Clinical and genetical heterogeneity of familial hypertrophic cardiomyopathy.
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease which has a benign clinical course in most patients but carries also the risk of sudden cardiac death. Initial genetic studies have revealed the beta-myosin heavy chain (beta-MHC) gene on chromosome 14q11-q12 as morbid gene. Several mutations have been identified, almost all of them are missense mutations of the area in the gene coding for the globular head region of the myosin. The codon 403 has been found to be a hot-spot for mutations. Both, mutant myosin messenger RNA and proteins have been found in cardiac and in skeletal muscle, indicating the presence of a normal protein synthesis of the mutant allele. Histological studies show that gross alterations in protein assembly do not occur (e.g. by introducing the 403Arg-->Gln mutation in cell expression systems) and in-vitro motility of distinct mutations may be reduced in comparison to wild type myosin. The exact mechanism, however, how myosin mutations cause FHC has not yet been elucidated. Three novel loci for FHC have been identified only recently on chromosomes 1q3, 11p13-q13, and 15q22. It can be hoped that the characterization of the morbid genes in these loci will provide valuable information for the clarification of the pathogenesis of FHC and possibly for future therapeutic approaches. The challenge for future studies is to identify the morbid genes of the new loci, their mutations and their proteins.
Hengstenberg
C
C
Philipps-University Marburg, Dept. of Internal Medicine and Cardiology, Marburg, Germany.
Carrier
L
L
Schwartz
K
K
Maisch
B
B
D002148:Calmodulin-Binding Proteins / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D016757:Death, Sudden, Cardiac / Q000209:etiology; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains; D024461:Myosin Type I; D010375:Pedigree; D012307:Risk Factors
D002148:Calmodulin-Binding Proteins; C062291:MYO1A protein, human; D024461:Myosin Type I; D018995:Myosin Heavy Chains