在小鼠Cdh23基因中,一种新的拷贝数变异导致严重的聋和前体功能障碍

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Nicholas A Boehler^1,2, Shane D I Seheult³, Muhammad Wahid^1,2

¹Department of Biology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada.

Human molecular genetics

|July 9, 2024

概括

鉴定了一种具有严重聋的新型小鼠模型,原因是cadherin 23基因中的副本数变异删除. 这凸显了改善检测这些遗传突变的必要性,以便更好地诊断听力损失.

科学领域:

遗传学是一个遗传学.
神经科学是一个神经科学.
听力学听力学是指听力学.

背景情况:

听力损失是一种常见的先天性缺陷,具有各种遗传原因.
识别新突变是准确诊断和个性化治疗的关键.
副本数变异 (CNVs) 是遗传性听力损失的研究不足的贡献者.

研究的目的:

描述了一种具有严重聋和相关神经症状的新型鼠标突变.
为了确定异常波动步行 (AWG) 鼠标观察到的表型的遗传原因.
为了强调检测遗传聋的副本数变异的重要性.

主要方法:

异常摇摆步行 (AWG) 鼠标模型的表型分析.
全基因组测序 (WGS) 和常规变异检测.
用CRISPR-Cas9基因编辑进行变异验证.
定量PCR (qPCR) 用于mRNA表达分析.
西方涂抹用于蛋白质分析.
PCR和桑格测序用于CNV验证.

主要成果:

这只AWG鼠标表现出类似华尔兹舞的运动器官功能障碍,多动,循环,以及严重的聋.
一个自发的10.4kb删除在cadherin 23 (Cdh23) 基因,包括外子11和12,被确定为致病突变.
在AWG新生儿中观察到Cdh23mRNA的下调和CDH23全长蛋白质的缺失.
传统的WGS管道无法检测致病性CNV,因此需要手动检查读取深度图.

结论:

该研究发现了Cdh23中一种新的CNV缺失,导致AWG小鼠的严重聋和神经缺陷.
通过标准变异检测方法可以忽略致病性CNV,强调需要精细的诊断策略.
改进的CNV检测将提高遗传异质性听力损失疾病的诊断精度.

关键词:

听觉脑干反应的响应卡德林 23 卡德林 23 副本编号变化副本编号变化听力损失听力损失是什么一个自发的老鼠突变突变.

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