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在综合性口腔口腔裂中明显的IRF6功能障碍机制:计算证据证明了全osteric与直接干扰的结论
Ana Luiza Meneguci Moreira Franco1,2, Deborah Antunes3, Ana Clara Rodrigues Moreira Gomes2,4
1Programa de Pós-Graduação em Genética da Universidade Federal do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco, Centro de Ciências da Saúde, Ilha do Fundão, Rio de Janeiro, 21941-617, Rio de Janeiro, Brazil.
Computational and structural biotechnology journal
|November 17, 2025
概括
这项研究在范德伍德综合征和波普立体膜综合征病例中发现了两种致病性IRF6变体. 计算机建模揭示了不同的分子机制,这些变体破坏了IRF6功能和DNA结合.
科学领域:
- 遗传学和分子生物学
- 发育生物学 发展生物学
- 计算生物学 计算生物学
背景情况:
- 耳面裂 (OC) 是一种先天性异常,其综合征形式如范德伍德综合征 (VWS) 和民间综合征 (PPS) 经常与IRF6基因变异有关.
- IRF6编码了一个关键的转录因子,用于面部发育,其致病变体可以导致发育缺陷.
研究的目的:
- 在VWS和PPS试验中识别和描述IRF6变体.
- 通过使用计算建模来评估IRF6变体的结构和功能后果.
主要方法:
- 在VWS和PPS试验体及其父体中测序关键的IRF6表因子.
- 基于IRF4-DNA复合体的比较建模.
- 分子动力学模拟,MM/GBSA计算和键占用分析以评估结构和结合的影响.
主要成果:
- 确定了两个新发病的IRF6变体,p.(Ala16Val) 在VWS和p.(Arg84Cys) 在PPS中.
- p.(Ala16Val) 变体显示出长距离的全效应和增加的波动;p.(Arg84Cys) 直接破坏了DNA结合相互作用.
- 这两种变体都表现出较低的DNA结合亲和力,p.(Arg84Cys) 导致更严重的静电干扰.
结论:
- 致病性IRF6变体可以通过不同的分子机制损害面部发育.
- p.(Ala16Val) 可能通过异质变化影响IRF6功能,而p.(Arg84Cys) 可能会直接破坏DNA结合.
- 计算建模提供了关于IRF6变体在综合征性口腔口腔裂中的致病性方面的见解.
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