Rare variants in TULP3 abolish the suppressive effect on sonic hedgehog signaling and contribute to human neural tube defects.
Rare variants in TULP3 abolish the suppressive effect on sonic hedgehog signaling and contribute to human neural tube defects.
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DOI：
10.1016/j.gendis.2021.11.010
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发表时间：
2022-09
期刊：
影响因子：
6.8
通讯作者：
Wang, Hongyan
中科院分区：
文献类型：
--
作者：
Kuang, Lele;Jiang, Yuchao;Chen, Shuxia;Su, Ke;Peng, Rui;Yang, Xueyan;Wang, Hongyan
神经管缺陷（NTD）是最常见的人类出生缺陷之一，影响全球约1/1000的活产婴儿。1 NTD的病因归因于复杂的遗传和环境危险因素。超过200个基因已被确定在动物模型中引起NTD，这表明NTD病因学中涉及不同的分子基础，包括Sonic hedgehog（Shh）信号传导。近年来，一些Shh通路的负调控因子无效突变体显示出严重的NTDs，表明Shh信号的异常激活通常与NTDs有关。2 Tubby样蛋白3（Tulp 3）是Shh信号传导的典型阻遏物，敲除Tulp 3可导致小鼠严重的头部和尾部NTD。3这强烈暗示了TULP 3对胚胎神经管发育是必需的，并且TULP 3的变体可能有助于人类NTDs，这到目前为止还没有被证明。为了阐明这一点，我们在中国NTDs队列中进行了下一代测序，包括352名患者和224名匹配的健康对照，以筛选TULP 3变体。我们确定了三种病例特异性罕见变异：c。871C> T（p. Arg291Trp），c. 1115C> G（p.Thr372Ser）和c. 1144 C> T（p.Arg382Trp）在TULP 3中的表达，其仅发生在NTDs患者中，并且在我们的对照中完全不存在。变异携带者的临床表型见表S1。所有这三种变体都是杂合的，并通过桑格测序进行验证（图S1 A）。它们都位于TULP 3的C-末端tubby结构域中（图1A）。序列比对表明，p.Thr372Ser和p.Arg382Trp在物种间高度保守，甚至在无脊椎动物中也是如此，而p.Arg291Trp则不保守（图S1 B）。基于SIFT、PolyPhen 2、PROVEAN和Mutation Taster的计算机模拟预测一致表明，变体p.Arg382Trp可能对TULP 3功能有害。该变体在gnomAD数据库中的频率为1.6 e-05（表S2）。其在NTDs组中的分布与一般人群中的分布有显著差异（1/352 vs. 1.6 e-05，P= 0.007，Fisher精确检验）。
Neural tube defects (NTDs) are among the most common human birth defects affecting about 1/1000 live births worldwide. 1 The etiology of NTDs is attributed to complex genetic and environmental risk factors. Over 200 genes have been identified to cause NTDs in animal models, suggesting the involvement of distinct molecular basis in NTD etiology, including the Sonic hedgehog (Shh) signaling. Recently, several negative regulators of Shh pathway null mutants displayed severe NTDs, indicating abnormal activation of Shh signaling is commonly associated with NTDs. 2 Tubby-like protein 3 (Tulp3) is a typical repressor of Shh signaling and knock out Tulp3 causes severe cranial and caudal NTDs in mice. 3 This strongly implied that TULP3 is essential for embryonic neural tube development and that variants in TULP3 might contribute to human NTDs, which hasn't been demonstrated thus far.To clarify this, we conducted next generation sequencing in a Chinese NTDs cohort including 352 patients and 224 matched healthy controls to screen TULP3 variants. We identified three case-specific rare variants: c. 871C> T (p. Arg291Trp), c. 1115C> G (p. Thr372Ser) and c. 1144C> T (p. Arg382Trp) in TULP3, which only occurred in NTDs patients and were totally absent in our controls. The clinical phenotypes of variants carriers were listed in Table S1. All these three variants were heterozygous and verified by Sanger sequencing (Fig. S1A). They were all located in the C-terminal tubby domain of TULP3 (Fig. 1 A). Sequences alignment implied that variant p. Thr372Ser and p. Arg382Trp were highly conserved among spices, even in invertebrates, while variant p. Arg291Trp wasn't conserved (Fig. S1B). In silico predictions based on SIFT, PolyPhen2, PROVEAN and Mutation Taster uniformly suggested that variant p. Arg382Trp was probably deleterious to TULP3 function. This variant had a frequency of 1.6 e-05 in the gnomAD database (Table S2). Its distribution in our NTDs group was significantly different from that in the general population (1/352 vs. 1.6 e-05, P= 0.007, Fisher's exact test).
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DOI：
10.1038/nrdp.2015.7
发表时间：
2015-04-30
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Copp AJ;Adzick NS;Chitty LS;Fletcher JM;Holmbeck GN;Shaw GM
通讯作者：
Shaw GM
影响因子：
56.9
作者：
Santagata, S;Boggon, TJ;Shapiro, L
通讯作者：
Shapiro, L
影响因子：
64.5
作者：
Mukhopadhyay, Saikat;Wen, Xiaohui;Jackson, Peter K.
通讯作者：
Jackson, Peter K.
DOI：
10.1002/bdra.20686
发表时间：
2010-08
影响因子：
--
作者：
Murdoch, Jennifer N.;Copp, Andrew J.
通讯作者：
Copp, Andrew J.