A polymorphic modifier gene alters the hypertrophic response in a murine model of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disorder caused by mutationally altered dominant-acting sarcomere proteins, exhibits significant clinical heterogeneity. To determine whether genetic background could influence the expression of this disease, we studied a murine model for this human condition. Hypertrophic responses to the Arg403Gln missense mutation in a cardiac myosin heavy chain gene were compared in 129SvEv (inbred; designated 129SvEv- alpha MHC403/+) and Black Swiss (outbred; designated BSw- alpha MHC403/+) strains. At 30-50 weeks of age all 129SvEv- alpha MHC403/+ showed left ventricular hypertrophy, while left ventricular wall thickness was increased in only half of BSw- alpha MHC403/+ mice demonstrating that a polymorphic modifier gene can determine the hypertrophic response to this dominant-acting sarcomere protein mutation. Further analysis suggests that SJL/J mice bear a recessive allele of this modifier gene that prevents a hypertrophic response to the Arg403Gln missense mutation. We conclude that genetic modifiers in mice, and presumably in man, can alter the hypertrophic response to sarcomere protein gene missense mutations.