By: David Shifrin, PhD Science Writer, Filament Life Science Communications

Another small but important piece has been fitted in to the endless puzzle of genetic predisposition to disease. This time, a gene responsible for a cardiac condition found in ~2% of individuals has been uncovered by researchers at Massachusetts General Hospital.

Mitral valve prolapse (MVP) has long been known to have a heritable component. Figuring out what that component is, however, has been a challenge. Now, with some help with a favorite model system of developmental biologists, the team from Mass General has pinpointed one strong candidate gene and published their results in Nature.

Earlier chromosomal mapping had narrowed down the likely MVP-causing mutation to a region on chromosome 11. In the current study, titled Mutations in DCHS1 cause mitral valve prolapse, the team of researchers used capture sequencing to look more closely at that region. Using this method, the investigators were able to hone in on the region of interest while minimizing the number of steps required to get there. Samples were acquired from four individuals, all from the same family with a strong history of MVP.

High-throughput sequencing that followed the capture sequencing revealed almost 5,000 variants (including single nucleotide and in/dels) in the samples. Cross referencing these variants to find those that were consistent in all four individuals and represented protein-coding sequences led to three candidates mutations. Two were in the same gene, DCHS1, which encodes for a cadherin protein (cadherins are involved in cell adhesion and some signaling events, as well as promoting cell polarity). The researchers also looked at the second gene, but didn’t find cardiac mutations in follow up studies with animal models.

From this point, the team stepped up their work to move beyond genetic analysis into true functional validation of their findings. They used zebrafish, a common model system for developmental biology due to the powerful genetic tools available and the ease with which it can be visualized (the fish are largely transparent). When a mutated form of DCHS1 was expressed in zebrafish, dramatic cardiac defects were observed. More importantly, these defects could be rescued by expression of normal human DCHS1, but not with versions of the human gene carrying the mutations revealed by sequencing.

With this valuable in vivo information in hand, the authors went back to human populations to see whether DCHS1 showed up outside of the one family initially screened. The answer, in at least two additional families with MVP, was yes. This is where the story gets really fun, since cells were isolated from the mitral valve of an individual in one of these families during valve repair. The investigators were therefore able to use these cells to test the consequences of the novel DCHS1 mutations at a protein level. Not surprisingly, one of the mutations led to a dramatically reduced stability of the resulting protein.

Finally, with the zebrafish developmental model and the human cardiac cell culture model in hand, the authors looked at one more system to confirm their results. In mice, knocking out both copies of DCHS1 led to death shortly after birth. When only one copy was eliminated, though (which, the authors point out, is the relevant equivalent to the human condition), MVP occurred. The valve defects occurred during embryonic development.

By discovering a candidate gene and confirming it through multiple cell culture and in vivo systems, the authors provide a relevant model for what has long been known to be a developmental disease. Additionally, they suggest, their work will open up the field to more readily discovering additional candidate genes, which could “hold the potential for pre-surgical therapy” for mitral valve prolapse.

For more on this study, see the commentaries from GEN here and here.

Tue. December 15, 2015