title: A polymorphic modifier gene alters the hypertrophic response in a murine model of familial hypertrophic cardiomyopathy.
abstract: 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.
authors.affiliation: Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: C
authors.initials: C
authors.lastname: Semsarian
authors.forename: M J
authors.initials: MJ
authors.lastname: Healey
authors.forename: D
authors.initials: D
authors.lastname: Fatkin
authors.forename: M
authors.initials: M
authors.lastname: Giewat
authors.forename: C
authors.initials: C
authors.lastname: Duffy
authors.forename: C E
authors.initials: CE
authors.lastname: Seidman
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
mesh_terms: D000483:Alleles; D000818:Animals; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D004195:Disease Models, Animal; D004452:Echocardiography; D005080:Exercise Test; D005799:Genes, Dominant; D006321:Heart / Q000502:physiology; D006801:Humans; D006984:Hypertrophy; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism; D051379:Mice; D009154:Mutation; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D010805:Physical Conditioning, Animal; D011110:Polymorphism, Genetic; D012518:Sarcomeres / Q000378:metabolism; D013997:Time Factors
chemical_list: D018995:Myosin Heavy Chains