ZFIN ID: ZDB-PUB-141005-4
Compound Heterozygosity Deteriorates Phenotypes of Hypertrophic Cardiomyopathy with Founder MYBPC3 Mutation: Evidence From Patients and Zebrafish Models
Hodatsu, A., Konno, T., Hayashi, K., Funada, A., Fujita, T., Nagata, Y., Fujino, N., Kawashiri, M.A., Yamagishi, M.
Date: 2014
Source: American journal of physiology. Heart and circulatory physiology   307(11): H1594-604 (Journal)
Registered Authors:
Keywords: Cardiac remodeling, Compound heterozygotes, Hypertrophic cardiomyopathy, Myosin binding protein C
MeSH Terms:
  • Adult
  • Aged
  • Aging/physiology
  • Animals
  • Cardiomyopathy, Hypertrophic, Familial/genetics*
  • Carrier Proteins/genetics*
  • Female
  • Genotype
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation/genetics
  • Pedigree
  • Phenotype
  • Sarcomeres/genetics
  • Sarcomeres/pathology
  • Zebrafish/physiology*
PubMed: 25281569 Full text @ Am. J. Physiol. Heart Circ. Physiol.
Although most of founder mutation carriers of hypertrophic cardiomyopathy (HCM) such as cardiac myosin-binding protein C gene (MYBPC3) that 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 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 the mutation carriers from 488 unrelated HCM probands. A prevalent founder mutation (Val762Asp) in the MYBPC3 was identified in 33 subjects from 19 families. Among them, 28 carriers harbored isolated Val762Asp mutation and exhibited a late onset of overt HCM than other MYBPC3 mutations carriers (62.8±3.0 years vs 50.1±2.6 years, p<0.05). In contrast, remaining 5 carriers had additional sarcomere-genes mutations (3 in the MYBPC3, 2 in the cardiac troponin T gene). Of these 5 carriers, 2 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 the ventricular dimension or function, but the ventricular dimension was significantly increased when MYBPC3 Val762Asp mRNA was co-injected with MYBPC3 Arg820Gln mRNA. These results demonstrate that MYBPC3 Val762Asp may be associated with unfavorable HCM phenotypes in some cases when combined with another MyBP-C mutations.