Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene.

Abstract

Familial hypertrophic cardiomyopathy (FHC) is a clinically and genetically heterogeneous disease. The first identified disease gene, located on chromosome 14qll-ql2, encodes the #-myosin heavy chain. We have performed linkage analysis of two French FHC pedigrees, 720 and 730, with two microsatellite markers located in the #-myosin heavy chain gene (MYO I and MYO II) and with four highly informative markers, recently mapped to chromosome 14qll-ql2. Significant linkage was found with MYO I and MYO II in pedigree 720, but results were not conclusive for pedigree 730. Haplotype analysis of the six markers allowed identification of affected individuals and of some unaffected subjects carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing, 403 '" and 403ig-TriP in families 720 and 730, respectively. The 403ArgI' mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the 403 r"T'P mutation appeared less severe. Haplotyping of polymorphic markers in close linkage to the #-myosin heavy chain gene can, thus, provide rapid analysis of non informative pedigrees and rapid detection of carrier status. Our results also indicate that codon 403 of the j-myosin heavy chain gene is a hot spot for mutations causing FHC. (J. Clin. Invest. 1993. 92:2807-2813.) Key words: familial hypertrophic cardiomyopathy * molecular genetics -mutation hot spot * -jmyosin heavy chain * microsatellite are diverse, including syncope, angina, heart failure, and sudden death (even in asymptomatic patients). The major common denominator of these various presentations is ventricular hypertrophy usually associated with microscopic evidence of myocardial fiber disarray (1, 2). Linkage of the disease with a locus on chromosome 14q11 -q 12 was found in approximately one third of the affected families (3-8). The #-myosin heavy chain gene (MYH7) is the disease gene of this locus, and 16 different missense mutations, localized in exons coding for the head and the head rod regions of the protein, were found in various pedigrees (9-21). The most common mutation is in exon 13, affecting the second nucleotide of codon 403 and results in the substitution ofan arginine by a glutamine residue. It was found in eight families of various ethnic origin (9-14), and it is associated with an early onset ofthe disease and a high frequency of sudden deaths.

Beta myosin heavy chain mutations R403QLW, V606M, K615N and R663H in patients with hypertrophic cardiomyopathy

“…In the other study, four mutations (R403Q, R453C, R719W, R719Q) were investigated in MYH7 gene and similar to our results none of the mutations were found in patients (n=18) with HCM (27). The R403QLW mutations occurs in close proximity to actin-miyosin interface of the myosin motor domain (28) greatly decrease the actin translocating activity (19) and were associated with high incidence of morbidity and early mortality (29)(30)(31). Although 26 percent of our study population have a family history of sudden cardiac death, we could not find the R403Q mutation in any of the patients.…”

Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations.

“…'-" In some kindreds, the disease has been linked to the f-myosin heavy chain (3-MHC) gene locus on chromosome 14ql. [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] In these kindreds, HCM has been associated with substitutions of single highly conserved amino acids in the head or head-rod junction of the ,B-MHC molecule. We have previously reported that clinical expression has differed significantly in two kindreds with distinct 3-IMHC gene mutations: The 908``u va1 mutation has been associated with low disease penetrance and a benign prognosis.…”

Genetic Bases of Hypertrophic Cardiomyopathy

“…The near-totality of the missense mutations is localized in the first 23 exons, which encode the globular head and the head-tail junction of the protein 45 . This gene is highly susceptible to mutagenesis in special codons 403, 719, and 741 46,47 . It is suspected that the arginine residue plays a fundamental role in the protein's normal function 46 .…”

“…This gene is highly susceptible to mutagenesis in special codons 403, 719, and 741 46,47 . It is suspected that the arginine residue plays a fundamental role in the protein's normal function 46 . However, no mutation has a predominant character, although Arg403Gln is a frequent one.…”

“…Leu908Val has a better prognosis: 92% of patients are alive at 60 years 48 . Gly256Glu like Arg 403Trp and Arg870His are also benign 46,51,52 . Mutation Val606Met is described as benign but can eventually have a bad prognosis 45,52 .…”