Alpha B-crystallin mutation in dilated cardiomyopathy

Biochem Biophys Res Commun. 2006 Apr 7;342(2):379-86. doi: 10.1016/j.bbrc.2006.01.154. Epub 2006 Feb 8.

Abstract

Mutations in genes for sarcomeric proteins such as titin/connectin are known to cause dilated cardiomyopathy (DCM). However, disease-causing mutations can be identified only in a small proportion of the patients even in the familial cases, suggesting that there remains yet unidentified disease-causing gene(s) for DCM. To explore the novel disease gene for DCM, we examined CRYAB encoding alphaB-crystallin for mutation in the patients with DCM, since alphaB-crystallin was recently reported to associate with the heart-specific N2B domain and adjacent I26/I27 domain of titin/connectin, and we previously reported a N2B mutation, Gln4053ter, in DCM. A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient and the mutation affected the evolutionary conserved amino acid residue among alpha-crystallins. Functional analysis revealed that the mutation decreased the binding to titin/connectin heart-specific N2B domain without affecting distribution of the mutant crystallin protein in cardiomyocytes. In contrast, another CRYAB mutation, Arg120Gly, reported in desmin-related myopathy decreased the binding to both N2B and striated muscle-specific I26/27 domains and showed intracellular aggregates of the mutant protein. These observations suggest that the Arg157His mutation may be involved in the pathogenesis of DCM via impaired accommodation to the heart-specific N2B domain of titin/connectin and its disease-causing mechanism is different from the mutation found in desmin-related myopathy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amino Acid Sequence
  • Amino Acid Substitution / genetics
  • Animals
  • Animals, Newborn
  • Cardiomyopathy, Dilated / enzymology
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / metabolism*
  • Cells, Cultured
  • Connectin
  • Female
  • HeLa Cells
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Mutation, Missense*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sequence Alignment
  • alpha-Crystallin B Chain / genetics*
  • alpha-Crystallin B Chain / metabolism

Substances

  • CRYAB protein, human
  • Connectin
  • Muscle Proteins
  • TTN protein, human
  • alpha-Crystallin B Chain
  • Protein Kinases