title: CASZ1 loss-of-function mutation contributes to familial dilated cardiomyopathy.
abstract: BACKGROUND
  The zinc finger transcription factor CASZ1 plays a key role in cardiac development and postnatal adaptation, and in mice, deletion of the CASZ1 gene leads to dilated cardiomyopathy (DCM). However, in humans whether genetically defective CASZ1 contributes to DCM remains unclear.
  
  
  METHODS
  The coding exons and splicing junction sites of the CASZ1 gene were sequenced in 138 unrelated patients with idiopathic DCM. The available family members of the index patient harboring an identified CASZ1 mutation and 200 unrelated, ethnically matched healthy individuals used as controls were genotyped for CASZ1. The functional characteristics of the mutant CASZ1 were analyzed in contrast to its wild-type counterpart using a luciferase reporter assay system.
  
  
  RESULTS
  A novel heterozygous CASZ1 mutation, p.K351X, was identified in an index patient with DCM. Genetic analysis of the mutation carrier's family showed that the mutation co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation, which was absent in 400 referential chromosomes, altered the amino acid that was highly conserved evolutionarily. Biological investigations revealed that the mutant CASZ1 had no transcriptional activity.
  
  
  CONCLUSIONS
  The current study reveals CASZ1 as a new gene responsible for human DCM, which provides novel mechanistic insight and potential therapeutic target for CASZ1-associated DCM, implying potential implications in improved prophylactic and therapeutic strategies for DCM, the most common type of primary myocardial disease.
authors.affiliation: .
authors.forename: Xing-Biao
authors.initials: XB
authors.lastname: Qiu
authors.affiliation: .
authors.forename: Xin-Kai
authors.initials: XK
authors.lastname: Qu
authors.affiliation: .
authors.forename: Ruo-Gu
authors.initials: RG
authors.lastname: Li
authors.affiliation: .
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.affiliation: .
authors.forename: Ying-Jia
authors.initials: YJ
authors.lastname: Xu
authors.affiliation: .
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: .
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Shi
authors.affiliation: .
authors.forename: Xu-Min
authors.initials: XM
authors.lastname: Hou
authors.affiliation: .
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: .
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: .
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Sun
authors.affiliation: .
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: .
authors.forename: Ri-Tai
authors.initials: RT
authors.lastname: Huang
authors.affiliation: .
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.affiliation: .
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C511127:CASZ1 protein, human; D004268:DNA-Binding Proteins; D014157:Transcription Factors
keywords: CASZ1; dilated cardiomyopathy; genetics; reporter gene assay; transcription factor