The causes of mitral valve prolapse (MVP), a common congenital defect that can lead to arrhythmias, heart failure and sudden cardiac death, are not well understood. A new study now reveals that this condition can be caused by defects in primary cilia. Primary cilia are microtubule-based structures that project from the cell and function as sensory organelles and signalling platforms. Toomer et al. show that mutations in genes associated with primary cilia development and cilia-regulated signalling can cause familial and sporadic nonsyndromic MVP.
First, the researchers studied the involvement of primary cilia in cardiac valve development in mice. They found that these structures varied spatially and temporally during vavulogenesis, mostly disappearing from valve cells after birth, and that primary cilia regulated extracellular matrix (ECM) deposition in valve development. Loss of primary cilia in mice caused valve developmental defects characterized by ECM expansion and altered tissue architecture that led to MVP in adulthood.
Next, Toomer et al. assessed the involvement of primary cilia gene mutations in patients with MVP by performing a gene-set enrichment analysis in a cohort of patients from previous genome-wide association studies. They observed a significant enrichment of MVP-associated variants in the cilia gene set. Further genetic analysis of a large family with inherited, autosomal dominant, nonsyndromic MVP identified a deleterious missense mutation in DZIP1, which encodes a protein involved in the regulation of ciliogenesis and cilia signalling. The pathogenicity of the DZIP1 variant was then confirmed in mice; mice harbouring the DZIP1 familial mutation had impaired ciliogenesis during development that progressed to MVP in adulthood.
Together, these findings reveal a developmental basis for MVP, caused by altered primary cilia-mediated regulation of ECM deposition, and suggest that mutations in primary cilia genes can be the cause of MVP in some patients.
Toomer, K. A. et al. Primary cilia defects causing mitral valve prolapse. Sci. Transl Med. 11, eaax0290 (2019)
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Fernández-Ruiz, I. Cilia defects linked to mitral valve prolapse. Nat Rev Cardiol 16, 456 (2019). https://doi.org/10.1038/s41569-019-0231-0