title: Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.
abstract: We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the alpha-tropomyosin gene cause familial hypertrophic cardiomyopathy (FHC) linked to chromosome 15q2. These findings implicated components of the troponin complex as candidate genes at other FHC loci, particularly cardiac troponin T, which was mapped in this study to chromosome 1q. Missense mutations (Ile79Asn; Arg92Gln) and a mutation in the splice donor sequence of intron 15 of the cardiac troponin T gene are also shown to cause FHC. Because alpha-tropomyosin and cardiac troponin T as well as beta myosin heavy chain mutations cause the same phenotype, we conclude that FHC is a disease of the sarcomere. Further, because the splice site mutation is predicted to function as a null allele, we suggest that abnormal stoichiometry of sarcomeric proteins can cause cardiac hypertrophy.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: L
authors.initials: L
authors.lastname: Thierfelder
authors.forename: H
authors.initials: H
authors.lastname: Watkins
authors.forename: C
authors.initials: C
authors.lastname: MacRae
authors.forename: R
authors.initials: R
authors.lastname: Lamas
authors.forename: W
authors.initials: W
authors.lastname: McKenna
authors.forename: H P
authors.initials: HP
authors.lastname: Vosberg
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: C E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D008040:Genetic Linkage; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics; D051381:Rats; D012518:Sarcomeres / Q000378:metabolism; D014335:Tropomyosin / Q000235:genetics*; D014336:Troponin / Q000235:genetics*; D020107:Troponin T
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D014335:Tropomyosin; D014336:Troponin; D020107:Troponin T