Genetic and phenotypic characterization of mutations in myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophic cardiomyopathy: Total or partial haploinsufficiency

Paal S. Andersen, Ole Havndrup, Henning Bundgaard, Lars A. Larsen, Jens Vuust, Anders K. Pedersen, Keld Kjeldsen, Michael Christiansen

    Publikation: Bidrag til tidsskriftArtikelForskningpeer review

    Abstrakt

    Mutations in the MYBPC3 gene, encoding the sarcomere protein myosin-binding protein C, are among the most frequent causes of autosomal dominant familial hypertrophic cardiomyopathy (FHC). We studied the frequency, type, and pathogenetic mechanism of MYBPC3 mutations in an unselected cohort of 81 FHC families, consecutively enrolled at a tertiary referral center. Nine mutations, six of which were novel, were found in 10 (12.3%) of the families using single-strand conformation polymorphism and DNA sequencing. A frameshift mutation in exon 2 clearly suggests that haploinsufficiency is a pathogenetic mechanism in FHC. In addition, splice site mutations in exon 6 and intron 31, a deletion in exon 13, and a nonsense mutation in exon 25, all lead to premature termination codons, most likely causing loss of function and haploinsufficiency. Furthermore, there were two missense mutations (D228N and A833 T) and one inframe deletion (ΔLys813). A considerable intrafamilial variation in phenotypic expression of MYBPC3-based FHC was noted, and we suggest that mutations influencing stability of mRNA could play a role in the variable penetrance and expressivity of the disease, perhaps via partial haploinsuffciency.

    OriginalsprogEngelsk
    Sider (fra-til)673-677
    Antal sider5
    TidsskriftEuropean Journal of Human Genetics
    Vol/bind12
    Udgave nummer8
    DOI
    StatusUdgivet - 1 aug. 2004

    Fingeraftryk Udforsk hvilke forskningsemner 'Genetic and phenotypic characterization of mutations in myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophic cardiomyopathy: Total or partial haploinsufficiency' indeholder.

    Citationsformater