Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy.
Proteins in cardiac myocytes assemble into contractile units known as sarcomeres. Contractile force is generated by interaction between sarcomeric thick and thin filaments. Thin filaments also transmit force within and between myocytes. Mutations in genes encoding the thin filament proteins actin and tropomyosin cause hypertrophic cardiomyopathy. Mutations affecting functionally distinct domains of actin also cause dilated cardiomyopathy (DCM). We used a non-positional candidate gene approach to test further the hypothesis that dysfunction of sarcomeric thin filaments, due to different mutations in the same gene, can lead to either hypertrophic or dilated cardiomyopathy. Mutational analyses of alpha-tropomyosin 1 were performed in patients with idiopathic DCM. We identified two mutations that alter highly conserved residues and that, unlike hypertrophic cardiomyopathy-associated mutations, cause localized charge reversal on the surface of tropomyosin. Therefore, substitution of different amino acid residues in the same thin filament proteins is associated with the distinct phenotypes of cardiac hypertrophy or congestive heart failure.
Olson
T M
TM
Department of Pediatrics, Division of Cardiology and Biochemistry, University of Utah, Salt Lake City, UT 84113, USA. olson.timothy@mayo.edu
Kishimoto
N Y
NY
Whitby
F G
FG
Michels
V V
VV
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010375:Pedigree; D011487:Protein Conformation; D012518:Sarcomeres / Q000648:ultrastructure; D014335:Tropomyosin / Q000737:chemistry / Q000235:genetics*
D029721:Drosophila Proteins; C490775:TPM1 protein, human; C097163:Tm2 protein, Drosophila; D014335:Tropomyosin