Different expressivity of a ventricular essential myosin light chain gene Ala57Gly mutation in familial hypertrophic cardiomyopathy

Background Familial hypertrophic cardiomyopathy (HCM] is a clinically and g enetically heterogeneous disease of the sarcomere. Molecular genetic studie s have shown that familial HCM involves mutations in 8 different genes that encode proteins of the myofibrillar apparatus. Methods We thoroughly searched these genes to find the mutations in 38 prob ands of unrelated families with familial HCM. Results We found a novel missense mutation that resulted in Ala57Gly amino acid substitution of the ventricular essential myosin light chain (vMLC1) g ene in two unrelated Korean families with familiar HCM and one Japanese pat ient. The mutated site is located in the putative helix-loop-helix region ( named EF-hand domain) of the calcium-binding site that is highly conserved in vMLC1 isoforms across the various species. The phenotype of this mutatio n in the affected families is a classic asymmetric septal hypertrophy, and the disease penetrance in genotyped members older than 18 years is 78%. In one Korean family a 42-year-otd woman and two brothers (34 and 38 years old ) with the mutation had fully expressed the disease, but two sisters (39 an d 29 years old) with the mutation had no phenotypic expression of HCM. Conclusions Ala57Gly mutation in the vMLC1 gene may exhibit the classic for m of familial HCM and widely different penetration of the disease phenotype in the family members with mutation, especially in women.