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New gene for mitral valve prolapse discovered
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Mitral valve prolapse is known to be one of the most common cardiac abnormalities in the general population.
The diagnosis is subject to considerable variability. But even with strict echocardiographic diagnostic criteria, mitral valve prolapse is estimated to occur in about 2.4% of the population, which represents 170 million people worldwide. Although many of these individuals have essentially no symptoms, it is not surprising that mitral valve prolapse is the single most common reason for surgical repair of the mitral valve.
Discovery of an inherited defect
It was previously established that in a proportion of individuals with mitral valve prolapse the defect is inherited. This syndrome was first reported by Barlow and Bosman in the 1960s; the two observed several members of a single family who had this disorder. The first chromosomal locus for mitral valve prolapse was mapped to chromosome 16 on the short arm (p) at band 11.2 designated as 16p11.2. The second locus was mapped to 11p15.4 in 2003, and a third locus on the long arm (q) of chromosome designated as 13q31.3.
In all of the families studied, the pattern of inheritance is autosomal dominant, meaning a single copy of the mutant gene is sufficient to induce the disease and only 50% of the offspring are expected to have the mutation. This has important management implications since the half of the offspring without the mutation do not have to undergo serial echocardiograms and are free of the psychological stress of not knowing when the disease will develop.
Mutations in DCHS1
In 2005, I predicted in an editorial published in Circulation that very soon we would know the gene responsible for mitral valve prolapse. However, this was not to happen until 10 years later with a publication in Nature. In this publication, Durst and colleagues identified mutations in the DCHS1 gene located in the previously mapped chromosomal locus 11p15.4. Utilizing several techniques, they documented the function of these mutations to be responsible for mitral valve prolapse. The investigators also showed DCHS1 mutations segregated with mitral valve prolapse in three separate families.
We are hopeful that finding a gene responsible for mitral valve prolapse will not only lead to improved pathogenesis of mitral valve prolapse, but will also provide targets for therapies to prevent or ameliorate its development.
The mitral valve is composed of two leaflets attached at their base to the annulus fibrosa and the free edges to their chordae tendineae. The leaflets are part of a complex apparatus with a dynamic and complex function. During diastole, the leaflets open and enable blood to flow from the left atrium to the left ventricle; during systole, the leaflets properly close and co-apt to prevent any blood from going in the opposite direction from the ventricle to the atrium. Nature designed the valve to withstand more than 3 billion heartbeats sufficient to maintain an average human lifespan.
The major defect leading to mitral valve prolapse is thinning and elongation, which leads to “billowing” of the leaflet and prolapse into the atrium inducing mitral regurgitation. The leaflets have four anatomically defined layers, all of which are rich in collagen, elastin fibers and their secreted products of proteoglycans. The primary abnormality in mitral valve prolapse occurs in the spongiosa layer, which is characterized by increased deposition of proteoglycans that disrupts the normal support of the leaflet, enabling hemodynamic stretch and derangement of the leaflet. Collagen content type III is said to be increased from 53% to 74%. The increased proteoglycans, primarily chondroitin, dermatan sulfate and keratan sulfate, retain water, which gives the leaflet a myxomatous appearance and the floppy nature characteristic of this disorder.
In the Nature publication, Durst and colleagues showed mutations in the DCHS1 gene segregated with individuals affected with mitral valve prolapse in three separate families. The mutations are all substitutions of a single nucleotide referred to as missense mutations and are associated with loss of function of the DCHS1 protein.
Effect on the heart
To determine the function of DCHS1 on the heart, several studies were performed. DCHS1 is a member of the cadherin superfamily, a family of proteins that induce calcium-dependent cell-to-cell adhesion. DCHS1 is a transmembrane glycoprotein with a peptide signal, a large extracellular component consisting of 27 cadherin repeats together with a domain that binds to the cytoplasm. Cadherins are a group of transmembrane glycoproteins and are the major adhesion molecules located within adherens junctions. The adheren junction is responsible for binding cells and maintaining the structure necessary to perform their inherent function. The dysfunctional protein induced by the mutant DCHS1 gene leads to elongation and thinning of the leaflets, which ultimately prolapse into the atrium causing mitral regurgitation. This family of molecules is also important in early organ development. Of note, DCHS1 is particularly expressed in fibroblasts, which positions it to be a good target responsible for mitral valve prolapse.
Expression of the mutant DCHS1 in zebrafish showed significant changes in cardiac morphology, including impaired formation of the atrioventricular canal. Human wild-type (normal) DCHS1 mRNA rescued the canal defect, whereas injection of the mutant DCHS1 mRNA failed to rescue the defect. To further determine the function of DCHS1, cells were transfected with either the wild-type or mutant DCHS1. Expression of the DCHS1 mutant protein was 60% less than wild-type with no significant change in mRNA levels. This observation strongly indicates that the DCHS1 mutation induces protein instability. The protein encoded by the mutant DCHS1 gene was shown to have a half-life of 1.6 hours, whereas the wild-type protein was shown to have a half-life of 5.8 hours. Knockout of both copies (homozygous) of the DCHS1 gene in the mouse resulted in neonatal lethality, whereas knockout of one copy (heterozygous) resulted in elongation and prolapse of the posterior leaflet of the mitral valve, and shifted the leaflet coaptation anteriorly. Histological examination in the mouse showed leaflet thickening with myxomatous degeneration and increased proteoglycan accumulation in both mitral leaflets.
The investigators identified two additional families and demonstrated that individuals affected with mitral valve prolapse had inherited mutations in the DCHS1 gene. One affected family member was operated on for mitral valve repair and pathological examination of the leaflet tissue showed classic myxomatous degeneration. Results of these functional studies, along with showing that the mutations segregate with affected family members, confirm the DCHS1 mutations to be the cause of mitral valve prolapse in these families.
Further research underway
It is expected that other genes will soon be identified to be responsible for this disease at these other mapped loci. Genes residing at these loci that encode for proteins related to collagen and extracellular matrix would be likely candidates responsible for mitral valve prolapse. These genetic underpinnings often provide knowledge fundamental to our development of tissue-derived human valves.
- References:
- Barlow JB, Bosman CK. Am Heart J. 1966;71:166-178.
- Disse S, et al. Am J Hum Genet. 1999;65:1242-1251.
- Durst R, et al. Nature. 2015;doi:10.1038/nature14670.
- Freed LA, et al. N Engl J Med. 1999;341:1-7.
- Freed L, et al. J Am Coll Cardiol. 2002;40:1298-1304.
- Freed LA, et al. Am J Hum Genet. 2003;72:1551-1559.
- Nesta F, et al. Circulation. 2005;112:2022-2030.
- Roberts R. Circulation. 2005;112:1924-1926.
- For more information:
- Justin Zeien, BS, is an MPH student at the University of Arizona Mel & Enid Zuckerman College of Public Health. Robert Roberts, MD, MACC, FRSC, is professor of medicine and International Society of Cardiovascular Translational Research Chair at University of Arizona College of Medicine, Phoenix.
Disclosure: The authors report no relevant financial disclosures.