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 backgroun d 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 (in bred; designated 129SvEv-alpha MHC403/+) and Black Swiss (outbred designate d BSw-alpha MHC403/+) strains, At 30-50 weeks of age all 129SvEv-alpha MHC4 03/+ showed left ventricular hypertrophy, while left ventricular wall thick ness was increased in only half of BSw-alpha MHC403/+ mice demonstrating th at a polymorphic modifier gene can determine the hypertrophic response to t his 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 t hat genetic modifiers in mice, and presumably in man, can alter the hypertr ophic response to sarcomere protein gene missense mutations. (C) 2001 Acade mic Press.