A De Novo Mutation in α-Tropomyosin That Causes Hypertrophic Cardiomyopathy

Abstract

De novo mutations in the alpha-tropomyosin gene can result in hypertrophic cardiomyopathy that may appear to be sporadic but in subsequent generations gives rise to familial disease. Individuals with sporadic hypertrophic cardiomyopathy should be advised of the risk of transmission to offspring. In addition, these findings provide the strongest genetic evidence that mutations in the alpha-tropomyosin gene are directly responsible for hypertrophic cardiomyopathy.

Electrophysiological abnormalities and arrhythmias in alpha MHC mutant familial hypertrophic cardiomyopathy mice.

“…Thus far, the abnormal genes identified in humans with FHC encode for mutations in sarcomeric proteins, such as ␣-and ␤-myosin heavy chain, ␣-tropomyosin, and cardiac troponin T (4,19,20). The clinical course of FHC is highly variable, with a spectrum at presentation that ranges from the asymptomatic carrier state to premature sudden death in childhood.…”

Founder mutations in hypertrophic cardiomyopathy patients in the Netherlands*

“…[47][48][49][50][51] Because most mutations are unique for a family, many of the identified mutations have therefore not been described before. In certain countries and populations, however, founder mutations have been identified, arising from a common ancestor many generations ago.…”

Genetic Bases of Hypertrophic Cardiomyopathy

“…De novo mutation involving the α tropomyosin gene have been reported. They can result in transmission to descendants and can cause familial hypertrophic cardiomyopathy, as already referred to in relation to mutation Asp175Asn 64 . Carriers of apparently sporadic forms of mutation of this gene should be warned about the risk of transmission.…”

“…Some of these mutations can interfere with calcium regulation in the thin filaments. Contrary to mutations of other genes, they are expressed in various structures like gametes, lymphocytes, and myocytes, but being only capable of producing myocardial disease 64 . Mutation Asp175Asn seems to predominate and produced a mutated protein expressed in the myocardium and skeletal musculature 65 .…”