title: 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.affiliation: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Chiu
authors.forename: Molly
authors.initials: M
authors.lastname: Tebo
authors.forename: Jodie
authors.initials: J
authors.lastname: Ingles
authors.forename: Laura
authors.initials: L
authors.lastname: Yeates
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Arthur
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Lind
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000378:metabolism; D001315:Australia; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics; D037282:Calreticulin / Q000235:genetics; D002155:Calsequestrin / Q000235:genetics; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D016384:Consensus Sequence; D017124:Conserved Sequence; D005260:Female; D005820:Genetic Testing; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D006801:Humans; D008297:Male; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D017434:Protein Structure, Tertiary; D000099211:Phospholamban
chemical_list: D001120:Arginine; D002118:Calcium; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D002155:Calsequestrin; D018698:Glutamic Acid; D005978:Glutathione; D005998:Glycine; D000099211:Phospholamban; C443109:CASQ2 protein, human