title: PITX2c loss-of-function mutations responsible for congenital atrial septal defects.
abstract: Congenital heart disease (CHD) is the most common form of developmental anomaly and is the leading non-infectious cause of infant mortality. A growing body of evidence demonstrates that genetic risk factors are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic determinants for CHD in most patients remain unclear. In the present study, the entire coding region and splice junction sites of the PITX2c gene, which encodes a homeobox transcription factor crucial for normal cardiovascular genesis, was sequenced in 150 unrelated patients with various CHDs. The 200 unrelated control individuals were subsequently genotyped. The functional characteristics of the mutations were explored using a dual-luciferase reporter assay system. As a result, two novel heterozygous PITX2c mutations, p.H98Q and p.M119T, were identified in 2 unrelated patients with atrial septal defects, respectively. The variations were absent in 400 control chromosomes and the affected amino acids were completely conserved evolutionarily. The two variants were both predicted to be disease-causing by MutationTaster and PolyPhen-2, and the functional analysis revealed that the PITX2c mutants were consistently associated with significantly reduced transcriptional activity compared with their wild-type counterpart. These findings firstly link PITX2c loss-of-function mutations to atrial septal defects in humans, which provide novel insight into the molecular mechanism responsible for CHD, suggesting potential implications for the early prophylaxis and allele-specific treatment of CHD.
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China.
authors: Fang
authors: F
authors: Yuan
authors: Lan
authors: L
authors: Zhao
authors: Juan
authors: J
authors: Wang
authors: Wei
authors: W
authors: Zhang
authors: Xin
authors: X
authors: Li
authors: Xing-Biao
authors: XB
authors: Qiu
authors: Ruo-Gu
authors: RG
authors: Li
authors: Ying-Jia
authors: YJ
authors: Xu
authors: Lei
authors: L
authors: Xu
authors: Xing-Kai
authors: XK
authors: Qu
authors: Wei-Yi
authors: WY
authors: Fang
authors: Yi-Qing
authors: YQ
authors: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006344:Heart Septal Defects, Atrial / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2
keywords: Atrial septal defect; Congenital heart disease; Genetics; PITX2c; Transcription factor
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