Most cells in the body have a small appendage called a primary cilium. In recent years, a variety of studies have linked the cilium to "the vast majority" of cellular signaling pathways, and cilia dysfunction has been connected with diseases called ciliopathies. Reporting in Science Translational Medicine, scientists have now found that certain genetic mutations that cause ciliary dysfunction in heart valve cells during development can influence mitral valve prolapse. The disorder is thought to impact as many as one in forty people, and this work may help in the development of diagnostic tools.
"These tiny structures are really important in establishing how the heart valve develops in utero," said the senior author of the study, Russell A. Norris, Ph.D., associate professor of medicine in the Department of Regenerative Medicine and Cell Biology the Medical University of South Carolina (MUSC).
The mitral valve ensures that blood flows from the heart’s left atrium to the left ventricle. If the two flaps on the mitral valve enlarge and don’t properly close, blood can flow bidirectionally. The condition, mitral valve prolapse, may not cause many symptoms as it progresses but can cause damage to the heart muscle over long periods of time in some people. They may then experience scarring in the heart, congestive heart failure, or sudden cardiac death.
This team of researchers has previously found genetic variants that are associated with mitral valve prolapse. They noticed that the genes carrying the variations were connected with a ciliary pathway. They created a mouse model to assess the impact of removing cilia in the cells making up the valve.
"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," revealed Norris. They were able to follow up on these findings in a family with a history of the disorder.
"Through our existing, long-term collaborations with geneticist Dr. Susan Slaugenhaupt, cardiologist Dr. David Milan and echocardiographer Dr. Robert Levine at Mass General Hospital, genetic analyses of this family were performed. Through many years of study, we were able to identify a causative gene in this family, which ended up being a cilia gene," said Norris.
With the CRISPR gene-editing tool, they inserted the mutation they identified in the family into a mouse model. "We knocked in the mutation, and it fully recapitulated the phenotypic spectrum of the disease and impaired formation of primary cilia during development," noted 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."
The research team also assessed genetic data for 300 cilia genes in humans. "We found that there was an increased prevalence of cilia gene variants in the mitral valve prolapse population," said Norris. "Whether it's relevant to ten, 40, or 70 percent of the broader population, we don't know yet."
Now that the scientists have created a mouse model of the disease, they want to learn more about how it progresses, and potentially develop ways to diagnose the disease sooner. Their work so far appears to confirm that the disease can start early on without causing symptoms, and take many years to become diagnosable. The anatomy and geometry of the heart and valve may degenerate, and contribute to the disease as well.
"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 non-surgical therapies to treat the disease," Norris concluded.