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在核因子I/X (NFIX) 基因中具有移突变的小鼠模型具有马歇尔-史密斯综合征的表型特征

Kreepa G Kooblall¹, Mark Stevenson¹, Michelle Stewart²

¹Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) University of Oxford Oxford UK.

|June 7, 2023

概括

NFIX基因突变导致发育障碍. 鼠标模型显示,NFIX外显子7的移删除,逃避无意中介衰变 (NMD),导致骨和神经异常,模仿马歇尔-史密斯综合征 (MSS).

科学领域:

遗传学和分子生物学
发展生物学发展生物学
骨和骨生物学骨和骨生物学

背景情况:

核因子I/X (NFIX) 基因的突变导致马兰综合征 (MAL) 和马歇尔-史密斯综合征 (MSS),其特点是发育,骨和神经异常.
在MAL中NFIX突变通常通过无意中介衰变 (NMD) 清除,从而导致哈普隆不充足.
在MSS中NFIX突变逃脱了NMD,产生主导负型突变蛋白质,这表明了不同的分子后果.

研究的目的:

为了研究与马歇尔-史密斯综合征 (MSS) 相关的NFIX外基因7突变的体内影响.
使用CRISPR-Cas9生成和描述小鼠模型,以研究NFIX第7个外显子的删除.

主要方法:

使用CRISPR-Cas9基因编辑来创建具有特定NFIX外子7删除的小鼠模型 (框架移动Del2,框架内Del24和Del140).
在生成的Nfix突变小鼠中评估了生命力,骨形态,骨矿物质含量,血生物化学和大脑结构.
对生成的Nfix突变进行了评估,对无意中介衰变 (NMD) 逃逸进行了评估.

主要成果:

Nfix Del2的移删除逃脱了NMD,并导致同卵性小鼠 (Nfix^Del2/Del2) 的活力显著降低.
Nfix^Del2/Del2小鼠表现出生长迟缓,身高矮且有形,头骨长度缩短,脊椎多孔性,骨矿物质含量降低,以及大脑形态变化 (大脑皮层和心室扩大,牙状缩小).
其他删除 (Del24,Del140) 并没有导致显著的发育异常或减少活力.

结论:

逃脱NMD的NFIX外显子7移删除重复了马歇尔-史密斯综合征 (MSS) 中发现的关键发育异常.
Nfix^Del2/Del2小鼠模型对于研究NMD.逃脱NFIX突变的体内致病机制非常有价值.
这项研究阐明了NFIX突变基于其NMD易感性的明显后果,影响骨和神经发育.

关键词:

在 NFIX 系统中,NFIX 是大脑异常脑部异常框架移位突变突变是什么?基索斯 (Kyphosis) 是一种神经的形成.骨质疏松症是一种骨质疏松症.

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