PITX2c Loss-of-Function Mutations Responsible for Congenital Atrial Septal Defects

Fang, Yuan; Zhao, Lan; Wang, Juan; Zhang, Wei; Li, Xin; Qiu, Xing‐Biao; Li, Ruogu; Xu, Ying‐Jia; Xu, Lei; Qu, Xing-Kai; Fang, Wei-Yi; Yang, Yi‐Qing

doi:10.7150/ijms.6809

Cited by 22 publications

(10 citation statements)

References 47 publications

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“…Subsequent screening in a small cohort of transposition of great arteries (TGA) patients similarly failed to identify PITX2 causal mutations [ 122 ]. More recently, PITX2 point mutations have been identified in distinct isolated cardiac congenital heart diseases [ 123 ], such as atrial septal defects (ASD) [ 124 ], TGA [ 125 ], ventricular septal defect (VSD) [ 125 , 126 ] and Tetralogy of Fallot [ 127 ]. A PITX2 mutation has also been identified in a patient with compound congenital heart disease (CHD), i.e., DORV and VSD.…”

Section: Pitx2 and Congenital Heart Diseasesmentioning

confidence: 99%

“…A PITX2 mutation has also been identified in a patient with compound congenital heart disease (CHD), i.e., DORV and VSD. In all cases, functional analyses of their corresponding PITX2 mutation leads to decreased transcriptional activity and reduced synergistic activation with NKX2.5 [ 124 , 125 , 126 , 127 ] ( Table 1 ). Furthermore, point mutations in CITED2 , identified in a Tetralogy of Fallot patient with aortic stenosis, impaired PITX2 and VEGF expression [ 128 ], further support a functional role for PITX2 in this type of CHD.…”

Section: Pitx2 and Congenital Heart Diseasesmentioning

confidence: 99%

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Multiple Roles of Pitx2 in Cardiac Development and Disease

Franco

Sedmera

Lozano-Velasco

2017

JCDD

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Cardiac development is a complex morphogenetic process initiated as bilateral cardiogenic mesoderm is specified at both sides of the gastrulating embryo. Soon thereafter, these cardiogenic cells fuse at the embryonic midline configuring a symmetrical linear cardiac tube. Left/right bilateral asymmetry is first detected in the forming heart as the cardiac tube bends to the right, and subsequently, atrial and ventricular chambers develop. Molecular signals emanating from the node confer distinct left/right signalling pathways that ultimately lead to activation of the homeobox transcription factor Pitx2 in the left side of distinct embryonic organ anlagen, including the developing heart. Asymmetric expression of Pitx2 has therefore been reported during different cardiac developmental stages, and genetic deletion of Pitx2 provided evidence of key regulatory roles of this transcription factor during cardiogenesis and thus congenital heart diseases. More recently, impaired Pitx2 function has also been linked to arrhythmogenic processes, providing novel roles in the adult heart. In this manuscript, we provide a state-of-the-art review of the fundamental roles of Pitx2 during cardiogenesis, arrhythmogenesis and its contribution to congenital heart diseases.

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Section: Pitx2 and Congenital Heart Diseasesmentioning

confidence: 99%

Section: Pitx2 and Congenital Heart Diseasesmentioning

confidence: 99%

Multiple Roles of Pitx2 in Cardiac Development and Disease

Franco

Sedmera

Lozano-Velasco

2017

JCDD

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“…In mice, targeted deletion of PITX2c has been shown to lead to embryonic lethality due to distinct types of CHD, including atrial isomerism, double-outlet right ventricle, atrial septal defect, ventricular septal defect, transposition of the great arteries, and abnormal aortic arch, as well as incomplete closure of the body wall (42). In humans, PITX2c mutations have been implicated in congenital atrial septal defect, ventricular septal defect, double outlet of the right ventricle and atrial fibrillation (51)(52)(53)(54). These findings justify screening PITX2c in other cohorts of patients with CHD.…”

Section: Introductionmentioning

confidence: 63%

Novel PITX2c loss-of-function mutations associated with complex congenital heart disease

Wei

Gong

Qiu

et al. 2014

International Journal of Molecular Medicine

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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.

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“…Wang and co-workers [ 82 ] screened PITX2c in 382 unrelated patients with CHDs and found two heterozygous mutations, p.W147X and p.N153D, in two patients with CHD, respectively, including a one-year-old male patient with double outlet right ventricle in combination with ventricular septal defect and a four-year-old female patient with isolated ventricular septal defect. Yuan et al [ 83 ] scanned PITX2c in 150 unrelated patients with CHDs and identified two novel heterozygous PITX2c mutations, p.H98Q and p.M119T, in two patients with atrial septal defects, respectively. Wei and colleagues [ 84 ] also sequenced PITX2c in 170 unrelated neonates with CHDs and detected two novel heterozygous PITX2c mutations, p.R91Q and p.T129S, in two unrelated newborns with transposition of the great arteries and ventricular septal defect, respectively.…”

Section: Discussionmentioning

confidence: 99%

PITX2 Loss-of-Function Mutation Contributes to Congenital Endocardial Cushion Defect and Axenfeld-Rieger Syndrome

Zhao

Peng

et al. 2015

PLoS ONE

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Congenital heart disease (CHD), the most common type of birth defect, is still the leading non-infectious cause of infant morbidity and mortality in humans. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous and the genetic components underpinning CHD in an overwhelming majority of patients remain unclear. In the present study, the coding exons and flanking introns of the PITX2 gene, which encodes a paired-like homeodomain transcription factor 2essential for cardiovascular morphogenesis as well as maxillary facial development, was sequenced in 196 unrelated patients with CHD and subsequently in the mutation carrier’s family members available. As a result, a novel heterozygous PITX2 mutation, p.Q102X for PITX2a, or p.Q148X for PITX2b, or p.Q155X for PITX2c, was identified in a family with endocardial cushion defect (ECD) and Axenfeld-Rieger syndrome (ARS). Genetic analysis of the pedigree showed that the nonsense mutation co-segregated with ECD and ARS transmitted in an autosomal dominant pattern with complete penetrance. The mutation was absent in 800 control chromosomes from an ethnically matched population. Functional analysis by using a dual-luciferase reporter assay system revealed that the mutant PITX2 had no transcriptional activity and that the mutation eliminated synergistic transcriptional activation between PITX2 and NKX2.5, another transcription factor pivotal for cardiogenesis. To our knowledge, this is the first report on the association of PITX2 loss-of-function mutation with increased susceptibility to ECD and ARS. The findings provide novel insight into the molecular mechanisms underpinning ECD and ARS, suggesting the potential implications for the antenatal prophylaxis and personalized treatment of CHD and ARS.

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PITX2c Loss-of-Function Mutations Responsible for Congenital Atrial Septal Defects

Cited by 22 publications

References 47 publications

Multiple Roles of Pitx2 in Cardiac Development and Disease

Multiple Roles of Pitx2 in Cardiac Development and Disease

Novel PITX2c loss-of-function mutations associated with complex congenital heart disease

PITX2 Loss-of-Function Mutation Contributes to Congenital Endocardial Cushion Defect and Axenfeld-Rieger Syndrome

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