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Updated: Jan 24, 2026
Using Primary Neurosphere Cultures to Study Primary Cilia
Published on: April 14, 2017
Primary cilia defects causing mitral valve prolapse
Katelynn A Toomer1, Mengyao Yu2,3, Diana Fulmer1
1Cardiovascular 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.
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.
Insights
Defects in primary cilia genes cause mitral valve prolapse (MVP), a common heart condition. This study reveals primary cilia
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Genetics
Background:
- Mitral valve prolapse (MVP) affects 1 in 40 individuals and is a leading cause of mitral valve surgery.
- The underlying causes of MVP, which can lead to arrhythmias, heart failure, and sudden cardiac death, remain poorly understood.
- Primary cilia are crucial cellular organelles whose role in MVP pathogenesis has not been previously established.
Purpose of the Study:
- To investigate the role of primary cilia genes and their associated pathways in the etiology of familial and sporadic nonsyndromic mitral valve prolapse.
- To elucidate the developmental mechanisms by which primary cilia influence mitral valve structure and function.
Main Methods:
- Expression studies and genetic ablation experiments in model systems to assess primary cilia function during cardiac development.
- Analysis of a large family with inherited MVP to identify causative genetic mutations.
- Generation and characterization of a mouse model harboring a specific cilia gene mutation.
- Pathway enrichment analysis of genome-wide association study (GWAS) data from MVP patients and controls.
Main Results:
- Primary cilia are essential for regulating extracellular matrix (ECM) deposition during cardiac development.
- Loss of primary cilia function leads to progressive myxomatous degeneration and severe mitral valve pathology in adult models.
- A mutation in the cilia gene DZIP1 was identified in a family with inherited MVP, and a mouse model confirmed its pathogenicity and association with myxomatous valve disease.
- GWAS data analysis confirmed the significant involvement of primary cilia genes in common forms of MVP.
Conclusions:
- Primary cilia play a critical role in the developmental regulation of the mitral valve through cilia-dependent ECM control.
- Defects in primary cilia genes represent a novel causative factor for mitral valve prolapse in both familial and sporadic cases.
- This research establishes a new developmental etiology for MVP, highlighting primary cilia as potential therapeutic targets.
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