Missense Mutations in the β-Myosin Heavy-Chain Gene Cause Central Core Disease in Hypertrophic Cardiomyopathy

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 90; no. 9; pp. 3993 - 3997
• Main Authors: Fananapazir, Lameh, Dalakas, Marinos C., Cyran, Francis, Cohn, Gabriel, Epstein, Neal D.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.05.1993; National Acad Sciences
• Subjects: Adolescent; Adult; Amino Acid Sequence; Arginine; Base Sequence; Biological and medical sciences; Biopsies; Bone diseases; Cardiology. Vascular system; cardiomyopathy; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - pathology; Cardiomyopathy, Hypertrophic - physiopathology; central core disease; Child, Preschool; Codon - genetics; DNA - blood; DNA - genetics; DNA - isolation & purification; Exons; Female; genes; Genetic loci; Genetic mutation; Glutamine; Heart; Heart diseases; heavy chains; Humans; Hypertrophic cardiomyopathy; Introns; Leucine; Leukocytes - metabolism; Male; man; Medical sciences; Microscopy, Electron; Middle Aged; missense mutant; Molecular Sequence Data; Muscles; Muscles - metabolism; Muscles - pathology; Muscles - ultrastructure; Muscular diseases; Myocarditis. Cardiomyopathies; myosin; Myosins - genetics; Oligodeoxyribonucleotides; Pedigree; Point Mutation; Polymerase Chain Reaction - methods; Polymorphism, Genetic; Skeletal muscle; Valine; Human; Family study; heavy-Peptide chain; Inheritance; Contractile protein; Cardiovascular disease; Striated muscle; Myocardial disease; Pathology; Gene; Biopsy; Heart disease; Myosin; Hypertrophic cardiomyopathy; Mutation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.9.3993

Hypertrophic cardiomyopathy (HCM) is an important cause of sudden death in apparently healthy young individuals. In less than half of kindreds with HCM, the disease is linked to the β-myosin heavy-chain gene locus (MYH7). We have recently described two missense MYH7 gene mutations [Arg-403 to Gln (R403Q) and Leu-908 to Val (L908V)] and found that the mutant message is present in skeletal muscle (soleus) and that the mutant β-myosin obtained from soleus muscle has abnormal in vitro motility activity. Having identified a second kindred with the R403Q mutation, and 3 other kindreds with two additional mutations (G741R and G256E), we performed histochemical analysis of soleus muscle biopsies from 25 HCM patients with one of these four mutations. Light microscopic examination of the NADH-stained biopsies revealed the presence of central core disease (CCD) of skeletal muscle, a rare autosomal dominant nonprogressive myopathy characterized by a predominance of type I "slow" fibers and an absence of mitochondria in the center of many type I fibers. CCD was present in 10 of 13 patients with the L908V mutation, 5 of 8 patients with the R403Q mutation, 1 of 3 patients with the G741R mutation, and 1 patient with the G256E mutation. Mild-to-moderate myopathic changes with muscle fiber hypertrophy were present in 16 patients. Notably, CCD was present in 2 adults and 3 children with the L908V mutation who did not have cardiac hypertrophy. In contrast, soleus muscle samples from 5 patients from 4 kindreds in which HCM was not linked to the MYH7 locus showed no myopathy or CCD. Soleus muscle biopsies from 5 control subjects also showed normal histology. This work demonstrates that (i) MYH7-associated HCM is often a disease of striated muscle but with predominant cardiac involvement and (ii) a subset of HCM patients with MYH7 gene missense mutations have CCD.