediatrics, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA
| | - Raymond A Poot
- Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands
| | - Kerstin S Wendt
- Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands
| | - Robert J Lipinski
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
- Molecular and Environmental Toxicology Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Maximilian Muenke
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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46
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Lindberg G. Pseudo-obstruction, enteric dysmotility and irritable bowel syndrome. Best Pract Res Clin Gastroenterol 2019; 40-41:101635. [PMID: 31594655 DOI: 10.1016/j.bpg.2019.101635] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 07/18/2019] [Indexed: 02/06/2023]
Abstract
New diagnostic techniques have advanced our knowledge about the irritable bowel syndrome. The majority of patients that we believed to have a psychosomatic disorder have received other diagnoses explaining their symptoms. Endoscopy makes it possible to diagnose celiac disease before it leads to malnutrition and allows the detection of microscopic colitis as a cause of watery diarrhea. At the severe end of the symptom spectrum enteric dysmotility marks the border at which IBS ceases to be a functional disorder and becomes a genuine motility disorder. Joint hypermobility or Ehlers-Danlos syndrome is present in a substantial proportion of patients with enteric dysmotility. Chronic intestinal pseudo-obstruction is the end-stage of a large number of very rare disorders in which failed peristalsis is the common denominator. Nutritional needs and symptom control are essential in the management of pseudo-obstruction. Home parenteral nutrition is life saving in more than half of patients with chronic intestinal pseudo-obstruction.
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Affiliation(s)
- Greger Lindberg
- Karolinska Institutet, Department of Medicine, Huddinge and Karolinska University Hospital Huddinge, Patient Area Gastroenterology, Dermatology, and Rheumatology, SE-14186, Stockholm, Sweden.
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47
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Hoefsmit EP, Rozeman EA, Haanen JBAG, Blank CU. Susceptible loci associated with autoimmune disease as potential biomarkers for checkpoint inhibitor-induced immune-related adverse events. ESMO Open 2019; 4:e000472. [PMID: 31423333 PMCID: PMC6677983 DOI: 10.1136/esmoopen-2018-000472] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 03/01/2019] [Accepted: 03/19/2019] [Indexed: 12/13/2022] Open
Abstract
Unprecedented successes regarding cancer immunotherapy have been achieved, in which therapeutic agents are used to target immune cells rather than cancer cells. The most effective immunotherapy to date is the group of immune checkpoint inhibitors (CPI), targeting, for example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death protein (PD-1). TThe combination of these therapies (anti-PD-1 with anti-CTLA-4) induces high response rates, and seem to be increased further when applied in early-stage disease. However, combined CTLA-4 plus PD-1 blockade causes frequent high-grade immune-related adverse events (irAE). To date, research on biological mechanism of irAEs is scarce and no widely accepted biomarkers predicting onset of severe irAEs have been identified. The similarity of irAEs to autoimmune disorders fuels the hypothesis that irAEs may be linked to susceptible genetic loci related to various autoimmune diseases. In this review, we extensively searched for susceptible loci associated with various autoimmune diseases, and pooled them in groups most likely to be associated with CPI-induced irAEs. These sets could be used in future research on predicting irAEs and guide physicians in a more refined and personal manner.
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Affiliation(s)
- Esmée P Hoefsmit
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Elisa A Rozeman
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Medical Oncology Department, Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands
| | - John B A G Haanen
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Medical Oncology Department, Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands
| | - Christian U Blank
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Medical Oncology Department, Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands
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48
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Moore-Morris T, van Vliet PP, Andelfinger G, Puceat M. Role of Epigenetics in Cardiac Development and Congenital Diseases. Physiol Rev 2019; 98:2453-2475. [PMID: 30156497 DOI: 10.1152/physrev.00048.2017] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The heart is the first organ to be functional in the fetus. Heart formation is a complex morphogenetic process regulated by both genetic and epigenetic mechanisms. Congenital heart diseases (CHD) are the most prominent congenital diseases. Genetics is not sufficient to explain these diseases or the impact of them on patients. Epigenetics is more and more emerging as a basis for cardiac malformations. This review brings the essential knowledge on cardiac biology of development. It further provides a broad background on epigenetics with a focus on three-dimensional conformation of chromatin. Then, we summarize the current knowledge of the impact of epigenetics on cardiac cell fate decision. We further provide an update on the epigenetic anomalies in the genesis of CHD.
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Affiliation(s)
- Thomas Moore-Morris
- Université Aix-Marseille, INSERM UMR- 1251, Marseille , France ; Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal, Quebec , Canada ; Université de Montréal, Montreal, Quebec , Canada ; and Laboratoire International Associé INSERM, Marseille France-CHU Ste Justine, Quebec, Canada
| | - Patrick Piet van Vliet
- Université Aix-Marseille, INSERM UMR- 1251, Marseille , France ; Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal, Quebec , Canada ; Université de Montréal, Montreal, Quebec , Canada ; and Laboratoire International Associé INSERM, Marseille France-CHU Ste Justine, Quebec, Canada
| | - Gregor Andelfinger
- Université Aix-Marseille, INSERM UMR- 1251, Marseille , France ; Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal, Quebec , Canada ; Université de Montréal, Montreal, Quebec , Canada ; and Laboratoire International Associé INSERM, Marseille France-CHU Ste Justine, Quebec, Canada
| | - Michel Puceat
- Université Aix-Marseille, INSERM UMR- 1251, Marseille , France ; Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal, Quebec , Canada ; Université de Montréal, Montreal, Quebec , Canada ; and Laboratoire International Associé INSERM, Marseille France-CHU Ste Justine, Quebec, Canada
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49
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Nelson D, Moreau C, de Vriendt M, Zeng Y, Preuss C, Vézina H, Milot E, Andelfinger G, Labuda D, Gravel S. Inferring Transmission Histories of Rare Alleles in Population-Scale Genealogies. Am J Hum Genet 2018; 103:893-906. [PMID: 30526866 DOI: 10.1016/j.ajhg.2018.10.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 10/22/2018] [Indexed: 01/06/2023] Open
Abstract
Learning the transmission history of alleles through a family or population plays an important role in evolutionary, demographic, and medical genetic studies. Most classical models of population genetics have attempted to do so under the assumption that the genealogy of a population is unavailable and that its idiosyncrasies can be described by a small number of parameters describing population size and mate choice dynamics. Large genetic samples have increased sensitivity to such modeling assumptions, and large-scale genealogical datasets become a useful tool to investigate realistic genealogies. However, analyses in such large datasets are often intractable using conventional methods. We present an efficient method to infer transmission paths of rare alleles through population-scale genealogies. Based on backward-time Monte Carlo simulations of genetic inheritance, we use an importance sampling scheme to dramatically speed up convergence. The approach can take advantage of available genotypes of subsets of individuals in the genealogy including haplotype structure as well as information about the mode of inheritance and general prevalence of a mutation or disease in the population. Using a high-quality genealogical dataset of more than three million married individuals in the Quebec founder population, we apply the method to reconstruct the transmission history of chronic atrial and intestinal dysrhythmia (CAID), a rare recessive disease. We identify the most likely early carriers of the mutation and geographically map the expected carrier rate in the present-day French-Canadian population of Quebec.
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50
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Pisani FM, Napolitano E, Napolitano LMR, Onesti S. Molecular and Cellular Functions of the Warsaw Breakage Syndrome DNA Helicase DDX11. Genes (Basel) 2018; 9:genes9110564. [PMID: 30469382 PMCID: PMC6266566 DOI: 10.3390/genes9110564] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 11/17/2018] [Accepted: 11/19/2018] [Indexed: 12/23/2022] Open
Abstract
DDX11/ChlR1 (Chl1 in yeast) is a DNA helicase involved in sister chromatid cohesion and in DNA repair pathways. The protein belongs to the family of the iron–sulphur cluster containing DNA helicases, whose deficiencies have been linked to a number of diseases affecting genome stability. Mutations of human DDX11 are indeed associated with the rare genetic disorder named Warsaw breakage syndrome, showing both chromosomal breakages and chromatid cohesion defects. Moreover, growing evidence of a potential role in oncogenesis further emphasizes the clinical relevance of DDX11. Here, we illustrate the biochemical and structural features of DDX11 and how it cooperates with multiple protein partners in the cell, acting at the interface of DNA replication/repair/recombination and sister chromatid cohesion to preserve genome stability.
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Affiliation(s)
- Francesca M Pisani
- Istituto di Biochimica delle Proteine, Consiglio Nazionale delle Ricerche, Via P. Castellino, 111, 80131 Napoli, Italy.
| | - Ettore Napolitano
- Istituto di Biochimica delle Proteine, Consiglio Nazionale delle Ricerche, Via P. Castellino, 111, 80131 Napoli, Italy.
| | - Luisa M R Napolitano
- Elettra⁻Sincrotrone Trieste S.C.p.A., AREA Science Park Basovizza, 34149 Trieste, Italy.
| | - Silvia Onesti
- Elettra⁻Sincrotrone Trieste S.C.p.A., AREA Science Park Basovizza, 34149 Trieste, Italy.
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