Research ArticleCardiovascular Disease

Primary cilia defects causing mitral valve prolapse

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Science Translational Medicine  22 May 2019:
Vol. 11, Issue 493, eaax0290
DOI: 10.1126/scitranslmed.aax0290

DZIPping along to diagnosis

Mitral valve prolapse is a common congenital abnormality that can cause severe complications. By combining studies of mitral valve development in mice with human genetic data, Toomer et al. found that mitral valve prolapse can be caused by abnormal cilia function. The authors tracked mitral valve development in mice from fetal life to adulthood and also performed genetic analysis of human patients with mitral valve prolapse, particularly one family with an inherited form of the disease. The affected members of this family had a mutation in DZIP1, a gene that regulates ciliogenesis, and mice with this mutation also developed mitral valve prolapse, supporting its pathogenic nature.


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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