识别与 orofacial 裂相关的功能非编码变异.
Priyanka Kumari1, Ryan Z Friedman2,3, Sarah W Curtis4
1Department of Oral Health Sciences, University of Washington, Seattle, WA, USA.
Nature communications
|July 16, 2025
概括
研究人员确定了与口腔面部裂 (OFC) 相关的特定遗传变异或单核酸多态 (SNP). 这些功能性SNP直接影响胚胎口腔表皮中的基因表达和转录因子结合,揭示了对OFC病变的新见解.
科学领域:
- 遗传学 是一个遗传学.
- 发展生物学 发展生物学
- 基因组医学是基因组医学.
背景情况:
- 口腔面部裂 (OFC) 是一种常见的出生缺陷,具有复杂的遗传基础.
- 全基因组关联研究 (GWAS) 已经确定了许多与OFC相关的基因组位置,但功能变异在很大程度上仍然未知.
- 涉及OFC的效应基因通常在胚胎口腔表皮表达.
研究的目的:
- 确定与已知的风险位置的口腔面部裂 (OFC) 相关的功能单核酸多态 (SNP).
- 研究这些SNP对相关细胞模型中增强剂活性和基因表达的影响.
- 为了将OFC中的遗传变异与特定的致病分子机制联系起来.
主要方法:
- 大规模并行报告员测试 (MPRA) 用于选胎儿口腔上皮细胞系中的具有异位基因特异增强因子活性的SNP.
- 使用染色体标记数据来过候选SNP,优先考虑那些位于活性增强剂中的SNP.
- 工程诱导多能干细胞 (iPSC) 被分化为胚胎口腔上皮,以评估顶级候选SNP对基因表达和转录因子结合的功能影响.
主要成果:
- 几种SNP在口腔上皮细胞中对增强剂活性表现出异位特异性影响.
- 在FOXE1,IRF6,MAFB,TFAP2A和TP63附近的SNP被验证为潜在的功能变体.
- 在IPSC衍生的口腔表皮中,IRF6和FOXE1附近的特定SNP改变了效应基因表达和转录因子结合.
- 条件GWAS分析表明,在IRF6附近的两个功能性SNP显著促进了带有或没有裂口 (CL/P) 的裂口唇风险.
结论:
- 这项研究成功地确定了与OFC相关的功能性SNP,证明了对口腔上皮质基因调节的等位基因特异性影响.
- 这些发现提供了基因变异与OFC,特别是CL/P的发病机制之间的联系.
- 在IRF6附近确定的功能变异是CL/P风险的主要贡献者,为未来的研究和潜在的治疗策略提供了目标.
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