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AFF3的变异特异性病理生理机制不同地影响转录组配置文件

Sissy Bassani^1,2, Jacqueline Chrast¹, Giovanna Ambrosini^3,4

¹Center for Integrative Genomics, University of Lausanne, Genopode Building, Lausanne, CH, 1015, Switzerland.

Genome medicine

|May 29, 2024

概括

在AFF3基因功能的微小变化导致KINSSHIP综合征和相关疾病. 在AFF3中增加的基因水平和功能丧失变异都会导致有害影响,影响发育和细胞通路.

科学领域:

遗传学遗传学是一个
分子生物学分子生物学
发展生物学发展生物学

背景情况:

由智力残疾,中粒体形和马脏为特征的KINSSHIP综合征与AFF3基因中的新变异有关.
之前的研究表明,AFF3变体具有主导负机制,其中AFF3水平增加会导致病理影响.

研究的目的:

调查AFF3相关疾病的其他遗传模式,超出新变种.
评估各种AFF3变异的致病性,包括功能丧失和误解突变,在智力残疾人中.

主要方法:

在AFF3.3中对预测的有害变异进行智力障碍队伍的查.
使用动物模型 (斑马鱼) 和细胞模型 (纤维细胞转录组学) 来评估变体的有害性.
在具有不同AFF3基因型 (野生型,KINSSHIP,LoF) 的工程细胞系中分析基因表达特征.

主要成果:

一个具有KINSSHIP类型的表型和部分AFF3重复的个体证实AFF3水平增加是病理性的.
在AFF3.3中,有17名患有较轻症候群的个体携带异合体功能丧失 (LoF) 或双类误解变体.
同卵性LoF和复合异卵性变体导致更严重的表型,与半主导相一致. 斑马鱼模型显示了人类AFF3mRNA的救援,而一些误解变体未能救援,过度表达导致发育缺陷.

结论:

AFF3基因功能的微小改变是有害的,导致了一系列疾病.
增加的AFF3水平 (如KINSSHIP综合征中所见) 和功能丧失变体都会导致病原性.
AFF3变种表现出高性,影响包括DNA修复在内的多种途径,根据变种类型 (LoF与主导-负) 有明显的调节效应.

关键词:

马的脏马的脏智力障碍智力障碍是一种智力障碍.半叶膜性质变形症 (Mesomelic Dysplasia) 是一种半叶膜性质变形症.转录组转录组就是一个转录组.斑马鱼模型模型

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