Moonlighting nuclear pore proteins: tissue-specific nucleoporin function in health and disease

The nuclear pore complex is the main transportation hub for exchange between the cytoplasm and the nucleus. It is built from nucleoporins that form distinct subcomplexes to establish this huge protein complex in the nuclear envelope. Malfunctioning of nucleoporins is well known in human malignancies, such as gene fusions of NUP214 and NUP98 in hematological neoplasms and overexpression of NUP88 in a variety of human cancers. In the past decade, the incremental utilization of next-generation sequencing has unraveled mutations in nucleoporin genes in the context of an increasing number of hereditary diseases, often in a tissue-specific manner. It emerges that, on one hand, the central nervous system and the heart are particularly sensitive to mutations in nucleoporin genes. On the other hand, nucleoporins forming the scaffold structure of the nuclear pore complex are eminently mutation-prone. These novel and exciting associations between nucleoporins and human diseases emphasize the need to shed light on these unanticipated tissue-specific roles of nucleoporins that may go well beyond their role in nucleocytoplasmic transport. In this review, the current insights into altered nucleoporin function associated with human hereditary disorders will be discussed.