title: PITX2 loss-of-function mutation contributes to tetralogy of Fallot.
abstract: Congenital heart disease (CHD) is the most prevalent developmental abnormality in humans and is the most common non-infectious cause of infant morbidity and mortality. Increasing evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous, and the genetic determinants underpinning CHD in most patients remain unknown. In this study, the whole coding region of the PITX2 gene (isoform c) was sequenced in 185 unrelated patients with CHD. The available relatives of a mutation carrier and 300 unrelated healthy individuals used as controls were also genotyped for PITX2. The functional characteristics of the mutation were delineated by using a dual-luciferase reporter assay system. As a result, a novel heterozygous PITX2 mutation, p.Q102L, was identified in a patient with tetralogy of Fallot (TOF). Genetic analysis of the index patient's pedigree showed that the mutation co-segregated with TOF. The mutation was absent in 600 reference chromosomes. Biochemical analysis revealed that the Q102L-mutant PITX2 is associated with significantly reduced transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation markedly decreased the synergistic activation between PITX2 and NKX2-5. This study firstly associates PITX2 loss-of-function mutation with increased susceptibility to TOF, providing novel insight into the molecular mechanism of CHD.
authors.affiliation: Department of Cardiology, Jing'an District Central Hospital, 259 Xikang Road, Shanghai 200040, PR China.
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Jing'an District Central Hospital, 259 Xikang Road, Shanghai 200040, PR China. Electronic address: wang_jun98@sina.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, PR China.
authors.forename: Xing-Biao
authors.initials: XB
authors.lastname: Qiu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, PR China.
authors.forename: Ying-Jia
authors.initials: YJ
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, PR China.
authors.forename: Ruo-Gu
authors.initials: RG
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, PR China.
authors.forename: Xin-Kai
authors.initials: XK
authors.lastname: Qu
authors.affiliation: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, PR China.
authors.forename: Ri-Tai
authors.initials: RT
authors.lastname: Huang
authors.affiliation: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, PR China.
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, PR China; Department of Cardiovascular Research Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, PR China; Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, PR China. Electronic address: dryyq@tongji.edu.cn.
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002675:Child, Preschool; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D019683:Penetrance; D012333:RNA, Messenger / Q000235:genetics; D013771:Tetralogy of Fallot / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2
keywords: Congenital heart disease; Genetics; PITX2; Reporter gene assay; Tetralogy of Fallot; Transcription factor