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.

LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is altered in Townes-Brocks Syndrome

“…Furthermore, LUZP1 shows homology to FILIP1, a protein interactor of FLNA and actin (21, 22). Interestingly, mutations in Luzp1 resulted in cardiovascular defects and cranial NTD in mice (23), phenotypes within the spectrum of those seen in TBS individuals and mouse models of dysfunctional cilia, respectively (16, 17, 24–27). LUZP1 was found to be mainly localized to the nuclei of brain neurons in mice and to have a crucial role in embryonic brain development (23, 28, 29).…”

Dynamic Expression Profiles of β-Catenin during Murine Cardiac Valve Development

“…It remains possible that β-catenin is interacting with other TCF factors within the heart. Indeed, our RNAseq datasets demonstrate that each of the other TCF factors (TCF7, TCF7L1 and TCF7L2) are expressed within the mitral valve at P0 and whole heart at E13.5, although Lef1 is the highest expressed, based on transcript counts [ 80 ]. Future studies should reveal whether these additional factors are co-expressed and interact with β-catenin and are needed to activate or repress target gene transcription.…”

Tugging at the Heart Strings: The Septin Cytoskeleton in Heart Development and Disease

“…Cilia defects during embryogenesis have been shown to disrupt the left-right asymmetry and result in congenital heart defects [36]. Additionally, loss of cilia was shown to result in abnormalities in aortic and mitral valve architecture and contributed to mitral valve prolapse disease phenotypes in humans and mice [31][32][33]. The latter findings were based on mutations discovered in patients and support the necessity for cilia in cardiovascular development.…”

“…Cilia, specifically non-motile primary cilia, were first identified in nonmitotic cardiomyocytes in 1969 via electron microscopy of chick, rabbit, mouse, and lizard embryonic hearts [28]. Since then, cilia have been found throughout the mammalian embryonic heart tube, the atria and trabeculated myocardium [29], in the endocardium and endocardially derived mesenchymal cells [30][31][32][33], and in the epicardium [34]. By adulthood, however, much less is known about cell-types that express primary cilia.…”

“…By adulthood, however, much less is known about cell-types that express primary cilia. Two recent reports have demonstrated that they are persistent on cardiac fibroblasts yet absent on most other cell types [31,35], suggesting they likely play a role during development and in adult ventricular homeostasis. Cilia defects during embryogenesis have been shown to disrupt the left-right asymmetry and result in congenital heart defects [36].…”