A Biallelic Variant of the RNA Exosome Gene EXOSC4 Causes Translational Defects Associated with a Neurodevelopmental Disorder.
A Biallelic Variant of the RNA Exosome Gene EXOSC4 Causes Translational Defects Associated with a Neurodevelopmental Disorder.
复制标题
RNA 外泌体基因 EXOSC4 的双等位变体会导致与神经发育障碍相关的翻译缺陷。
DOI：
10.1101/2023.10.24.23297197
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Corbett,AnitaH
中科院分区：
文献类型：
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作者：
Fasken,MiloB;Leung,SaraW;Cureton,LaurynA;Al-Awadi,Maha;Al-Kindy,Adila;Khoshnevis,Sohail;Ghalei,Homa;Al-Maawali,Almundher;Corbett,AnitaH
RNA外泌体是一种进化上保守的复合物，是RNA精确加工和降解所必需的。编码复合体结构亚基的EXOSC基因突变与几种常染色体隐性遗传疾病有关。在这里，我们描述了一个错义等位基因的EXOSC 4基因，导致收集的临床特征，在两个受影响的兄弟姐妹。该错义突变（NM_019037.3：外显子3：c.560T>C）将EXOSC 4的高度保守区域内的亮氨酸残基改变为脯氨酸（p.Leu187Pro）。这两个受影响的个体表现为产前生长受限、发育不良、全面发育迟缓、脑内和基底节钙化和肾衰竭。通过外显子组测序和桑格测序证实分离鉴定损伤性变体的纯合性。为了探索这种氨基酸变化的功能后果，我们在相应的芽殖酵母蛋白Rrp 41（Rrp 41-L187 P）中模拟了EXOSC 4-L187 P。表达Rrp 41-L187 P作为必需Rrp 41蛋白的唯一拷贝的细胞显示显著的生长缺陷。与对照Rrp 41/EXOSC 4相比，Rrp 41-L187 P和EXOSC 4-L187 P蛋白的稳态水平显著降低。与这一观察结果一致，RNA外泌体的靶标在rrp 41-L187 P细胞中积累，包括5.8S rRNA的7S前体。与对照细胞相比，多核糖体谱显示rrp 41-L187 P细胞的翻译显著降低，7S前rRNA明显掺入多核糖体中。总之，这项工作将RNA外泌体的EXOSC 4亚基添加到与人类疾病相关的复合物的结构亚基中，并定义了可能导致这种新型EXOSC 4致病性变体引起的不良生长表型的基础分子缺陷。
The RNA exosome is an evolutionarily conserved complex required for both precise RNA processing and decay. Mutations in EXOSC genes encoding structural subunits of the complex are linked to several autosomal recessive disorders. Here, we describe a missense allele of the EXOSC4 gene, which causes a collection of clinical features in two affected siblings. This missense mutation (NM_019037.3: exon3:c.560T>C), changes a leucine residue within a highly conserved region of EXOSC4 to proline (p.Leu187Pro). The two affected individuals presented with prenatal growth restriction, failure to thrive, global developmental delay, intracerebral and basal ganglia calcifications, and kidney failure. Homozygosity for the damaging variant was identified through exome sequencing and Sanger sequencing confirmed segregation. To explore the functional consequences of this amino acid change, we modeled EXOSC4-L187P in the corresponding budding yeast protein, Rrp41 (Rrp41-L187P). Cells that express Rrp41-L187P as the sole copy of the essential Rrp41 protein show significant growth defects. The steady-state level of both the Rrp41-L187P and the EXOSC4-L187P proteins is significantly decreased compared to control Rrp41/EXOSC4. Consistent with this observation, targets of the RNA exosome accumulate in rrp41-L187P cells, including the 7S precursor of 5.8S rRNA. Polysome profiles show a significant decrease in translation in rrp41-L187P cells as compared to control cells with apparent incorporation of 7S pre-rRNA into polysomes. Taken together, this work adds the EXOSC4 subunit of the RNA exosome to the structural subunits of this complex that have been linked to human disease and defines foundational molecular defects that could contribute to the adverse growth phenotypes caused by this novel EXOSC4 pathogenic variant.