Phenotypic Variation of Familial Hypertrophic Cardiomyopathy Caused by the Phe¹¹⁰→Ile Mutation in Cardiac Troponin T

Abstract

Mutation of the cardiac troponin T (cTnT) gene is a genetic determinant of familial hypertrophic cardiomyopathy (HCM). A Japanese family of 14 individuals, including 6 with HCM, was subjected to genetic and clinical assessment. Five exons of the cTnT gene were sequenced in all family members. A heterozygous or homozygous T³⁴⁰→A (Phe¹¹⁰→Ile) mutation in exon 9 of the cTnT gene was detected in 11 subjects. Morphological and functional evaluation of the left and right ventricles by echocardiography revealed that 4 of 9 individuals heterozygous for the mutant allele exhibited HCM with moderate cardiac hypertrophy. Cardiac hypertrophy and other clinical features in the 2 subjects homozygous for the mutation were more severe than were those in heterozygous individuals with HCM. Thus, the clinical features of HCM due to the Phe¹¹⁰→Ile mutation in the cTnT gene appear to be modified by a gene dosage effect.

Familial Hypertrophic Cardiomyopathy Mutations from Different Functional Regions of Troponin T Result in Different Effects on the pH and Ca2+ Sensitivity of Cardiac Muscle Contraction

“…These results strongly suggest that various mutations alter contractile properties in different ways and that these differences may contribute to the molecular pathogenesis of TnT-linked FHC. Because of the limited amount of clinical data available, complicated backgrounds such as environmental factors or haplotype (49) or the possibility of additional mutations, including homozygous mutations (24,50,51), it is difficult to characterize phenotypes precisely. However, results from in vitro studies together with animal models might be helpful for elucidating the molecular mechanisms of the effect of these mutations on cardiac function.…”

Multiple Mutations in Genetic Cardiovascular Disease

“…Homozygous Phe110Ile and Ser179Phe mutations in the cardiac troponin T (cTnT) gene have been reported in 2 large HCM families, associated with significant biventricular hypertrophy and a high incidence of sudden death. 27,28 Each mutation was not fully penetrant as some heterozygous family members were asymptomatic, whereas others had mild left ventricular hypertrophy. The left ventricular septal wall thickness for 2 homozygous Phe110Ile patients was greater than family members heterozygous for this mutation, suggesting that 1 normal cTnT allele can largely compensate for the disruption caused by the Phe110Ile allele.…”

F110I and R278C Troponin T Mutations That Cause Familial Hypertrophic Cardiomyopathy Affect Muscle Contraction in Transgenic Mice and Reconstituted Human Cardiac Fibers

“…TnT was first associated with heart disease in 1994 where three mutations were reported to cause Familial Hypertrophic Cardiomyopathy (FHC) (6). Disease penetrance, however, is highly variable, with severity of heart disease ranging from asymptomatic to end-stage heart failure even in individuals having the same mutation within the same pedigree (7)(8)(9). The F110I mutation in TnT, occurring from a missense substitution in nucleotide 340 in a genomic hotspot (9), is particularly interesting because prognosis appears to rely on the gene dosage, where homozygous individuals present a more severe form of hypertrophy and a greater risk of sudden cardiac death (7).…”

“…Disease penetrance, however, is highly variable, with severity of heart disease ranging from asymptomatic to end-stage heart failure even in individuals having the same mutation within the same pedigree (7)(8)(9). The F110I mutation in TnT, occurring from a missense substitution in nucleotide 340 in a genomic hotspot (9), is particularly interesting because prognosis appears to rely on the gene dosage, where homozygous individuals present a more severe form of hypertrophy and a greater risk of sudden cardiac death (7). Nevertheless, the cardiac morphology again ranges from ventricular and apical hypertrophy to no detectable cardiac abnormalities among 16 individuals (within six families) with the F110I genotype (9).…”