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

Timothy Mark Olson, Nina Y. Kishimoto, Frank G. Whitby, Virginia V. Michels

Research output: Contribution to journalArticle

203 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)723-732
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume33
Issue number4
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

Tropomyosin
Dilated Cardiomyopathy
Hypertrophic Cardiomyopathy
Mutation
Genes
Sarcomeres
Proteins
Cardiomegaly
Amino Acid Substitution
Actin Cytoskeleton
Cardiac Myocytes
Muscle Cells
Actins
Heart Failure
Phenotype

Keywords

  • Cardiomyopathy
  • Genetics
  • Molecular biology
  • Mutation
  • Tropomyosin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. / Olson, Timothy Mark; Kishimoto, Nina Y.; Whitby, Frank G.; Michels, Virginia V.

In: Journal of Molecular and Cellular Cardiology, Vol. 33, No. 4, 2001, p. 723-732.

Research output: Contribution to journalArticle

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