Institute of Biochemistry and Molecular Cell Biology, Medical School, RWTH Aachen University, Aachen, Germany.
Biozentrum, University of Basel, Basel, Switzerland.
FEBS Lett. 2023 Nov;597(22):2750-2768. doi: 10.1002/1873-3468.14761. Epub 2023 Nov 1.
The subcellular compartmentalisation of eukaryotic cells requires selective exchange between the cytoplasm and the nucleus. Intact nucleocytoplasmic transport is vital for normal cell function and mutations in the executing machinery have been causally linked to human disease. Central players in nucleocytoplasmic exchange are nuclear pore complexes (NPCs), which are built from ~30 distinct proteins collectively termed nucleoporins. Aberrant nucleoporin expression was detected in human cancers and autoimmune diseases since quite some time, while it was through the increasing use of next generation sequencing that mutations in nucleoporin genes associated with mainly rare hereditary diseases were revealed. The number of newly identified mutations is steadily increasing, as is the number of diseases. Mutational hotspots have emerged: mutations in the scaffold nucleoporins seemingly affect primarily inner organs, such as heart, kidney, and ovaries, whereas genetic alterations in peripheral, cytoplasmic nucleoporins affect primarily the central nervous system and development. In this review, we summarise latest insights on altered nucleoporin function in the context of human hereditary disorders, with a focus on those where mechanistic insights are beginning to emerge.
真核细胞的亚细胞区室化需要细胞质和细胞核之间的选择性交换。完整的核质运输对于正常的细胞功能至关重要，执行机制中的突变已被因果关联到人类疾病。核质交换的核心参与者是核孔复合物（NPC），它由约 30 种不同的蛋白质组成，统称为核孔蛋白。核孔蛋白的异常表达在人类癌症和自身免疫性疾病中已经被检测到了相当长的一段时间，而正是通过新一代测序的广泛应用，与主要罕见遗传性疾病相关的核孔蛋白基因突变才被揭示出来。新发现的突变数量在稳步增加，疾病数量也是如此。突变热点已经出现：支架核孔蛋白的突变似乎主要影响内部器官，如心脏、肾脏和卵巢，而外周细胞质核孔蛋白的遗传改变主要影响中枢神经系统和发育。在这篇综述中，我们总结了核孔蛋白功能改变在人类遗传性疾病背景下的最新见解，重点关注那些开始出现机制见解的疾病。
