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Cilia Defects During Fetal Development Can Cause Mitral Valve Prolapse

Key findings

  • A specific mutation in the cilia gene DZIP1 was identified in a large family with inherited, autosomal dominant nonsyndromic mitral valve prolapse (MVP)
  • Analyses of a genome-wide association study dataset and a mouse model of mitral valve prolapse MVP indicated that cilia defects can cause MVP
  • Primary cilia are increasingly recognized to be molecular regulators of cardiac development
  • In knock-in mice that had the DZIP1 mutation, altered developmental processes involving primary cilia resulted in MVP
  • Better understanding of the function of primary cilia may lead to novel treatments for MVP

Until recently, some thought that primary (immotile) cilia are evolutionary remnants that no longer have any function. However, mutations in cilia genes have now been linked to a spectrum of syndromic diseases that can involve cardiac, renal, skeletal or neurologic tissues. A classic example of these "ciliopathies" is autosomal dominant polycystic kidney disease, in which it has been reported that about 25% of patients have mitral valve prolapse (MVP) at a rate 10 times higher than usual. Furthermore, MVP is congenital, and patients have molecular changes that culminate in tissue overgrowth, which interferes with the function of both mitral valves and kidneys.

Robert A. Levine, MD, senior physician in the Cardiac Ultrasound Laboratory, David J. Milan, MD, cardiologist and cardiac electrophysiologist in the Division of Cardiology, and Susan A. Slaugenhaupt, PhD, scientific director of the Massachusetts General Hospital Research Institute, are senior members of an international research collaborative that published a study in Nature on the genetic variants that cause MVP. Because of the reported comorbidity of MVP with autosomal dominant polycystic kidney disease, they wondered whether cilia gene defects play a role in MVP. This also reflects the work of colleagues in the Mass General-based Leducq Transatlantic MITRAL network, especially Russell Norris, PhD, a developmental biologist at the Medical University of South Carolina.

In Science Translational Medicine, the team reports that defects in primary cilia genes and their regulated pathways can cause nonsyndromic MVP in both familial and sporadic cases.

Three Approaches

Consulting a genome-wide association study published in Nature Genetics, the research team analyzed 278 genes that are implicated in primary cilia biology. They found that MVP-associated variants were overrepresented in that set of genes.

Next, the team evaluated two genes known to be associated with nonsyndromic MVP, DCHS1 and FLNA. In mice that had those genes knocked out, the length of primary cilia in mitral valves was significantly reduced, suggesting that cilia have a role in causing MVP.

In Circulation, the international team then looked back at three generations of a family that has inherited autosomal dominant MVP, which the team previously linked to an 8.2 Mb region of chromosome 13. Re-examination showed that DZIP1, a gene known to regulate ciliogenesis and/or cilia signaling, is located within that region.

Whole-exome sequencing of four affected family members revealed a serine-to-arginine variant in both known DZIP1 isoforms. Rare, potentially pathogenic DZIP1 variants were also found in two of 15 patients who had sporadic MVP.

Developmental Etiology for MVP

These findings prompted the researchers to create a genetically accurate model of nonsyndromic MVP. Using CRISPR-Cas9, they generated knock-in mice that have DzipS14R/+, the mouse version of the genetic mutation that was identified in the large family. They observed that adult mice harboring this single mutation developed myxomatous mitral valves and functional MVP, whereas MVP was never observed in wild-type animals.

The researchers found evidence that defects of cilia formation occur during fetal development, including:

  • 100% of newborn knock-in mice had reduced cilia length compared with littermate controls
  • On day 13 of life, the most significant differences in the hearts of knock-in mice compared with controls related to the composition of the extracellular matrix
  • When Dzip was removed from mitral valve progenitor cells of mice, there was a reduction in primary cilia length during development and concomitant anatomical change in the valves

An Enigma

How can a developmental defect give rise to pathology that isn't recognized until the adult years? The researchers propose that the altered developmental processes result in changes in valve geometry and biomechanics, which induce secondary factors such as inflammation that contribute to tissue destruction over time.

Just how those secondary factors arise is currently unknown. By using the models they generated, the researchers hope to uncover pathogenic mechanisms and disease pathways that will lead to additional treatment options for MVP.

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Robert Levine, MD, is a senior physician in Mass General's Cardiac Ultrasound Lab and was recently named an AHA Distinguished Scientist. In this video, he discusses his team's focus on discovering the genes causing mitral valve prolapse, the most common cause for operation for mitral regurgitation.