在患有ADHD的家庭中发现的一种低频破坏性SORCS2变体损害了受体稳定性并杀了活性
Mathias Kaas1, Sarah Broholt Dinesen1, Ole Ahlgreen1
1Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Molecular psychiatry
|September 18, 2025
概括
一种罕见的SORCS2基因变异扰乱了大脑信号,可能导致注意力缺陷/多动症 (ADHD) 风险. 这一发现突显了特定遗传变异在神经发育障碍中的作用.
科学领域:
- 神经遗传学 神经遗传学
- 分子精神病学分子精神病学
- 发育神经科学的发展神经科学.
背景情况:
- 注意缺陷/多动障碍 (ADHD) 是一种流行的神经发育障碍,具有多基因遗传模式.
- Vps10p域受体SorCS2通过脑衍生神经营养因子 (BDNF) 信号传递在神经元发育和突触可塑性中发挥作用.
研究的目的:
- 识别和描述与ADHD相关的SORCS2中的遗传变异.
- 研究特定SORCS2变异对受体功能和BDNF信号传递的功能影响.
主要方法:
- 基因测序用于识别SORCS2基因中的变异.
- 生物化学和细胞测试以评估受体处理,定位和连接体结合.
- 对BDNF信号通路的功能分析.
主要成果:
- 在SORCS2基因中,在两个患有ADHD的家庭成员中发现了一种异合体破坏性变异 (R到W替代).
- 鉴定的SORCS2变体导致受体处理,局部化发生变化,并以主导负态的方式废除了BDNF信号.
- 在SORCS2队列中的其他罕见误解变异表明易受Vps10p域变化的影响.
结论:
- 在SORCS2基因中的有害变异,特别是在Vps10p域内,可以损害受体功能和BDNF信号传递.
- 这些发现表明,SORCS2中的低频损害变体有助于ADHD的遗传风险.
- 这项研究提供了对ADHD病原体背后的分子机制的新见解.
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