HGM2002 Poster Abstracts: 8. Disease Mechanisms
POSTER NO: 399
Mechanism of Disease and Genetic and Phenotypic Characterization of Mutations in Myosin Binding Protein C (MYBPC3) in 81 Consecutive Families with Hypertrophic Cardiomyopathy
1Paal S. Andersen, 2Ole Havndrup, 2Henning Bundgaard, 3Jens Mogensen, 4Lars A. Larsen, 5Anders BÝrglum, 1Jens Vuust, 3Anders K. Pedersen, 2Keld Kjeldsen, 1Michael Christiansen
Mutations in the gene, MYBPC3, coding for the sarcomeric protein myosin binding protein-C (MyBPC) are a major cause of autosomal dominant familial hypertrophic cardiomyopathy (FHC). We studied the frequency, type, and clinical features of MYBPC3 mutations in an unselected cohort of 81 FHC families, consecutively enrolled from a tertiary referral center. All 34 coding exons in MYBPC3 were examined by SSCP and DNA sequencing. Splicing of mRNA was examined in leukocytes.
Eleven mutations, nine of which were novel, were found in 10 families (12.3%). Four mutations were base substitutions (D228, E258K, A833T, V986M), three were deletions (in exon 2, exon 13, and intron 31), two were intronic substitutions (intron 8 and 16), and two were insertions (exon 24 and 25). Eighteen single nucleotide polymorphisms, SNPs, were found, including one amino acid polymorphism (S236G) with a frequency of 9%. A nonsense mutation in exon 2, resulting in no detectable mRNA synthesis from the affected allele, in a family with highly penetrant FHC and two children with marked septal hypertrophy, provides the first direct evidence that haploinsuffiency is a pathogenetic mechanism in FHC. Two splice-site mutations were studied at the mRNA level and shown to result in exon skipping. In three families with a MYBPC3 mutation (33%) an additional mutation was found in MYH7 coding for the heavy chain of beta-myosin. This high frequency of double mutations makes it imperative that the clinical use of mutational knowledge in FHC is done with extreme caution and makes it necessary to reevaluate studies where not both MYBPC3 and MYH7 have been examined in the same patients.
The number of mutations and the size of the examined families precluded a clear definition of a phenotype-genotype relationship, but a number of symptom free gene carriers were identified, predominantly women and children.
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