Dataset Information

Primary cilia defects causing mitral valve prolapse.

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.

SUBMITTER: Toomer KA

PROVIDER: S-EPMC7331025 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Primary cilia defects causing mitral valve prolapse.

Toomer Katelynn A KA Yu Mengyao M Fulmer Diana D Guo Lilong L Moore Kelsey S KS Moore Reece R Drayton Ka'la D KD Glover Janiece J Peterson Neal N Ramos-Ortiz Sandra S Drohan Alex A Catching Breiona J BJ Stairley Rebecca R Wessels Andy A Lipschutz Joshua H JH Delling Francesca N FN Jeunemaitre Xavier X Dina Christian C Collins Ryan L RL Brand Harrison H Talkowski Michael E ME Del Monte Federica F Mukherjee Rupak R Awgulewitsch Alexander A Body Simon S Hardiman Gary G Hazard E Starr ES da Silveira Willian A WA Wang Baolin B Leyne Maire M Durst Ronen R Markwald Roger R RR Le Scouarnec Solena S Hagege Albert A Le Tourneau Thierry T Kohl Peter P Rog-Zielinska Eva A EA Ellinor Patrick T PT Levine Robert A RA Milan David J DJ Schott Jean-Jacques JJ Bouatia-Naji Nabila N Slaugenhaupt Susan A SA Norris Russell A RA

Science translational medicine 20190501 493

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 de ...[more]

PMID: 31118289

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Project description:BackgroundInitial studies have suggested the familial clustering of mitral valve prolapse, but most of them were either community based among unselected individuals or applied non-specific diagnostic criteria. Therefore little is known about the familial distribution of mitral regurgitation in a referral-type population with a more severe mitral valve prolapse phenotype. The objective of this study was to evaluate the presence of familial mitral regurgitation in patients undergoing surgery for mitral valve prolapse, differentiating patients with Barlow's disease, Barlow forme fruste and fibro-elastic deficiency.MethodsA total of 385 patients (62 ± 12 years, 63% men) who underwent surgery for mitral valve prolapse were contacted to assess cardiac family history systematically. Only the documented presence of mitral regurgitation was considered to define 'familial mitral regurgitation'. In the probands, the aetiology of mitral valve prolapse was defined by surgical observations.ResultsA total of 107 (28%) probands were classified as having Barlow's disease, 85 (22%) as Barlow forme fruste and 193 (50%) patients as fibro-elastic deficiency. In total, 51 patients (13%) reported a clear family history for mitral regurgitation; these patients were significantly younger, more often diagnosed with Barlow's disease and also reported more sudden death in their family as compared with 'sporadic mitral regurgitation'. In particular, 'familial mitral regurgitation' was reported in 28 patients with Barlow's disease (26%), 15 patients (8%) with fibro-elastic deficiency and eight (9%) with Barlow forme fruste (P < 0.001).ConclusionsIn a large cohort of patients operated for mitral valve prolapse, the self-reported prevalence of familial mitral regurgitation was 26% in patients with Barlow's disease and still 8% in patients with fibro-elastic deficiency, highlighting the importance of familial anamnesis and echocardiographic screening in all mitral valve prolapse patients.

Dataset Information

Primary cilia defects causing mitral valve prolapse.

Publications

Primary cilia defects causing mitral valve prolapse.

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