不确定意义的ESRRB变体的功能性致病性导致听力损失 (DFNB35)
Won Hoon Choi1, Yeijean Cho2, Ju Hyuen Cha1
1Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Scientific reports
|September 11, 2024
概括
这项研究揭示了ESRRB基因的一个变异,以前不确定,通过破坏蛋白质功能和基因表达,甚至在高等位基因频率的情况下,也会导致感觉神经听力损失 (DFNB35).
科学领域:
- 遗传学和分子生物学
- 听觉神经科学 听觉神经科学
- 人类疾病遗传学 人类疾病遗传学
背景情况:
- 下一代测序推进了听力损失遗传学.
- 在听力损失中,不确定意义的变异 (VUS) 的功能研究有限.
- DFNB35是一种感觉神经听力损失的形式,遗传机制不清楚.
研究的目的:
- 调查与DFNB35.35相关的ESRRB基因中复合异合体变异的功能致病性.
- 阐明ESRRB相关的DFNB35.35背后的分子机制.
- 重新评估具有高等位基因频率的不确定的意义变异 (VUS).
主要方法:
- 在ESRB中识别复合异构变体 (c.397+2T>G拼接和c.1144C>T p.
- 在 silico 预测和功能测试 (例如,拼接分析,蛋白质稳定性,转录活性).
- 在内耳下游目标基因表达的分析.
主要成果:
- 拼接变体 (c.397+2T>G) 诱导了前子跳转和无意中介衰变.
- 这种p.(Arg382Cys) 变体,最初是VUS,破坏了ESRRB蛋白相互作用和稳定性.
- 这种p.(Arg382Cys) 变异减少了转录活性,改变了内耳基因的表达.
结论:
- 这项研究扩大了DFNB35.5中ESRRB的遗传和表型谱.
- 功能性测试表明ESRRB p. ((Arg382Cys) 变异的致病性,即使具有高东亚等位基因频率.
- 研究结果强调了功能性表征对于重新解释VUS和理解复杂的遗传性听力损失的重要性.
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