Mitral valve prolapse (MVP) is a common congenital abnormality of the heart that can cause severe complications such as arrhythmias, heart failure, and sudden cardiac death. To date, the causes of MVP are poorly understood. A collaborative research group has recently shown, by combining studies of mitral valve development in mice with human genetic data, that MVP can be caused by abnormal cilia function.

The work, which tracked mitral valve development in mice from fetal life to adulthood and also performed genetic analysis of human patients with MVP, particularly one family with an inherited form of the disease, is published in Science Translational Medicine in a paper titled “Primary cilia defects causing mitral valve prolapse

The research group was established several years ago to identify genetic variants that cause MVP. The researchers noted that each of the genes they had identified could be linked to a pathway involving primary cilia. This led them to test whether removing cilia in mice would cause something like MVP. “We thought that if we took out the cilia in heart valve cells, then the mice should develop the same disease. And that turned out to be the case,” asserted Russell A. Norris, PhD, associate professor of medicine in the department of regenerative medicine and cell biology at the Medical University of South Carolina (MUSC) and senior author on the paper.

Russell A. Norris, PhD

Next, the team looked at a multigenerational family with a history of MVP to see if there was additional evidence for a causative role for cilia in 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 MVP, supporting its pathogenic nature. Norris added that, “through many years of study we were able to identify a causative gene in this family, which ended up being a cilia gene.”

The mutations cause defects in primary cilia that previously had no known function in the heart valves. “These tiny structures are really important in establishing how the heart valve develops in utero,” said Norris.

To further support that finding, they developed a mouse model of MVP. The team used CRISPR CAS-9 technology to “knock in” the genetic mutation identified in the large family. “We knocked in the mutation, and it fully recapitulated the phenotypic spectrum of the disease and impaired formation of primary cilia during development,” said Norris. “These mice were quite beneficial in that they confirmed that mitral valve prolapse could be caused by a defect in cilia formation during embryonic development.”

Finally, the research team used an existing dataset from a previously conducted genome-wide association study, in which they looked at 300 known cilia genes to see if there was an association between the variants and MVP. “We found that there was an increased prevalence of cilia gene variants in the mitral valve prolapse population,” said Norris.

Norris now hopes to use the unique mouse model the team has developed to better understand the temporal progression of the disease. “Mitral valve disease is most commonly seen when somebody in their fifties or sixties,” explained Norris. “Yet, all of these genes that we’ve identified that cause mitral valve prolapse do not appear to be expressed in the adult. So how can a developmental error result in an adult pathology?”

MVP can be present early but is clinically benign and not likely to present with any symptoms. The disease can take decades to become clinically relevant and represents a slow degeneration of the tissue. Possibly contributing to that degeneration are changes in the geometry of heart tissues and valve anatomy that cause secondary defects. Norris hopes to begin to identify biomarkers of disease severity that could inform treatment.

Norris will work with collaborators who collect biopsy specimens from patients with MVP. He will compare those specimens with tissue biopsies from his animal model. “Once we have the biopsies, we can then correlate changes in protein profiles in valve and heart tissues in humans with those in our animal models to look for markers of disease severity and/or progression,” explained Norris.

“If you have mitral valve prolapse, our findings suggest that you may not want to wait for intervention,” said Norris. “There’s a good chance that your heart is already being stressed and that changes in the heart muscle have already begun, which may be difficult to reverse. So earlier intervention is likely better. We’re hopeful that, with the help of additional funding, some of our discoveries will help change guidelines for the timing of surgical intervention as well as lead to nonsurgical therapies to treat the disease.”

The findings of a developmental cause for some forms of the disease by Norris and other members of the collaborative team could signal the importance of early intervention and lead to rethinking of current treatment guidelines.





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