title: ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene.
abstract: OBJECTIVE
  We evaluated ankyrin repeat domain 1 (ANKRD1), the gene encoding cardiac ankyrin repeat protein (CARP), as a novel candidate gene for dilated cardiomyopathy (DCM) through mutation analysis of a cohort of familial or idiopathic DCM patients, based on the hypothesis that inherited dysfunction of mechanical stretch-based signaling is present in a subset of DCM patients.
  
  
  BACKGROUND
  CARP, a transcription coinhibitor, is a member of the titin-N2A mechanosensory complex and translocates to the nucleus in response to stretch. It is up-regulated in cardiac failure and hypertrophy and represses expression of sarcomeric proteins. Its overexpression results in contractile dysfunction.
  
  
  METHODS
  In all, 208 DCM patients were screened for mutations/variants in the coding region of ANKRD1 using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. In vitro functional analyses of the mutation were performed using yeast 2-hybrid assays and investigating the effect on stretch-mediated gene expression in myoblastoid cell lines using quantitative real-time reverse transcription-polymerase chain reaction.
  
  
  RESULTS
  Three missense heterozygous ANKRD1 mutations (P105S, V107L, and M184I) were identified in 4 DCM patients. The M184I mutation results in loss of CARP binding with Talin 1 and FHL2, and the P105S mutation in loss of Talin 1 binding. Intracellular localization of mutant CARP proteins is not altered. The mutations result in differential stretch-induced gene expression compared with wild-type CARP.
  
  
  CONCLUSIONS
  ANKRD1 is a novel DCM gene, with mutations present in 1.9% of DCM patients. The ANKRD1 mutations may cause DCM as a result of disruption of the normal cardiac stretch-based signaling.
authors.affiliation: Department of Pediatrics, Division of Cardiology, University of Texas Medical School Houston, Houston, Texas, USA.
authors.forename: Mousumi
authors.initials: M
authors.lastname: Moulik
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.forename: Anita M
authors.initials: AM
authors.lastname: Arola
authors.forename: Ross T
authors.initials: RT
authors.lastname: Murphy
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.forename: Aladin M
authors.initials: AM
authors.lastname: Boriek
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Oka
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bowles
authors.forename: Takuro
authors.initials: T
authors.lastname: Arimura
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C491304:ANKRD1 protein, human; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins