Genetic screening of calcium regulation genes in familial hypertrophic cardiomyopathy.

Abstract

Genes encoding Ca(2+) regulatory proteins responsible for Ca(2+) homeostasis have been suggested as possible candidates for FHC. Mutations in sarcomere genes account for approximately 50% of all FHC cases indicating other genes, including those involved in Ca(2+) handling, may account for the remainder. The aim of this study was to identify causative mutations in genes involved in Ca(2+) regulation in patients with familial hypertrophic cardiomyopathy (FHC). An Australian cohort of 252 unrelated familial hypertrophic cardiomyopathy patients were screened for mutations in the Ca(2+) regulatory genes, sorcin (SRI), calstabin (FKBP1B), calsequestrin (CASQ2), phospholamban (PLN), sarcolipin (SLN), calreticulin (CALR3) and calmodulin (CALM). A total of 17 exonic DNA variants were identified in the 7 Ca(2+) regulatory genes studied, of which 4 were considered of pathogenic significance. Two novel mutations in the CALR3 gene were identified (Lys82Arg, Arg73Gln) and one truncation mutation in the PLN gene (Leu39Ter). A variant was also identified in the CASQ2 gene (Asp63Glu). These four variants were all novel, resulted in changes in conserved amino acids and were not identified in a normal population. In conclusion, mutations in Ca(2+) handling genes are an infrequent but important cause of FHC. DNA variants in Ca(2+) genes may also be involved as modifying factors in phenotype development. Further evaluation of the role of defects in Ca(2+) regulation will shed light on the molecular pathogenesis of FHC.

• Authors: Christine Chiu, Molly Tebo, Jodie Ingles, Laura Yeates, Jonathan W Arthur, Joanne M Lind, Christopher Semsarian
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 43 Issue 3 Pg. 337-43 (Sep 2007) ISSN: 0022-2828 [Print] England
• PMID: 17655857 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CASQ2 protein, human
• Calcium-Binding Proteins
• Calreticulin
• Calsequestrin
• phospholamban
• Glutamic Acid
• Arginine
• Glutathione
• Calcium
• Glycine

Topics

• Amino Acid Sequence
• Amino Acid Substitution
• Arginine (metabolism)
• Australia
• Calcium (metabolism)
• Calcium-Binding Proteins (genetics)
• Calreticulin (genetics)
• Calsequestrin (genetics)
• Cardiomyopathy, Hypertrophic, Familial (genetics, metabolism, pathology)
• Cohort Studies
• Consensus Sequence
• Conserved Sequence
• Female
• Genetic Testing
• Glutamic Acid (metabolism)
• Glutathione (metabolism)
• Glycine (metabolism)
• Humans
• Male
• Models, Genetic
• Models, Molecular
• Molecular Sequence Data
• Pedigree
• Protein Structure, Tertiary