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，对于组装存活运动神经元 (SMN) 蛋白复合物至关重要，并促进小核核糖核蛋白 (snRNP) 的形成，这是剪接体的组成部分。在这里，我们已经确定了来自 22 个无关家庭的 30 名受影响的个体，他们表现出发育迟缓、肌张力减退和小脑性共济失调，这些个体在GEMIN5基因中具有双等位基因变异。GEMIN5 中的突变扰乱了 GEMIN5 蛋白及其相互作用伙伴在患者 iPSC 衍生神经元中的亚细胞分布、稳定性和表达，表明潜在的功能丧失机制。GEMIN5 突变导致患者 iPSC 神经元中 snRNP 复合物组装形成的破坏。此外，击倒尸僵，人类GEMIN5的果蝇同系物，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物和通路，表明不同的分子病理机制。这些发现共同提供了证据，证明GEMIN5中的致病变异扰乱了生理功能并导致神经发育延迟和共济失调综合征。