According to an article published recently in HHMI, Christine Seidman, a Howard Hughes Medical Institute (HHMI) investigator at Brigham and Women’s Hospital in Boston, and her team have done extensive research on at least forty separate genes responsible for dilated cardiomyopathy. Dilated cardiomyopathy is a medical condition in which the heart becomes enlarged and weakened, thereby reducing its capacity to pump blood with enough vigor to deliver oxygen to the body effectively. Debilitating symptoms include shortness of breathe and persistent fatigue. Dilated cardiomyopathy tends to run in families, and so genetic causation is a likely explanation of its pathology. The fact that dilated cardiomyopathy is influenced by at least forty known genes means it can be considered polygenic inheritance, or an additive effect of two or more genes on a single phenotype, perhaps even resulting in a gradation termed quantitative character. Until recently, the genes suspected of contributing to dilated cardiomyopathy that have been sequenced have been relatively short, anywhere from the 675 amino acid residues of Lamin A/C to the 2,000 amino acid residues of the motor protein myosin. Titin, a protein which helps assemble the sarcomere as the heart muscle grows and also plays a role in muscle contractions, on the other hand is a staggering 33,000 amino acid residues long. As Dr. Seidman explains, “It wasn’t that we weren’t aware that titin caused disease—we were. The problem was that the technology was not sufficiently robust to allow comprehensive analysis of that gene in a large collection of patients.” As a result, genetic causation of dilated cardiomyopathy had remained not fully understood.
However, recent technological innovations which have made DNA sequencing fast and relatively inexpensive have allowed Dr. Seidman and her team to finally sequence the giant gene sequence of titin and record genetic mutations in the gene in patients who suffered from dilated cardiomyopathy. The results were fruitful: 28 percent of the people who had dilated cardiomyopathy also had dramatic mutations in the DNA encoding titin, mutatations which resulted in non-functional protein products. Among the forty known genes known to influence dilated cardiomyopathy, titin by far had the highest percent correlation between gene mutation and phenotypically observable disease state.
Dr. Seidman hopes that her team’s findings demonstrating the strong correlation between titin mutation and dilated cardiomyopathy will result in a more proactive approach to preventive medicine and prophylactic treatments. She also hopes that scientifically mapping the congenital causes of dilated cardiomyopathy might shed light on the pathophysiological mechanisms which enlarge and weaken the heart in afflicted patients in the first place, which would further lead scientists to curative medicines.