Department of Pediatrics, Childrens Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Nat Commun. 2021 May 7;12(1):2558. doi: 10.1038/s41467-021-22627-w.
GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.
GEMIN5 是一种 RNA 结合蛋白，对于运动神经元存活（SMN）蛋白复合物的组装以及小核核糖核蛋白（snRNP）的形成至关重要，后者是剪接体的组成部分。在此，我们在 22 个无关联的家系中鉴定了 30 名受影响的个体，这些个体均存在发育迟缓、张力减退和小脑共济失调，携带 GEMIN5 基因的双等位变异体。GEMIN5 突变会扰乱患者诱导多能干细胞衍生神经元中 GEMIN5 蛋白及其相互作用伙伴的亚细胞分布、稳定性和表达，提示存在潜在的功能丧失机制。GEMIN5 突变导致患者诱导多能干细胞神经元中 snRNP 复合物组装形成中断。此外，rigor mortis（果蝇中人类 GEMIN5 的同源物）的敲低会导致发育缺陷、运动功能障碍和寿命缩短。有趣的是，我们观察到与 SMA 患者神经元相比，GEMIN5 变体破坏了一组不同的转录本和途径，提示存在不同的分子发病机制。这些发现共同提供了证据，表明 GEMIN5 中的致病性变体扰乱了生理功能，导致神经发育迟缓和共济失调综合征。
