Novel TBX1 loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion

BMC Medical Genetics

Kun Sun⁴  Rang Xu⁵  Fen Li⁴  Qi-Hua Fu¹  Jian Wang¹  Qian-Qian Guo²  Shao-Hai Fang²  Jian Zhang³  Sun Chen²  Yue-Juan Xu² 

[1]Medical Laboratory, Shanghai Children’s Medical Center, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200127, China

[2]Department of Pediatric Cardiology, Xinhua hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China

[3]Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

[4]Department of Pediatric Cardiology, Shanghai Children’s Medical Center, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200127, China

[5]Scientific Research Center, Xinhua hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China

关键词: Molecular dynamics simulation;    Conotruncal heart defects;    22q11.2 deletion;    TBX1 haploinsufficiency;   

Others  :  848340
DOI  :  10.1186/1471-2350-15-78

 received in 2014-03-12, accepted in 2014-06-24,  发布年份 2014

【 摘 要 】

Background

TBX1 and CRKL haploinsufficiency is thought to cause the cardiac phenotype of the 22q11.2 deletion syndrome. However, few unequivocal mutations of TBX1 and CRKL have been discovered in isolated conotrucal heart defects (CTDs) patients. The aim of the study was to screen the mutation of TBX1 and CRKL in isolated CTDs Chinese patients without 22q11.2 deletion and identify the pathomechanism of the missense mutations.

Methods

We enrolled 199 non-22q11.2 deletion patients with CTDs and 139 unrelated healthy controls. Gene sequencing were performed for all of them. The functional data of mutations were obtained by in vitro transfection and luciferase experiments and computer modelling.

Results

Screening of the TBX1 coding sequence identified a de novo missense mutation (c.385G → A; p.E129K) and a known polymorphism (c.928G → A; p.G310S). In vitro experiments demonstrate that the TBX1^E129K variant almost lost transactivation activity. The TBX1^G310S variant seems to affect the interaction of TBX1 with other factors. Computer molecular dynamics simulations showed the de novo missense mutation is likely to affect TBX1-DNA interaction. No mutation of CRKL gene was found.

Conclusions

These observations suggest that the TBX1 loss-of-function mutation may be involved in the pathogenesis of isolated CTDs. This is the first human missense mutation showing that TBX1 is a candidate causing isolated CTDs in Chinese patients without 22q11.2 deletion.

【 授权许可】

   
2014 Xu et al.; licensee BioMed Central Ltd.

【 图 表 】

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