title: Novel PITX2c loss-of-function mutations associated with complex congenital heart disease.
abstract: Congenital heart disease (CHD) is the most common form of birth defect in humans and is the leading non-infectious cause of infant mortality. Emerging evidence strongly suggests that genetic risk factors play an important role in the pathogenesis of CHD. However, CHD is of pronounced genetic heterogeneity, and the genetic defects responsible for CHD in an overwhelming majority of patients remain unclear. In this study, the entire coding region and splice junction sites of the PITX2c gene, which encodes a paired-like homeodomain transcription factor crucial for proper cardiovascular morphogenesis, was sequenced in 170 unrelated neonates with CHD. The available relatives of the mutation carriers and 200 unrelated ethnically matched healthy individuals were genotyped. The disease-causing potential of the PITX2c sequence variations was predicted by MutationTaster and PolyPhen-2. The functional effect of the mutations was characterized using a luciferase reporter assay system. As a result, 2 novel heterozygous PITX2c mutations, p.R91Q and p.T129S, were identified in 2 unrelated newborns with transposition of the great arteries and ventricular septal defect, respectively. A genetic scan of the pedigrees revealed that each mutation co-segregated with CHD transmitted in an autosomal dominant pattern with complete penetrance. The mutations, which altered the amino acids completely conserved evolutionarily, were absent in 400 normal chromosomes and were predicted to be causative. Functional analysis revealed that the PITX2c mutations were both associated with significantly diminished transcriptional activity compared with their wild-type counterpart. This study demonstrates the association between PITX2c loss-of-function mutations and the transposition of the great arteries and ventricular septal defect in humans, providing further insight into the molecular mechanisms responsible for CHD.
authors.affiliation: Department of Neonatology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, P.R. China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Neonatology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, P.R. China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Gong
authors.affiliation: Department of Neonatology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Qiu
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Cardiovascular Research Laboratory and Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2