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Gene. 2016 Feb 15;577(2):258-64. doi: 10.1016/j.gene.2015.12.001. Epub 2015 Dec 2.

PITX2 loss-of-function mutation contributes to tetralogy of Fallot.

Author information

1
Department of Cardiology, Jing'an District Central Hospital, 259 Xikang Road, Shanghai 200040, PR China.
2
Department of Cardiology, Jing'an District Central Hospital, 259 Xikang Road, Shanghai 200040, PR China. Electronic address: wang_jun98@sina.cn.
3
Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, PR China.
4
Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, PR China.
5
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.

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.

KEYWORDS:

Congenital heart disease; Genetics; PITX2; Reporter gene assay; Tetralogy of Fallot; Transcription factor

PMID:
26657035
DOI:
10.1016/j.gene.2015.12.001
[Indexed for MEDLINE]

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