Mutations of the light meromyosin domain of the β-myosin heavy chain rod in hypertrophic cardiomyopathy

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dc.contributor.authorBlair E.
dc.contributor.authorRedwood C.
dc.contributor.authorDe Jesus Oliveira M.
dc.contributor.authorMoolman-Smook J.C.
dc.contributor.authorBrink P.
dc.contributor.authorCorfield V.A.
dc.contributor.authorOstman-Smith I.
dc.contributor.authorWatkins H.
dc.date.accessioned2011-05-15T16:16:03Z
dc.date.available2011-05-15T16:16:03Z
dc.date.issued2002
dc.description.abstractFamilial 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.
dc.description.versionArticle
dc.identifier.citationCirculation Research
dc.identifier.citation90
dc.identifier.citation3
dc.identifier.issn00097330
dc.identifier.other10.1161/hh0302.104532
dc.identifier.urihttp://hdl.handle.net/10019.1/13611
dc.subjectalanine
dc.subjectgene product
dc.subjectmeromyosin
dc.subjectmyosin heavy chain
dc.subjectmyosin heavy chain beta
dc.subjectserine
dc.subjectthreonine
dc.subjectunclassified drug
dc.subjectarticle
dc.subjectcontrolled study
dc.subjectdermatome
dc.subjectessential gene
dc.subjectgene amplification
dc.subjectgene mutation
dc.subjectgenetic association
dc.subjecthaplotype
dc.subjectheteroduplex analysis
dc.subjecthigh performance liquid chromatography
dc.subjecthuman
dc.subjecthuman cell
dc.subjecthypertrophic cardiomyopathy
dc.subjectmajor clinical study
dc.subjectmissense mutation
dc.subjectmotor performance
dc.subjectmyh7 gene
dc.subjectpathogenesis
dc.subjectpriority journal
dc.subjectprotein binding
dc.subjectprotein domain
dc.subjectsarcomere
dc.subjectstructure analysis
dc.subjectthermoregulation
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAged
dc.subjectCardiomyopathy, Hypertrophic, Familial
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectComorbidity
dc.subjectDeath, Sudden, Cardiac
dc.subjectDNA Mutational Analysis
dc.subjectEchocardiography
dc.subjectElectrocardiography
dc.subjectFemale
dc.subjectGenes, Dominant
dc.subjectGenetic Heterogeneity
dc.subjectGenetic Screening
dc.subjectGreat Britain
dc.subjectHaplotypes
dc.subjectHumans
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectMutation
dc.subjectMyosin Heavy Chains
dc.subjectMyosin Subfragments
dc.subjectPedigree
dc.subjectPenetrance
dc.subjectProtein Structure, Tertiary
dc.subjectSouth Africa
dc.subjectVentricular Myosins
dc.titleMutations of the light meromyosin domain of the β-myosin heavy chain rod in hypertrophic cardiomyopathy
dc.typeArticle
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