Abstract
Recent advances in the techniques of molecular genetics have brought the dawning of molecular medicine. The molecular mechanism of a number of cardiovascular diseases being deciphered. During the past few years, three genes and two loci for HCM have been identified. Mutations in the β myosin heavy chain gene (βMHC) on chromosome 14q1, cardiac troponin T gene on chromosome 1q3 and α-tropomyosin gene on chromosome 15q2 have been identified in a number of families with HCM. All three known genes for HCM code for sarcomeric proteins. This has raised the possibility that HCM is indeed a disease of the sarcomeric proteins. Two additional, yet unidentified, genes located on chromosome 11q11 and 7q3 are also responsible for HCM. Thus far, more than 40 mutations in βMHC, 10 mutations in cardiac troponin T, and 3 mutations in α-tropomyosin genes in patients with HCM have been identified. Genotype-phenotype correlation studies have shown that mutations are prognosticators in patients with HCM. In addition, a number of structure-function studies have provided significant insight into the pathogenesis of HCM. Isolated fibers containing mutant βMHC show impaired contractility. Expression of βMHC mutations in adulte feline cardiac myocytes disrupts the sarcomeric structure, a finding that is the hallmark of HCM. Functional studies provide credence to the hypothesis that the hypertrophy in HCM is compensatory to impaired function of the sarcomeric proteins. Two genes for LQT syndrome, a K+ related channel (HERG) gene on chromosome 7q3 and a Na+ channel (SCN5A) gene on chromosome 3p21 for LQT syndrome have been identified. Expression of mutant Na+ channel gene shows a prolonged inward current during membrane depolarization. The latter explains the observed LQT interval. Identification of the mutations in two ion channels has raised the possibility that the LQT syndrome may be the disease of the ion channels. Molecular genetic basis of additional cardiovascular diseases such as familial dilated cardiomyopathy, Marfan's syndrome, and muscular dystrophies are being investigated vigorously. Three loci for dilated cardiomyopathy on chromosome 1p-1q, 1q32, and 9q1 have been mapped. Mutations in the fibrillin gene in patients with Marfan's syndrome have been identified. These advances in the molecular genetics of cardiovascular disease have laid the foundation for genetic screening and diagnosis, genetic risk stratification and gene therapy.