title: Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy.
abstract: OBJECTIVE
  The purpose of this study was to explore a novel disease gene for hypertrophic cardiomyopathy (HCM) and to evaluate functional alterations caused by mutations.
  
  
  BACKGROUND
  Mutations in genes encoding myofilaments or Z-disc proteins of the cardiac sarcomere cause HCM, but the disease-causing mutations can be found in one-half of the patients, indicating that novel HCM-susceptibility genes await discovery. We studied a candidate gene, ankyrin repeat domain 1 (ANKRD1), encoding for the cardiac ankyrin repeat protein (CARP) that is a Z-disc component interacting with N2A domain of titin/connectin and N-terminal domain of myopalladin.
  
  
  METHODS
  We analyzed 384 HCM patients for mutations in ANKRD1 and in the N2A domain of titin/connectin gene (TTN). Interaction of CARP with titin/connectin or myopalladin was investigated using coimmunoprecipitation assay to demonstrate the functional alteration caused by ANKRD1 or TTN mutations. Functional abnormalities caused by the ANKRD1 mutations were also examined at the cellular level in neonatal rat cardiomyocytes.
  
  
  RESULTS
  Three ANKRD1 missense mutations, Pro52Ala, Thr123Met, and Ile280Val, were found in 3 patients. All mutations increased binding of CARP to both titin/connectin and myopalladin. In addition, TTN mutations, Arg8500His, and Arg8604Gln in the N2A domain were found in 2 patients, and these mutations increased binding of titin/connectin to CARP. Myc-tagged CARP showed that the mutations resulted in abnormal localization of CARP in cardiomyocytes.
  
  
  CONCLUSIONS
  CARP abnormalities may be involved in the pathogenesis of HCM.
authors.affiliation: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. akitis@mri.tmd.ac.jp
authors.forename: Takuro
authors.initials: T
authors.lastname: Arimura
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Bos
authors.forename: Akinori
authors.initials: A
authors.lastname: Sato
authors.forename: Toru
authors.initials: T
authors.lastname: Kubo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nishi
authors.forename: Haruhito
authors.initials: H
authors.lastname: Harada
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Koga
authors.forename: Mousumi
authors.initials: M
authors.lastname: Moulik
authors.forename: Yoshinori L
authors.initials: YL
authors.lastname: Doi
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: C491304:ANKRD1 protein, human; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins