TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

Abstract

Abstract. Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the TBX1 gene that codes for a T-box transcription factor essential for normal cardiovascular development, may contribute to the development of CTD. CTDs are genetically heterogeneous and the genetic defects responsible for CTDs in the majority of patients remain unknown. The present study sequenced the coding regions and splicing junction boundaries of TBX1 in 136 patients with CTDs and 300 matched healthy individuals. The disease-causing potential of the identified TBX1 sequence variation was evaluated using MutationTaster, PolyPhen-2, SIFT and PROVEN software. The functional characteristics of the mutant TBX1 gene were defined using a dual-luciferase reporter assay system. A novel heterozygous TBX1 mutation, p.S233Y, was identified in a patient with transposition of the great arteries (TGA) and a ventricular septal defect. This mutation was absent in the 300 controls and altered the amino acid produced, serine, which is evolutionarily conserved across several species, and was predicted to be pathogenic in silico. Luciferase assays conducted in COS-7 cells demonstrated that the newly identified TBX1 mutation was associated with significantly diminished transcriptional activation of the ANF promoter compared with the wild-type TBX1. To the best of our knowledge, the present study is the first to associate a TBX1 loss-of-function mutation with enhanced susceptibility to TGA, which adds significant insight to the molecular mechanism of TGA.

Genetic Imbalances in Argentinean Patients with Congenital Conotruncal Heart Defects

“…Different size of deletions in TBX1 have been reported in patients with VCF/DiGeorge syndrome [ 57 , 58 ]. In addition, TBX1 point mutations have also been linked to non-syndromic CHD in humans, including isolated TOF, VSD, PA, DORV, IAA and aortic arch anomalies [ 59 , 60 , 61 , 62 ]. Moreover, some authors reported that Tbx1 deficiency in mice may cause dosage-dependent anomalies of the cardiac outflow tract [ 63 , 64 , 65 ].…”

Intronic Polymorphisms in Gene of Second Heart Field as Risk Factors for Human Congenital Heart Disease in a Chinese Population

“…And dysregulation of TBX1 could lead to variant CHDs, including VSD, ASD, PDA, TOF, PA or PS with VSD. In other studies, the TBX1 loss-of-function mutation was found to contribute to congenital conotruncal defects in humans (Xu et al, 2014;Zhang et al, 2018).…”

“…Tbx1 also interacts with Foxa2 and is necessary for its expression in the pharyngeal mesoderm (Hu et al, 2004). Patients with haploinsufficiency for Tbx1 present a spectrum of conotruncal anomalies, including PA (Xu et al, 2011;Zhang et al, 2018).…”

“…The knockout of these genes could lead to different types of CHDs in mice (Dai, 2002;Cai et al, 2003;Dodou, 2004;Phan et al, 2005;Takeuchi, 2005;Vong et al, 2006;Tsuchihashi et al, 2011). Further studies revealed that the mutations in SHF genes played important roles in human CHDs (Huang et al, 2017;Wang et al, 2017;Li et al, 2018a;Xu et al, 2018;Zhang et al, 2018).…”

“…Although mutations of genes such as GATA4, GATA6, and TBX1 induce various CHDs in humans (Chen et al, 2016;Xu et al, 2018;Zhang et al, 2018), the associations of SHF intronic variations with CHDs remain unclear. This study revealed several intronic SNPs in the gene of SHF associated with CHDs.…”