Mutations of the light meromyosin domain of the β-myosin heavy chain rod in hypertrophic cardiomyopathy
Date
2002
Authors
Blair E.
Redwood C.
De Jesus Oliveira M.
Moolman-Smook J.C.
Brink P.
Corfield V.A.
Ostman-Smith I.
Watkins H.
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Familial hypertrophic cardiomyopathy (HCM) is caused by mutations in 9 sarcomeric protein genes. The most commonly affected is β-myosin heavy chain (MYH7), where missense mutations cluster in the head and neck regions and directly affect motor function. Comparable mutations have not been described in the light meromyosin (LMM) region of the myosin rod, nor would these be expected to directly affect motor function. We studied 82 probands with HCM in whom no mutations had been found in MYH7 exons encoding the head and neck regions of myosin nor in the other frequently implicated disease genes. Primers were designed to amplify exons 24 to 40 of MYH7. These amplimers were subjected to temperature modulated heteroduplex analysis by denaturing high-performance liquid chromatography. An Ala1379Thr missense mutation in exon 30 segregated with disease in three families and was not present in 200 normal chromosomes. The mutation occurred on two haplotypes, indicating that it was not a polymorphism linked with another disease-causing mutation. The position of this residue within the LMM region of myosin suggests that it may be important for thick filament assembly or for accessory protein binding. A further missense mutation in exon 37, Ser1776Gly, segregated with disease in a single family and was absent from 400 population-matched control chromosomes. Because the Ser1776 residue occupies a core position in the myosin rod at which the substitution of glycine is extremely energetically unfavorable, it is likely to disrupt the coiled-coil structure. We conclude that mutation of the LMM can cause HCM and that such mutations may act through novel mechanisms of disease pathogenesis involving myosin filament assembly or interaction with thick filament binding proteins.
Description
Keywords
alanine, gene product, meromyosin, myosin heavy chain, myosin heavy chain beta, serine, threonine, unclassified drug, article, controlled study, dermatome, essential gene, gene amplification, gene mutation, genetic association, haplotype, heteroduplex analysis, high performance liquid chromatography, human, human cell, hypertrophic cardiomyopathy, major clinical study, missense mutation, motor performance, myh7 gene, pathogenesis, priority journal, protein binding, protein domain, sarcomere, structure analysis, thermoregulation, Adolescent, Adult, Aged, Cardiomyopathy, Hypertrophic, Familial, Child, Child, Preschool, Comorbidity, Death, Sudden, Cardiac, DNA Mutational Analysis, Echocardiography, Electrocardiography, Female, Genes, Dominant, Genetic Heterogeneity, Genetic Screening, Great Britain, Haplotypes, Humans, Male, Middle Aged, Mutation, Myosin Heavy Chains, Myosin Subfragments, Pedigree, Penetrance, Protein Structure, Tertiary, South Africa, Ventricular Myosins
Citation
Circulation Research
90
3
90
3