Novel TBX1 loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion.
Novel TBX1 loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion.
复制标题
新型TBX1功能丧失突变导致中国患者出现孤立性圆锥干心脏缺陷，无22q11.2缺失
DOI：
10.1186/1471-2350-15-78
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发表时间：
2014-07-06
影响因子：
--
通讯作者：
Sun K
中科院分区：
文献类型：
--
作者：
Xu YJ;Chen S;Zhang J;Fang SH;Guo QQ;Wang J;Fu QH;Li F;Xu R;Sun K
背景：TBX 1和CRKL单倍不足被认为是导致22q11.2缺失综合征的心脏表型。然而，在孤立的圆锥形心脏缺陷（CTD）患者中很少发现TBX 1和CRKL的明确突变。本研究的目的是筛查中国孤立性CTD患者中TBX 1和CRKL基因的突变，并确定错义突变的病理机制。对所有样本进行基因测序。结果：TBX 1基因编码区存在一个错义突变（c.385G → A; p.E129K）和一个已知的多态性（c.928G → A; p.G310S）。体外实验表明TBX 1 E129 K变体几乎丧失了反式激活活性。TBX 1G 310 S变异体似乎影响TBX 1与其他因子的相互作用。计算机分子动力学模拟结果表明，TBX 1的错义突变可能影响TBX 1与DNA的相互作用。结论：TBX 1基因功能缺失突变可能与CTD的发病有关。这是第一个人类错义突变，表明TBX 1是导致中国患者孤立性CTD的候选基因，而没有22q11.2缺失。
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 TBX1E129K variant almost lost transactivation activity. The TBX1G310S 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.
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影响因子：
11.8
作者：
Guris, DL;Duester, G;Imamoto, A
通讯作者：
Imamoto, A
影响因子：
1.9
作者：
Meneghini, V;Odent, S;Merlo, GR
通讯作者：
Merlo, GR
DOI：
10.1073/pnas.0600206103
发表时间：
2006-05-16
影响因子：
11.1
作者：
Paylor, Richard;Glaser, Beate;Lindsay, Elizabeth
通讯作者：
Lindsay, Elizabeth
影响因子：
1.6
作者：
Scambler, Peter J.
通讯作者：
Scambler, Peter J.
影响因子：
4
作者：
Rauch, Ralf;Hofbeck, Michael;Rauch, Anita
通讯作者：
Rauch, Anita