title: Mutations in DCHS1 cause mitral valve prolapse.
abstract: Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1(+/-) mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1(+/-) mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.|Cardiology Division, Hadassah Hebrew University Medical Center, POB 12000 Jerusalem, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Durst
authors.affiliation: Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Sauls
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Peal
authors.affiliation: Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA.
authors.forename: Annemarieke
authors.initials: A
authors.lastname: deVlaming
authors.affiliation: Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA.
authors.forename: Katelynn
authors.initials: K
authors.lastname: Toomer
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.
authors.forename: Maire
authors.initials: M
authors.lastname: Leyne
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Salani
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.|Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.|Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Harrison
authors.initials: H
authors.lastname: Brand
authors.affiliation: INSERM, UMR-970, Paris Cardiovascular Research Center, 75015 Paris, France.
authors.forename: Maëlle
authors.initials: M
authors.lastname: Perrocheau
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Simpson
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Jett
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Stone
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.
authors.forename: Florie
authors.initials: F
authors.lastname: Charles
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.
authors.forename: Colby
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authors.affiliation: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Stacey N
authors.initials: SN
authors.lastname: Lynch
authors.affiliation: INSERM, UMR-970, Paris Cardiovascular Research Center, 75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, 75006 Paris, France.
authors.forename: Nabila
authors.initials: N
authors.lastname: Bouatia-Naji
authors.affiliation: Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Francesca N
authors.initials: FN
authors.lastname: Delling
authors.affiliation: Yale-New Haven Hospital Heart and Vascular Center, Yale School of Medicine, 20 York Street, New Haven, Connecticut 06510, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Freed
authors.affiliation: Department of Cardiology, University Hospital Amiens; INSERM U-1088, Jules Verne University of Picardie, 80000 Amiens, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Tribouilloy
authors.affiliation: Inserm U1087; Institut du Thorax; University Hospital, 44007 Nantes, France.
authors.forename: Thierry
authors.initials: T
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authors.affiliation: Inserm U1087; Institut du Thorax; University Hospital, 44007 Nantes, France.
authors.forename: Hervé
authors.initials: H
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authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), 28029 Madrid, Spain.|Hospital Universitario Monteprincipe, 28660 Madrid, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Fernandez-Friera
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), 28029 Madrid, Spain.|Hospital Universitario Monteprincipe, 28660 Madrid, Spain.
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authors.initials: J
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authors.affiliation: Genetic Causes of Disease Group, Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain.|Universitat Pompeu Fabra (UPF), 08002 Barcelona, Catalonia, Spain.|Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Catalonia, Spain.|CIBER in Epidemiology and Public Health (CIBERESP), 08036 Barcelona, Catalonia, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Trujillano
authors.affiliation: Universitat Pompeu Fabra (UPF), 08002 Barcelona, Catalonia, Spain.|Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain.
authors.forename: Stephan
authors.initials: S
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authors.affiliation: Genetic Causes of Disease Group, Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain.|Universitat Pompeu Fabra (UPF), 08002 Barcelona, Catalonia, Spain.|Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Catalonia, Spain.|CIBER in Epidemiology and Public Health (CIBERESP), 08036 Barcelona, Catalonia, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.affiliation: Inserm U1087; Institut du Thorax; University Hospital, 44007 Nantes, France.|CNRS, UMR 6291, 44007 Nantes, France.|Université de Nantes, 44322 Nantes, France.|CHU Nantes, l'Institut du Thorax, Service de Cardiologie, 44093 Nantes, France.
authors.forename: Christian
authors.initials: C
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authors.affiliation: Service d'Anatomie Pathologique, Hôpital Européen Georges Pompidou, 75015 Paris, France.
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authors.initials: P
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authors.affiliation: National Heart and Lung Institute, Harefield, Heart Science Centre, Imperial College London, London SW7 2AZ, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Chester
authors.affiliation: Inserm U1087; Institut du Thorax; University Hospital, 44007 Nantes, France.|CNRS, UMR 6291, 44007 Nantes, France.|Université de Nantes, 44322 Nantes, France.|CHU Nantes, l'Institut du Thorax, Service de Cardiologie, 44093 Nantes, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.affiliation: Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, USA.
authors.forename: Kenneth D
authors.initials: KD
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authors.affiliation: Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, USA.
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authors.initials: Y
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authors.affiliation: Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA.
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authors.affiliation: Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA.
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authors.affiliation: INSERM UMR_S910, Team physiopathology of cardiac development Aix-Marseille University, Medical School La Timone, 13885 Marseille, France.
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authors.affiliation: Department of Cellular and Molecular Biology, University of Texas Health Science Center Northeast Tyler, Texas75708, USA.
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authors.affiliation: Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
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authors.initials: DR
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authors.affiliation: Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
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authors.initials: H
authors.lastname: Kasiganesan
authors.affiliation: Department of Radiology and Radiological Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
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authors.affiliation: Department of Radiology and Radiological Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
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authors.initials: AM
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authors.affiliation: Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA.
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authors.affiliation: Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA.
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authors.affiliation: Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA.
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authors.initials: RR
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authors.affiliation: INSERM, UMR-970, Paris Cardiovascular Research Center, 75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, 75006 Paris, France.|Assistance Publique - Hôpitaux de Paris, Département de Génétique, Hôpital Européen Georges Pompidou, 75015 Paris, France.
authors.forename: Xavier
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authors.affiliation: INSERM, UMR-970, Paris Cardiovascular Research Center, 75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, 75006 Paris, France.|Assistance Publique - Hôpitaux de Paris, Département de Cardiologie, Hôpital Européen Georges Pompidou, 75015 Paris, France.
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authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, 75006 Paris, France.|Cardiac Ultrasound Laboratory, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Robert A
authors.initials: RA
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authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.|Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: David J
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authors.affiliation: Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Norris
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.
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mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008943:Mitral Valve / Q000002:abnormalities / Q000196:embryology / Q000473:pathology / Q000601:surgery; D008945:Mitral Valve Prolapse / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000070585:Cadherin Related Proteins; D015820:Cadherins; D012333:RNA, Messenger; D029961:Zebrafish Proteins; C442479:DCHS1 protein, human; C000601556:DCHS1b protein, zebrafish; C506554:Dchs1 protein, mouse