Mutations of the   myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis

Abstract

Objectives: To assess patients with different types of mutations of the β myosin heavy chain (β MHC) gene causing hypertrophic cardiomyopathy (HCM) and to determine the prognosis of patients according to the affected functional domain of β MHC. Design and setting: Cohort study of subjects referred to an HCM clinic at an academic hospital. Patients: 70 probands from the HCM clinic were screened for mutations of the β MHC gene and 148 family members of the genotype positive probands were further assessed. The control group for the genetic studies consisted of 106 healthy subjects. Main outcome measures: Direct DNA sequencing was used to screen 70 probands for mutations of the β MHC gene. Family members underwent genotypic and detailed clinical, ECG, and echocardiographic assessments. The survival of genotype positive subjects was evaluated according to the type of functional domain affected by the missense mutation and according to phenotypic characteristics. Results: A mutation of the β MHC gene was detected in 15 of 70 probands (21%). Of 148 family members studied in these 15 families, 74 were identified with a β MHC defect. Eleven mutations were detected, including four novel mutations: Ala196Thr, Pro211Leu, Val404Leu, and Arg870Cys. Median survival was 66 years (95% confidence interval (CI) 64 to 77 years) in all affected subjects. There was a significant difference in survival between subjects according to the affected functional domain (p = 0.02). Significant independent predictors of decreased survival were the non-conservative (that is, associated with a change in the amino acid charge) missense mutations that affected the actin binding site (hazard ratio 4.4, 95% CI 1.6 to 11.8; p = 0.003) and those that affected the rod portion of β MHC (hazard ratio 4.8, 95% CI 1.2 to 19.4; p = 0.03). No phenotypic characteristics were associated with decreased survival or cardiovascular morbidity. Conclusions: The type of β MHC functional domain affected by the missense mutation is predictive of overall prognosis in HCM.H ypertrophic cardiomyopathy (HCM) is a primary and clinically diverse cardiac disorder that is caused by a defect in one of 10 genes encoding proteins of the myofibrillar apparatus: β myosin heavy chain (β MHC), α myosin heavy chain, myosin binding protein C, troponin T, α tropomyosin, troponin I, myosin essential light chain 1, myosin regulatory light chain 2, α cardiac actin, or titin. [1][2][3] There is significant genetic heterogeneity in HCM with more than 150 mutations now implicated in its pathogenesis. The β MHC gene was the first gene identified with this condition.6 Defects of the β MHC gene account for the largest proportion of cases of HCM and many of the initial genotypephenotype correlative studies of HCM were based on subjects with defects of β MHC. Certain mutations have been associated with a significantly shorter life expectancy in patients with HCM. 4 7-10 However, the associations between specific genotypes and overall prognosis are based on findings from a limited number of familie...

Cardiomyopathy: A Systematic Review of Disease-Causing Mutations in Myosin Heavy Chain 7 and Their Phenotypic Manifestations

“…It has been suggested that mutations in the head or neck regions are more likely to cause a severe outcome, but these conclusions were drawn from relatively small cohorts [40,42]. It is apparent from the data presented in figure 2 that a notably larger proportion of malignant phenotypes arise as a result of mutations in the head region (49%) compared to the tail (20%).…”

“…Some studies support this hypothesis [2,40,42], while others do not find a correlation [50,81]; however, these studies were performed in relatively small cohorts. The data described in the present analysis of 70 missense mutations does, to a certain degree, support this correlation.…”

“…Therefore, the positioning of the mutations along the gene and protein may offer insights into the mechanism by which normal protein function is impaired. It has also been postulated that a change in the amino acid charge may affect the severity of the phenotype [40,42,43,44]. We suggest that this may also be the case for hydropathy.…”

“…Of particular interest to this study is MYH7 (also known as beta-myosin heavy chain), as this gene is commonly mutated in cardiomyopathy patients [38], and the presence of such a mutation is often considered to be associated with a poor prognosis [39,40]. It is a large gene located on chromosome 14q11.2–q13 in humans, with the 40 exons forming a transcript of 6,027 bp which gives rise to a 1,935-amino acid protein.…”

The Regulatory Effects of Tropomyosin and Troponin-I on the Interaction of Myosin Loop Regions with F-actin

“…Interaction of this segment of intact myosin with F-actin appears to be nucleotide-dependent and a critical contribution to the strong binding of myosin to actin (3,4,(7)(8)(9). This region of myosin further contains sites of mutation (residues 403, 404, and 411) that are associated with hypertrophic cardiomyopathy (18,32). However, care should be exercised in extrapolating the results obtained with isolated fragments to properties associated with the intact myosin head.…”