title: Novel TBX1 loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion.
abstract: BACKGROUND
  TBX1 and CRKL haploinsufficiency is thought to cause the cardiac phenotype of the 22q11.2 deletion syndrome. However, few unequivocal mutations of TBX1 and CRKL have been discovered in isolated conotrucal heart defects (CTDs) patients. The aim of the study was to screen the mutation of TBX1 and CRKL in isolated CTDs Chinese patients without 22q11.2 deletion and identify the pathomechanism of the missense mutations.
  
  
  METHODS
  We enrolled 199 non-22q11.2 deletion patients with CTDs and 139 unrelated healthy controls. Gene sequencing were performed for all of them. The functional data of mutations were obtained by in vitro transfection and luciferase experiments and computer modelling.
  
  
  RESULTS
  Screening of the TBX1 coding sequence identified a de novo missense mutation (c.385G → A; p.E129K) and a known polymorphism (c.928G → A; p.G310S). In vitro experiments demonstrate that the TBX1E129K variant almost lost transactivation activity. The TBX1G310S variant seems to affect the interaction of TBX1 with other factors. Computer molecular dynamics simulations showed the de novo missense mutation is likely to affect TBX1-DNA interaction. No mutation of CRKL gene was found.
  
  
  CONCLUSIONS
  These observations suggest that the TBX1 loss-of-function mutation may be involved in the pathogenesis of isolated CTDs. This is the first human missense mutation showing that TBX1 is a candidate causing isolated CTDs in Chinese patients without 22q11.2 deletion.
authors.forename: Yue-Juan
authors.initials: YJ
authors.lastname: Xu
authors.forename: Sun
authors.initials: S
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Shao-Hai
authors.initials: SH
authors.lastname: Fang
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Guo
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Qi-Hua
authors.initials: QH
authors.lastname: Fu
authors.forename: Fen
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pediatric Cardiology, Xinhua hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. rang_xu@hotmail.com.
authors.forename: Rang
authors.initials: R
authors.lastname: Xu
authors.forename: Kun
authors.initials: K
authors.lastname: Sun
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D044466:Asian People / Q000235:genetics; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005260:Female; D057809:HEK293 Cells; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D010802:Phylogeny; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017422:Sequence Analysis, DNA; D020825:T-Box Domain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D009687:Nuclear Proteins; D020825:T-Box Domain Proteins; C108625:TBX1 protein, human; D004247:DNA