In the large French-Canadian kindred originally reported by Pare et al. (1961) and shown to have linkage of the cardiac disorder (CMH1; 192600) to markers on the proximal portion of 14q, Geisterfer-Lowrance et al. (1990) found a missense mutation in the beta cardiac myosin heavy chain that converted arginine-403 to glutamine (R403Q). A guanine residue at position 10,162 (enumerated as in Jaenicke et al., 1990) was mutated to an adenine residue. The mutation generated a new DdeI site and changed the CGG(arg) codon to CAG(gln). Perryman et al. (1992) found that the R403Q mutation was identifiable in myocardial mRNA. Ross and Knowlton (1992) reviewed this discovery beginning with the patients first seen by Pare in the 1950s.
Using an isolated, isovolumic heart preparation where cardiac performance was measured simultaneously with cardiac energetics using (31)P nuclear magnetic resonance spectroscopy, Spindler et al. (1998) studied the effects of the codon 403 missense mutation. They observed 3 major alterations in the physiology and bioenergetics of the mutant mouse hearts. First, while there was no evidence for systolic dysfunction, diastolic function was impaired during inotropic stimulation. Diastolic dysfunction was manifest as both a decreased rate of left ventricular relaxation and an increase in end-diastolic pressure. Second, under baseline conditions the mutant R403Q mouse hearts had lower phosphocreatine and increased inorganic phosphate contents resulting in a decrease in the calculated value for the free energy released from ATP hydrolysis. Third, mutant hearts that were studied unpaced responded to increased perfusate calcium by decreasing heart rate approximately twice as much as wildtypes. The authors concluded that the hearts from mice carrying the R403Q mutation have workload-dependent diastolic dysfunction resembling the human form of familial hypertrophic cardiomyopathy. Changes in high-energy phosphate content suggested that an energy-requiring process may contribute to the observed diastolic dysfunction.
Bashyam et al. (2003) pointed out that polymorphism in the ACE1 gene (106180) had been shown to affect the prognosis in familial hypertrophic cardiomyopathy. The DD allele of the ACE1 gene (106180.0001) was associated with a severe form of hypertrophy and sudden death in patients with familial hypertrophic cardiomyopathy (Iwai et al., 1994). Tesson et al. (1997) established an association of the D allele at the ACE1 locus with the R403Q mutation in MYH7, but not with MYBPC3 (600958) mutations.
