上游开放的读取框架引入的变体在患有初级家族脑化的患者
Anne Rovelet-Lecrux1, Antoine Bonnevalle2, Olivier Quenez1
1Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, CNRMAJ and Reference Center for Neurogenetics Disorders, F-76000, Rouen, France.
European journal of human genetics : EJHG
|March 3, 2024
概括
在PDGFB的5'未翻译区域 (UTR) 的遗传变异可能导致初级家族性脑化 (PFBC). 这些上游引入AUG的变种可以导致PFBC患者的功能丧失突变.
科学领域:
- 神经遗传学 神经遗传学
- 分子遗传学 分子遗传学
背景情况:
- 主要家族性脑化 (PFBC) 是一种罕见的神经疾病,超过50%的病例仍无法从遗传学上解释.
- 非编码变异,特别是在5'未翻译区域 (UTR) 中,经常被忽视为遗传疾病的潜在原因.
研究的目的:
- 调查5'UTR变异引入上游AUG编码的作用,导致PFBC基因的功能丧失突变.
- 在未被诊断的患者中识别PFBC的新型遗传原因.
主要方法:
- 从113个无关的PFBC试验对象的外基因组测序数据的重新注释.
- 上游开放阅读框架 (ORF) 创建的in silico预测.
- GFP 记者测定和西部抹杀以评估翻译启动和蛋白质水平.
主要成果:
- 在PDGFB的5'UTR中,在2/113 (1.7%) 未被诊断的PFBC病例中发现了两种上游引入AUG的变异.
- 一种变异 (c.-373C>G) 与PFBC分离,并预测将创建一个上游ORF.
- 另一种变体 (c.-318C>T) 导致了重叠的ORF与移,并在报告员测试中显示出强烈的翻译启动,导致蛋白质水平降低.
结论:
- 在PDGFB的5'UTR中,上游引入AUG的变体是PFBC的潜在原因.
- 这些变异代表了一种新型的致病变异类别,有助于遗传学上无法解释的PFBC病例.
- 对5'UTR变异的进一步调查对于诊断罕见的遗传神经系统疾病至关重要.
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