Genetic contribution of retinoid-related genes to neural tube defects.
Genetic contribution of retinoid-related genes to neural tube defects.
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类维生素A相关基因对神经管缺陷的遗传贡献
DOI：
10.1002/humu.23397
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发表时间：
2018-04
期刊：
影响因子：
3.9
通讯作者：
Niswander L
中科院分区：
文献类型：
--
作者：
Li H;Zhang J;Chen S;Wang F;Zhang T;Niswander L
罕见变异被认为是复杂疾病的根本原因。神经管缺陷（NTD）是一组复杂而严重的疾病，它是由早期胚胎发育过程中神经管闭合失败引起的。神经管闭合需要协调许多信号通路，包括精确调节维甲酸（RA）浓度，其由参与RA合成和降解的酶控制。在这里，我们使用了病例对照突变筛查研究，揭示罕见的变异维甲酸相关基因在汉族NTD人群中，通过测序6个基因在355例NTD和225名对照。NTD特异性罕见变异存在于外显子区和上游区。RA应答基因CYP26A1、CRABP 1和ALDH1A2在其上游区域具有NTD特异性罕见变异。出乎意料的是，NTD病例中的大多数错义变体发现于编码RA降解酶的CYP26 B1中，而在对照中未发现该基因的错义变体。使用RA诱导的转录和RA启动的神经元分化测定，功能分析表明CYP 26 B1 NTD变体在RA降解中效率低下。我们的研究支持RA相关基因的罕见变异对人类NTD病因学的贡献。
Rare variants are considered underlying causes of complex diseases. The complex and severe group of disorders called neural tube defects (NTDs) results from failure of the neural tube to close during early embryogenesis. Neural tube closure requires the coordination of numerous signaling pathways, including the precise regulation of retinoic acid (RA) concentration which is controlled by enzymes involved in RA synthesis and degradation. Here we used a case-control mutation screen study to reveal rare variants in retinoid related genes in a Han Chinese NTD population by sequencing six genes in 355 NTD cases and 225 controls. NTD-specific rare variants were found in exonic regions and upstream regions. The RA-responsive genes CYP26A1, CRABP1 and ALDH1A2 harbored NTD-specific rare variants in their upstream regions. Unexpectedly, the majority of missense variants in NTD cases were found in CYP26B1 which encodes a RA degradation enzyme, whereas no missense variants in this gene were found in controls. Functional analysis indicated that the CYP26B1 NTD variants were inefficient in the degradation of RA using assays of RA-induced transcription and RA-initiated neuronal differentiation. Our study supports the contribution of rare variants in RA related genes to the etiology of human NTDs.
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