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Titin genetic mutations identified as cause of dilated cardiomyopathy
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Researchers have identified genetic mutations that truncate titin, a muscle filament, and cause dilated cardiomyopathy.
“These results give us a detailed understanding of the molecular basis for dilated cardiomyopathy,” Stuart Cook, MBBS, PhD, MRCP, from the Medical Research Council Clinical Science Centre at Imperial College London, said in a press release. “We can use this information to identify those at risk of developing the disease, and help them manage their condition early.”
Previous research had identified titin mutations and suggested a link to end-stage dilated cardiomyopathy, but the burden of the mutations in the general population was not known and their effects on health and disease were uncertain, according to the study background.
Cook and colleagues sequenced titin genes and matched the results with cardiac phenotyping in 5,267 people of varying cardiac physiology. They then integrated those data with RNA and protein analyses of human heart tissues.
Titin-truncating variants occurred in approximately 2% of the general population, in 13% of ambulatory unselected patients with dilated cardiomyopathy and in 20% of patients with end-stage dilated cardiomyopathy.
Comparing variants found in those with dilated cardiomyopathy and those without it, the researchers found that nonsense, frameshift and canonical splice site titin-truncating variants were much more likely to be found in people with dilated cardiomyopathy (OR = 17; 95% CI, 11-25).
Other variants that had been predicted to alter noncanonical splice signals also were more common in people with dilated cardiomyopathy (OR = 4.2; 95% CI, 1.8-9.7), but not as strongly, and were often present in conjunction with other titin-truncating variants, according to the researchers.
In addition, titin-truncating variants were more likely to be located in the A-band in those with dilated cardiomyopathy than in those without it (cardiomyopathy group, 61 of 87 variants; controls, 21 of 56 variants; OR = 3.9; 95% CI, 1.8-8.3).
The researchers conducted a validation study in 163 patients with familial dilated cardiomyopathy and 667 healthy participants. Compared with controls, titin-truncating variants affecting the N2A and N2B full-length titan isoforms were more prevalent in the dilated cardiomyopathy group (OR = 78; 95% CI, 20-460).
Cook and colleagues also compared clinical phenotypes in titin-truncating variant-positive (n=42) and titin-truncating variant-negative (n=277) patients with dilated cardiomyopathy. Those positive for a titin-truncating variant had more impaired left ventricular ejection fraction (P = .047), lower stroke volume (P = .041), thinner LV walls (P = .003) and greater incidence of sustained ventricular tachycardia (OR = 6.7; P = .001).
Analysis of titan RNA and protein expression demonstrated that patients with dilated cardiomyopathy with or without titin-truncating variants had comparable total titin transcript levels, comparable expression of single nucleotide polymorphisms and no difference in the abundance of N2A and N2B protein isoforms, leading the researchers to conclude that titin-truncating variants “may cause [dilated cardiomyopathy] by a dominant negative effect.”
Disclosure: The researchers report no relevant financial disclosures.
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