Genetic screening of calcium regulation genes in familial hypertrophic cardiomyopathy

Genes encoding Ca²⁺ regulatory proteins responsible for Ca²⁺ 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 Ca²⁺ handling, may account for the remainder. The aim of this study was to identify causative mutations in genes involved in Ca²⁺ regulation in patients with familial hypertrophic cardiomyopathy (FHC). An Australian cohort of 252 unrelated familial hypertrophic cardiomyopathy patients were screened for mutations in the Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ handling genes are an infrequent but important cause of FHC. DNA variants in Ca²⁺ genes may also be involved as modifying factors in phenotype development. Further evaluation of the role of defects in Ca²⁺ regulation will shed light on the molecular pathogenesis of FHC.