Alt. symbols: ANE1 | NUP358 | ADANE

Approved name: RAN binding protein 2
Alt. names: acute necrotizing encephalopathy 1 (autosomal dominant) | nucleoporin 358

Location: 2q13: 108719482 - 108785810 (+)
Gene type: protein_coding, 19 transcripts.

Scores: LoFtool: 0.481000 | pLI: 1.00000000 | LOEUF: 0.142

HGNC: 9848

NCBI: 5903, RefSeq: NG_012210.1

Ensembl: ENSG00000153201.17

LRG_ | Status: none

OMIM: 601181

Expression | ProteinAtlas

The gene RANBP2 encodes the Ran binding protein 2, which is an E3 SUMO-protein ligase and also known as nucleoporin 358 (Nup358), as it is a member of the family of nucleoporins (NUP). Nucleoporins are proteins that constitute the nuclear pore complex (NPC). RANBP2 is the largest component of the NPC, where, during the interphase, it is situated on the cytoplasmic filaments emanating from the nuclear pore. During mitosis, when the nuclear envelope (NE) breaks down and the NPC disassembles, RANBP2 localizes to the microtubules of the forming mitotic spindle, with an accumulation at the poles, being a fraction recruited to chromosomal kinetochores. NPCs are the gateways across the nuclear envelope where the exchange of macromolecules between cytoplasm and nucleus takes place. During the interphase, this nucleocytoplasmic transport is essential for many of the processes occurring inside and outside the nucleus. RANBP2 helps to mediate nuclear import by at least two mechanisms: serving as a docking site for nuclear import complexes by capturing transport receptors through its FG-repeats; or by interacting with selected cargos in a receptor-independent manner. In this way, RANBP2 is implicated in the nuclear delivery and integration of certain human viruses, such as the Herpes simplex or the immunodeficiency virus-1 (HIV-1). In addition, RANBP2 seems to facilitate nuclear export of polyA+ mRNAs, although it may not be an indispensable component for this process. Overall, RANBP2 is actively involved in the nucleocytoplasmic transport and exchange of transcriptional and epigenetic factors. RANBP2 also has structural functions at the nuclear envelope and NPC since it is required for SUMOylation of proteins associated with the formation of subnuclear structures. It may also contribute to Golgi membrane remodelling because it binds to the COPI complex that coat Golgi vesicles. RANBP2 is indirectly involved in the regulation of dynein-dynactin motor complexes at the NPC and centrosome tethering to the NE prior to mitotic entry, because it binds and recruits BICD2 to the NPC. In nerve cells in the brain, RANBP2 is likely involved in the regulation of energy and the maintenance of the blood-brain barrier, which allows only the passing of certain substances from the blood to the brain. At the onset of mitosis, RANBP2 recruits motor proteins at the NE to regulate NE breakdown, and during mitosis, it contributes to mitotic spindle organization, microtubule-kinetochore interactions, and regulation of the SUMO conjugation pathway. At the end of mitosis, in early telophase, RANBP2 is recruited back around the chromatin of the reforming nuclei as the NE and NPC reorganize.

Monoallelic missense mutations in RANBP2 have been associated with susceptibility to acute encephalopathy [MIM:608033]. Although the pathogenesis of acute encephalopathy is only partially described, it has been brought into context with acute viral illness as it develops secondary to viral infections, including influenza, parainfluenza, varicella-zoster, and enterovirus. Affected individuals are previously healthy children that develop encephalopathy, seizures, focal neurological signs and coma within days after the onset of infection. To date, three heterozygous missense mutations (p.Thr585Met, p.Thr653Ile, and p.Ile656Val) in the leucine-rich domain (LD) of RANBP2 have been detected in affected patients with acute encephalopathy (Neilson et al., 2009 and Denier et al., 2014). However, those missense mutations are not causing a fully penetrant phenotype, for which additional genetic and environmental factors, such as a viral infection, may be required. [Load More]