Mutated NUP188 and Other Nucleoporins as Gateways to Developmental Syndromes

rier that prevents membrane proteins from passing from the outer nuclear membrane to the inner nuclear membrane [Busayavalasa et al., 2012]. Fourth, the channel NUPs, NUP62, NUP58 (alias NUPL1), and its splice variants NUP45 and NUP54, constitute the innermost cylinder of the NPC. NUP54/NUP58 are thought to form a midplane ring that undergoes reversible expansion and contraction to regulate nucleocytoplasmic traffic [Solmaz et al., 2011]. Fifth, the nuclear basket NUPs, NUP153, TPR, and NUP50, which are involved in nuclear import/ export processes [Wälde and Kehlenbach, 2010]. Specifically, NUP153 and NUP50 form a ring, which facilitates nucleocytoplasmic transport [Hoelz et al., 2011]. The NUP50 protein is highly mobile and its dynamics depends upon active RNA polymerase II-mediated transcription. In addition, depletion of Nup50 inhibits differentiation of myoblasts into myotubes [Buchwalter et al., 2014]. Sixth, the cytoplasmic filaments emerging from the NPC are composed of 7 proteins, RANBP2 (alias NUP358), NUP214, NUP98, NUP88, ALADIN, NUPL2 (alias hCG1), and RAE1, and provide interaction sites for the nucleocytoplasmic transport [Hoelz et al., 2011]. Two other members of the NPC, the mRNA export factor GLE1 and the DEAD-box-containing RNA helicase DDX19, are involved in mRNA trafficking. Some NUPs have been related to immune disease, viral infections, and malignant disease [Nofrini et al., 2016]. Since the NUPs perform in concert essential functions, which are pivotal to the functioning of each body cell, it is difficult to conceive that germline mutations in the genes encoding NUPs may be compatible with life. NevIn each eukaryotic cell, the nucleus is surrounded by the nuclear envelope (NE) in which the nuclear pore complex (NPC) is embedded. In vertebrates, the NPC is roughly 60 Mda in size and comprises approximately 30 distinct proteins. The NPC forms an octagonal channel across the NE and functions in nucleocytoplasmic transport, maintaining the nuclear framework, and regulation of gene expression [Nofrini et al., 2016]. The number of NPCs per nucleus varies with environmental conditions and cellular activity, such that it increases during interphase and reaches a peak during the S-phase of the cell cycle. The NPC is formed by the nucleoporins (NUPs) and consists of 4 concentric cylinders, which surround an inner channel of 40–50 nm in diameter. NUPs are named after their molecular weight and fall into 6 main categories [Hoelz et al., 2011]. First, the transmembrane NUPs, NUP210, NDC1, and POM121, which are integral membrane proteins. They are thought to participate in NPC assembly and anchoring to the NE. Second, the membrane-apposed coat NUPs, which include NUP160, NUP133, NUP107, NUP96, NUP85, SEH1L, NUP43, NUP37, and SEC13. They form the nonameric Nup107– 160 complex that is required for early steps in NPC assembly. The ELYS protein is thought to be the tenth member of this Nup107–160 complex. Third, the adapter NUPs, NUP205, NUP188, NUP155, NUP93, and NUP35, which constitute the NUP93 complex. NUP188 and NUP93 control the organization of the subcompartments of the NE, such as the outer nuclear membrane, which is contiguous with the endoplasmic reticulum, and the inner nuclear membrane. NUP188 and NUP93 form a barAccepted: February 11, 2020 Published online: February 15, 2020