Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy

Proteins in cardiac myocytes assemble into contractile units known as sarco meres. Contractile force is generated by interaction between sarcomeric thi ck and thin filaments. Thin filaments also transmit force within and betwee n myocytes. Mutations in genes encoding the thin filament proteins actin an d tropomyosin cause hypertrophic cardiomyopathy, Mutations affecting functi onally distinct domains of actin also cause dilated cardiomyopathy (DCM). W e used a non-positional candidate gene approach to test further the hypothe sis that dysfunction of sarcomeric thin filaments, due to different mutatio ns in the same gene, can lead to either hypertrophic or dilated cardiomyopa thy. Mutational analyses of alpha-tropomyosin I were performed in patients with idiopathic DCM. We identified two mutations that alter highly conserve d residues and that, unlike hypertrophic cardiomyopathy-associated mutation s, cause localized charge reversal on the surface of tropomyosin. Therefore , substitution of different amino acid residues in the same thin filament p roteins is associated with the distinct phenotypes of cardiac hypertrophy o r congestive heart failure. (C) 2001 Academic Press.