IDENTIFICATION OF 2 NOVEL MUTATIONS IN THE VENTRICULAR REGULATORY MYOSIN LIGHT-CHAIN GENE (MYL2) ASSOCIATED WITH FAMILIAL AND CLASSICAL FORMS OF HYPERTROPHIC CARDIOMYOPATHY

Five disease genes encoding sarcomeric proteins and associated with fa milial and classical forms of hypertrophic cardiomyopathy have been de termined since 1989, In 1996 two other genes encoding ventricular regu latory and essential myosin light chains were shown to be associated w ith a particular phenotype of the disease characterized by mid left ve ntricular obstruction. The aim of the present study was to search for mutations in the ventricular regulatory myosin light chain gene (MYL2) , located on chromosome 12q23q24.3, in a panel of 42 probands presenti ng a classical phenotype of familial hypertrophic cardiomyopathy. Sing le-strand conformation polymorphism analysis was used to search for mu tations in the coding segments of the MYL2 gene, and the abnormal prod ucts were sequenced. Two novel missense mutations. Phe18Leu in exon 2 and Arg58Gln in exon 4 were identified in three unrelated families. No ne of the affected patients had hypertrophy localized only at the leve l of the papillary muscle with mid left ventricular obstruction. By an alysis of genetic recombinations. one of these mutations identified in a large family allowed us to refine the localization of the MYL2 gene on the genetic map. in an interval of 6 cM containing six informative microsatellite markers. In conclusion, we show that mutations in the MYL2 gene may be involved in familial and classical forms of hypertrop hic cardiomyopathy, and we provide new tools for the genetic analysis of patients with familial hypertrophic cardiomyopathy.