title: HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy.
abstract: BACKGROUND
  The basic helix-loop-helix transcription factor HAND1 is essential for cardiac development and structural remodeling, and mutations in HAND1 have been causally linked to various congenital heart diseases. However, whether genetically compromised HAND1 predisposes to dilated cardiomyopathy (DCM) in humans remains unknown.
  
  
  METHODS
  The whole coding region and splicing junctions of the HAND1 gene were sequenced in 140 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 260 unrelated ethnically matched healthy individuals used as controls were genotyped for HAND1. The functional effect of the mutant HAND1 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system.
  
  
  RESULTS
  A novel heterozygous HAND1 mutation, p.R105X, was identified in a family with DCM transmitted as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The nonsense mutation was absent in 520 control chromosomes. Functional analyses unveiled that the mutant HAND1 had no transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM.
  
  
  CONCLUSIONS
  This study firstly reports the association of HAND1 loss-of-function mutation with increased susceptibility to DCM in humans, which provides novel insight into the molecular mechanisms underpinning DCM.
authors.forename: Yi-Meng
authors.initials: YM
authors.lastname: Zhou
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Dai
authors.forename: Xing-Biao
authors.initials: XB
authors.lastname: Qiu
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.forename: Ruo-Gu
authors.initials: RG
authors.lastname: Li
authors.forename: Ying-Jia
authors.initials: YJ
authors.lastname: Xu
authors.forename: Xin-Kai
authors.initials: XK
authors.lastname: Qu
authors.forename: Ri-Tai
authors.initials: RT
authors.lastname: Huang
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis* / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D041681:NIH 3T3 Cells; D010375:Pedigree; D010641:Phenotype
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D008156:Luciferases; C097341:helix-loop-helix protein, eHAND