Pathogenic variants in the survival of motor neurons complex gene GEMIN5 cause cerebellar atrophy
Pathogenic variants in the survival of motor neurons complex gene GEMIN5 cause cerebellar atrophy
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DOI：
10.1111/cge.14066
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发表时间：
2021-10-07
影响因子：
3.5
通讯作者：
Matsumoto，Naomichi
中科院分区：
文献类型：
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作者：
Saida，Ken;Tamaoki，Junya;Matsumoto，Naomichi
小脑性共济失调是一种遗传异质性疾病。GEMIN5编码运动神经元复合体存活的RNA结合蛋白，对于小核核糖核蛋白的生物发生至关重要，最近报道双等位基因功能丧失变异会导致神经发育迟缓、张力减退和小脑性共济失调。在这里，全外显子组分析揭示了我们的 162 名小脑萎缩/发育不全患者队列中的两名个体存在复合杂合 GEMIN5 变异。鉴定出三种新的截短变体和一种先前报道的错义变体：个体 1 中的 c.2196dupA, p.(Arg733Thrfs*6) 和 c.1831G > A, p.(Val611Met)，以及 c.3913delG, p.(Ala1305Leufs*14) 和 c.4496dupA， p.(Tyr1499*) 在个体 2 中。使用来自两个受影响个体的类淋巴母细胞系进行的蛋白质印迹分析显示 GEMIN5 蛋白水平显着降低。无效变体 p.(Arg733Thrfs*6) 和 p.(Ala1305Leufs*14) 的斑马鱼模型在 2 周时表现出完全致死性，并重现了独特的发育不良表型。受影响个体的表型和斑马鱼突变模型强烈表明，GEMIN5 中的双等位基因功能丧失变异会导致小脑萎缩/发育不全。
Cerebellar ataxia is a genetically heterogeneous disorder.GEMIN5encoding an RNA‐binding protein of the survival of motor neuron complex, is essential for small nuclear ribonucleoprotein biogenesis, and it was recently reported that biallelic loss‐of‐function variants cause neurodevelopmental delay, hypotonia, and cerebellar ataxia. Here, whole‐exome analysis revealed compound heterozygousGEMIN5variants in two individuals from our cohort of 162 patients with cerebellar atrophy/hypoplasia. Three novel truncating variants and one previously reported missense variant were identified: c.2196dupA, p.(Arg733Thrfs*6) and c.1831G > A, p.(Val611Met) in individual 1, and c.3913delG, p.(Ala1305Leufs*14) and c.4496dupA, p.(Tyr1499*) in individual 2. Western blotting analysis using lymphoblastoid cell lines derived from both affected individuals showed significantly reduced levels of GEMIN5 protein. Zebrafish model for null variants p.(Arg733Thrfs*6) and p.(Ala1305Leufs*14) exhibited complete lethality at 2 weeks and recapitulated a distinct dysplastic phenotype. The phenotypes of affected individuals and the zebrafish mutant models strongly suggest that biallelic loss‐of‐function variants inGEMIN5cause cerebellar atrophy/hypoplasia.