The nuclear pore complex (NPC) is a multi-protein complex that regulates the trafficking of macromolecules between the nucleus and cytoplasm. Genetic variants in components of the NPC have been shown to cause a range of neurological disorders, including intellectual disability and microcephaly. Translocated promoter region, nuclear basket protein (TPR) is a critical scaffolding element of the nuclear facing interior of the NPC. Here we present two siblings with biallelic variants in TPR who present with a phenotype of microcephaly, ataxia and severe intellectual disability. The variants result in a premature truncation variant, and a splice variant leading to a 12-amino acid deletion respectively. Functional analyses in patient fibroblasts demonstrate significantly reduced TPR levels, and decreased TPR-containing NPC density. A compensatory increase in total NPC levels was observed, and decreased global RNA intensity in the nucleus. The discovery of variants that partly disable TPR function provide valuable insight into this essential protein in human disease, and our findings suggest that TPR variants are the cause of the siblings’ neurological disorder.

中文翻译：

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核孔蛋白 TPR（易位启动子区、核篮蛋白）的致病性变异会导致人类严重智力障碍


核孔复合物（NPC）是一种多蛋白复合物，调节细胞核和细胞质之间大分子的运输。 NPC 组成部分的遗传变异已被证明会导致一系列神经系统疾病，包括智力障碍和小头畸形。易位启动子区核篮蛋白 (TPR) 是 NPC 面向核内部的关键支架元件。在这里，我们介绍了两个患有TPR双等位基因变异的兄弟姐妹，他们表现出小头畸形、共济失调和严重智力障碍的表型。这些变体分别导致过早截短变体和导致 12 个氨基酸缺失的剪接变体。患者成纤维细胞的功能分析表明，TPR 水平显着降低，并且含有 TPR 的 NPC 密度也降低。观察到总 NPC 水平代偿性增加，并且细胞核中整体 RNA 强度降低。部分禁用 TPR 功能的变体的发现为了解人类疾病中的这种必需蛋白质提供了宝贵的见解，我们的研究结果表明TPR变体是兄弟姐妹神经系统疾病的原因。