Abstract 914: Myozenin 2 (MYOZ2) Is a Novel Gene For Human Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in sarcomeric proteins (excluding phenocopy). The known genes account for approximately 2/3 of HCM. Hence, the genetic basis of HCM is unknown in approximately 1/3 of the families. We identified a family comprised of 6 clinically affected members with HCM, diagnosed based on the presence of wall thickness of >13 mm on echocardiograms in the absence of a known cause of cardiac hypertrophy. The phenotype was characterized by early onset of clinical symptoms, severe cardiac hypertrophy and cardiac arrhythmias. To identify the causal mutation, we performed locus-specific haplotype analysis of sarcomeric genes followed by mutation screening of the specific sarcomeric gene mapped to the locus. We genotyped 5 short-tandem repeat markers spanning a 7.8 cM chromosomal region on 4q26-q27 locus, which encompasses sarcomeric gene myozenin 2 (MYOZ2). All affected members shared a common haplotype for the 4q26-q27 locus, implicating MYOZ2 as the potential causal gene. To detect the causal mutation, we sequenced all 6 exons and exon-intron boundaries of MYOZ2 in the family members. We identified a T>C missense mutation that changes amino acid Serine at position 48 to Proline (S48P). The mutation co-segregated with inheritance of the phenotype. It was absent in all clinically normal family members and in 1010 normal chromosomes. To determine the frequency of MYOZ2 mutations in HCM, we sequenced MYOZ2 in 516 probands. We detected a A>G missense mutation, corresponding to I245M in affected members of another family. It was absent in 1034 normal chromosomes. Based on in silico structure-function analysis, we propose the molecular mechanism of HCM caused by MYOZ2 mutations entails activation of calcineurin, which mediates the hypertrophic phenotype. Studies are ongoing to test the hypothesis and elucidate the molecular basis of HCM caused by MYOZ2 mutations.