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加强PSMC5作为与神经发育障碍相关的潜在基因的作用

Mirella Vinci¹, Antonino Musumeci¹, Carla Papa¹

¹Oasi Research Institute-IRCCS, 94018 Troina, Italy.

International journal of molecular sciences

|July 12, 2025

概括

在发育迟缓和智力残疾的个体中,发现了PSMC5基因的新de novo变异. 这一发现扩大了与PSMC5相关的已知的神经发育表型,并建议它作为潜在的治疗点.

科学领域:

分子生物学分子生物学
遗传学遗传学是一个
神经科学是一个神经科学.

背景情况:

26S蛋白质酶通过降解无处不在的蛋白质来调节蛋白质稳态.
26S蛋白质组的组成部分PSMC5以前没有与特定的表型联系在一起.
发育迟缓和智力障碍可能源于细胞蛋白质降解途径的破坏.

研究的目的:

研究患者及其父母发育迟缓和智力障碍的遗传基础.
识别和描述与神经发育障碍相关的新型遗传变异.
探索PSMC5基因在神经发育中的作用.

主要方法:

在受影响的个体及其未受影响的父母身上进行了全外体测序 (WES).
生物信息分析,包括in silico预测和蛋白质结构建模 (AlphaFold3),用于评估变体的致病性.
变体数据与公共数据库 (ClinVar,gnomAD,dbSNP) 和文献进行了交叉引用.

主要成果:

在PSMC5基因中发现了一种新型变异c.959C>G (p.Pro320Arg).
PSMC5 p.Pro320Arg 变种被 in silico 工具归类为致病性,并且显示出强大的进化保护.
这种变种以前具有不确定的意义,在六个具有相似临床特征的无关个体中被发现,并在ClinVar.中被重新归类为致病性.
由于p.Pro320Arg的替代,AlphaFold3预测了PSMC5蛋白中的显著结构变化.

结论:

该PSMC5 p.Pro320Arg变体与发育迟缓和轻度智力障碍有关.
这项研究扩大了与PSMC5相关的表型谱,并表明它在神经发育中的关键作用.
鉴定的变异对PSMC5结构和功能的影响可能会损害26S蛋白酶体活性,突出显示PSMC5是潜在的治疗标.

关键词:

26S 蛋白质酶体是一种26S蛋白质体.这是20S监管子单位.无处不在的蛋白质酶体系统

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