title: Compound heterozygosity deteriorates phenotypes of hypertrophic cardiomyopathy with founder MYBPC3 mutation: evidence from patients and zebrafish models.
abstract: Although most founder mutation carriers of hypertrophic cardiomyopathy (HCM), such as the cardiac myosin-binding protein C gene (MYBPC3), arose from a common ancestor exhibit favorable clinical phenotypes, there still remain small fractions of these carriers associated with increased cardiovascular events. However, few data exist regarding the defining factors that modify phenotypes of these patients, particularly in terms of multiple gene mutations. Therefore, we assessed genotype-phenotype correlations and investigated factors that contribute to phenotypic diversities of mutation carriers from 488 unrelated HCM probands. A prevalent founder mutation (Val762Asp) in MYBPC3 was identified in 33 subjects from 19 families. Among them, 28 carriers harbored an isolated Val762Asp mutation and exhibited a late onset of overt HCM compared with other MYBPC3 mutation carriers (62.8 ± 3.0 vs 50.1 ± 2.6 yr, P < 0.05). In contrast, the remaining five carriers had additional sarcomere gene mutations (3 carriers in MYBPC3 and 2 carriers in the cardiac troponin T gene). Of these five carriers, two carriers showed early disease onset and one carrier exhibited end-stage HCM. These phenotypes were recapitulated in zebrafish models; injection of MYBPC3 Val762Asp alone did not alter ventricular size or function, but ventricular dimension was significantly increased when MYBPC3 Val762Asp mRNA was coinjected with MYBPC3 Arg820Gln mRNA. These results demonstrate that MYBPC3 Val762Asp may be associated with unfavorable HCM phenotypes in some cases when combined with another MYBPC3 mutation.
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; and.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Hodatsu
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; and Research and Education Center for Innovative and Preventive Medicine, Kanazawa University, Kanazawa, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Konno
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; and.
authors.forename: Kenshi
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; and.
authors.forename: Akira
authors.initials: A
authors.lastname: Funada
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; and.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; and.
authors.forename: Noboru
authors.initials: N
authors.lastname: Fujino
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; and.
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Kawashiri
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; and myamagi@med.m.kanazawa-u.ac.jp.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamagishi
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology; D000818:Animals; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012518:Sarcomeres / Q000235:genetics / Q000473:pathology; D015027:Zebrafish / Q000502:physiology*; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C
keywords: cardiac remodeling; compound heterozygotes; hypertrophic cardiomyopathy; myosin-binding protein C