| Title: |
Isolated prolapse of the posterior mitral valve leaflet: phenotypic refinement, heritability and genetic etiology |
| Authors: |
Rimbert, Antoine; Duval, Damien; Trujillano, Daniel; Kyndt, Florence; Jobbé-Duval, Antoine; Lindenbaum, Pierre; Tucker, Nathan; Lecointe, Simon; Labbé, Pauline; Toquet, Claire; Karakachoff, Matilde; Roussel, Jean-Christian; Baufreton, Christophe; Bruneval, Patrick; Cueff, Caroline; Donal, Erwan; Redon, Richard; Olaso, Robert; Boland, Anne; Deleuze, Jean-François; Estivill, Xavier; Slaugenhaupt, Susan; Markwald, Roger; Norris, Russel; Verhoye, Jean-Philippe; Probst, Vincent; Hagège, Albert; Levine, Robert; Jeunemaitre, Xavier; Marec, Hervé Le; Capoulade, Romain; Bouatia-Naji, Nabila; Dina, Christian; Milan, David; Ossowski, Stephan; Schott, Jean-Jacques; Mérot, Jean; Scouarnec, Solena Le; Le Tourneau, Thierry |
| Contributors: |
ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX-lab); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE); Nantes Université - pôle Santé; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ); Centre Hospitalier Universitaire de Nantes = Nantes University Hospital (CHU Nantes); Centre Hospitalier Universitaire d'Angers (CHU Angers); PRES Université Nantes Angers Le Mans (UNAM); Centre for Genomic Regulation - Centre de Regulació Genòmica Barcelona (CRG); Universitat Pompeu Fabra Barcelona (UPF)-Centro Nacional de Analisis Genomico Barcelona (CNAG); Universitat Pompeu Fabra Barcelona (UPF); Hospital del Mar Medical Research Institute Barcelona, Spain (IMIM); Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública = Consortium for Biomedical Research of Epidemiology and Public Health (CIBERESP); MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC); Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Hôpital Européen Georges Pompidou APHP (HEGP); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO); Centre Hospitalier Universitaire de Rennes CHU Rennes = Rennes University Hospital Pontchaillou; Laboratoire Traitement du Signal et de l'Image (LTSI); Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM); CIC-IT Rennes; Centre Hospitalier Universitaire de Rennes CHU Rennes = Rennes University Hospital Pontchaillou -Institut National de la Santé et de la Recherche Médicale (INSERM); Centre National de Recherche en Génomique Humaine (CNRGH); Institut de Biologie François JACOB (JACOB); Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA); Medical University of South Carolina Charleston (MUSC); Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); Massachusetts General Hospital Boston; Eberhard Karls Universität Tübingen = University of Tübingen |
| Source: |
https://hal.science/hal-04751125 ; 2024. |
| Publisher Information: |
HAL CCSD |
| Publication Year: |
2024 |
| Collection: |
Université de Rennes 1: Publications scientifiques (HAL) |
| Subject Terms: |
PostMVP; inheritance; genetics; FilGAP; mechano-transduction; [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system; [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics |
| Description: |
International audience ; BACKGROUND: Isolated posterior leaflet mitral valve prolapse (PostMVP), a common form of MVP, often referred as fibroelastic deficiency, is considered a degenerative disease. PostMVP patients are usually asymptomatic and often undiagnosed until chordal rupture. The present study aims to characterize familial PostMVP phenotype and familial recurrence, its genetic background, and the pathophysiological processes involved.METHODS: We prospectively enrolled 284 unrelated MVP probands, of whom 178 (63%) had bi-leaflet MVP and 106 had PostMVP (37%). Familial screening within PostMVP patients allowed the identification of 20 families with inherited forms of PostMVP for whom whole genome sequencing was carried out in probands. Functional in vivo and in vitro investigations were performed in zebrafishand in Hek293T cells.RESULTS: In the 20 families with inherited form of PostMVP, 38.8% of relatives had a MVP/prodromal form, mainly of the posterior leaflet, with transmission consistent with an autosomal dominant mode of inheritance. Compared with control relatives, PostMVP family patients have clear posterior leaflet dystrophy on echocardiography. Patients with PostMVP present a burden of rare genetic variants in ARHGAP24. ARHGAP24 encodes the filamin A binding RhoGTPase-activating protein FilGAP and its silencing in zebrafish leads to atrioventricular regurgitation. In vitro functional studies showed that variants of FilGAP, found in PostMVP families, are loss-of-function variants impairing cellular adhesion and mechano-transduction capacities. CONCLUSIONS PostMVP should not only be considered an isolated degenerative pathology but as a specific heritable phenotypic trait with genetic and functional pathophysiological origins. The identification of loss-of-function variants in ARHGAP24 further reinforces the pivotal role of mechano-transduction pathways in the pathogenesis of MVP.CLINICAL PERSPECTIVE Isolated posterior mitral valve prolapse (PostMVP), often called fibro-elastic deficiency MVP, is ... |
| Document Type: |
report |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/39484266; MEDRXIV: 2024.10.16.24315096; PUBMED: 39484266; PUBMEDCENTRAL: PMC11527059 |
| DOI: |
10.1101/2024.10.16.24315096 |
| Availability: |
https://hal.science/hal-04751125; https://hal.science/hal-04751125v1/document; https://hal.science/hal-04751125v1/file/2024.10.16.24315096v1.full.pdf; https://doi.org/10.1101/2024.10.16.24315096 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.184730D4 |
| Database: |
BASE |