影响动因结合域的PLS3误解变异会导致X结合的先天性隔膜和身体壁缺陷
Florence Petit1, Mauro Longoni2, Julie Wells3
1Clinique de Génétique, CHU de Lille, Lille, France; EA7364 RADEME, Université de Lille, Lille, France.
American journal of human genetics
|September 26, 2023
概括
塑3 (PLS3) 基因中的特定突变会导致X结合的先天性隔膜 (CDH),这是一个先天性缺陷. 这些PLS3变异可能导致功能增益效应,与导致骨质疏松症的突变不同.
科学领域:
- 遗传学 遗传学 是一个
- 发展生物学 发展生物学
- 分子生物学分子生物学
背景情况:
- kongenital diaphragmatic hernia (CDH) 是一种严重的出生缺陷,死亡率高.
- 遗传异质性有助于CDH,但特定的致病基因通常是未知的.
- 以前的研究将PLS3功能丧失变体与X相关骨质疏松症联系起来.
研究的目的:
- 调查X链接疾病的遗传基础,其中包括隔膜缺陷,身体壁异常和面部异形.
- 确定塑3 (PLS3) 变体在先天性隔膜 (CDH) 中的作用.
- 区分导致CDH与骨质疏松症的PLS3变体的分子机制.
主要方法:
- 在八个无关家族中进行链接分析和外基因组/基因组测序.
- 在蛋白模型中评估变异对PLS3结构的影响.
- 产生和分析一个PLS3鼠标的Knockin模型.
主要成果:
- 在所有患有CDH的家族中,在PLS3中确定了共同分离的误解变异.
- 与CDH相关的PLS3变体位于actin结合域中,但预计不会破坏蛋白质结构.
- 鼠标模型和人类数据表明,CDH相关的PLS3变体具有功能增强效应,观察到骨密度增加.
结论:
- 在PLS3中特定的误解变异会导致X结合的先天性疾病,其特征是腹膜缺陷.
- 这些与CDH相关的PLS3变体可能会产生功能增益效应.
- 这些发现揭示了一种新的孟德尔先天性疾病,与PLS3活性蛋白结合域变异有关.
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