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Sci Transl Med. 2019 May 22;11(493). pii: eaax0290. doi: 10.1126/scitranslmed.aax0290.

Primary cilia defects causing mitral valve prolapse.

Author information

1
Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, College of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA.
2
INSERM, UMR-970, Paris Cardiovascular Research Center, 75015 Paris, France.
3
Paris Descartes University, Sorbonne Paris Cité, Faculty of Medicine, 75006 Paris, France.
4
Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
5
Department of Medicine, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, USA.
6
Department of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143, USA.
7
Assistance Publique-Hôpitaux de Paris, Département de Génétique, Hôpital Européen Georges Pompidou, 75015 Paris, France.
8
INSERM, CNRS, Univ Nantes, L'Institut du Thorax, Nantes 44093, France.
9
CHU Nantes, L'Institut du Thorax, Service de Cardiologie, Nantes 44093, France.
10
Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, 185 Cambridge St., Boston, MA 02114, USA.
11
Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
12
Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
13
Center for Genomic Medicine, Medical University of South Carolina, 135 Cannon Street, Suite 303 MSC 835, Charleston, SC 29425, USA.
14
Faculty of Medicine, Health and Life Sciences School of Biological Sciences, Institute for Global Food Security (IGFS), Queen's University Belfast, Belfast, Northern Ireland, BT7 1NN, UK.
15
Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
16
Cardiology Division, Hadassah Hebrew University Medical Center, POB 12000, Jerusalem, Israel.
17
Assistance Publique-Hôpitaux de Paris, Department of Cardiology, Hôpital Européen Georges Pompidou, 75015 Paris, France.
18
University Heart Center Freiburg, Bad Krozingen and Faculty of Medicine of the Albert-Ludwigs University Freiburg, Institute for Experimental Cardiovascular Medicine, Elsässerstr 2Q, 79110 Freiburg, Germany.
19
Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital Research Institute, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
20
Cardiac Ultrasound Laboratory, Cardiology Division, Massachusetts General Hospital Research Institute, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
21
Leducq Foundation, 265 Franklin Street, Suite 1902, Boston, MA, 02110, USA.
22
Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, College of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA. norrisra@musc.edu.

Abstract

Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the causes of this disease are poorly understood. We now demonstrate that defects in primary cilia genes and their regulated pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene, DZIP1 A mouse model harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with MVP and controls from previously generated genome-wide association studies (GWAS), which confirmed the involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP through altered cilia-dependent regulation of ECM and suggest that defects in primary cilia genes can be causative to disease phenotype in some patients with MVP.

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