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Other entities represented in this entry:
HGNC Approved Gene Symbol: NUP214
Cytogenetic location: 9q34.13 Genomic coordinates (GRCh38): 9:131,125,586-131,234,663 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.13 | {Encephalopathy, acute, infection-induced, susceptibility to, 9} | 618426 | Autosomal recessive | 3 |
| Leukemia, acute myeloid, somatic | 601626 | 3 | ||
| Leukemia, T-cell acute lymphoblastic, somatic | 613065 | 3 |
The NUP214 gene encodes a subunit of the nuclear pore complex (NPC), which mediates nucleocytoplasmic transport. NUP214 forms a subcomplex with other proteins to form the cytoplasmic annual ring that anchors the cytoskeleton to the NPC. It also plays a role in export of mRNA from the nucleus (summary by Shamseldin et al., 2019).
CAN/Nup214 is an FXFG repeat-containing protein involved in myeloid leukemia in humans (summary by van Deursen et al., 1996).
Von Lindern et al. (1990) reported the complete cDNA-derived primary structure of the human CAN protein. The CAN gene on human 9q34 forms a fusion gene with the DEK (125264) gene at 6p23 in a subset of acute myeloid leukemia (acute nonlymphocytic leukemia) carrying a t(6;9)(p23;q34) translocation. Von Lindern et al. (1990) estimated that the CAN gene lies 360 kb distal to ABL (189980). The breakpoints in the translocations were clustered in an 8-kb intron of a gene encoding a 7.5-kb transcript. The gene was called Cain (symbol, CAN), presumably for 'cancer intron on nine.' The gene measured more than 65 kb and was transcribed 5-prime centromeric-to-3-prime telomeric on the chromosome. It is the 3-prime portion of the CAN gene that participates in the fusion gene in the leukemogenic translocation t(6;9).
Using Western blot and immunofluorescence analyses, Kinoshita et al. (2012) showed that NUP62 (605815) and NUP214 were differentially distributed between nuclear pore complexes (NPCs) on flattened surfaces and the peripheral rim of the nucleus, with architectural microheterogeneity among NPC populations.
Gross (2019) mapped the NUP214 gene to chromosome 9q34.13 based on an alignment of the NUP214 sequence (GenBank BC045620) with the genomic sequence (GRCh38).
By interspecific backcross linkage analysis, Pilz et al. (1995) mapped the Nup214 gene to mouse chromosome 2.
Kraemer et al. (1994) found that the partial amino acid sequence of a putative nuclear pore complex protein (nucleoporin) of rat showed a high degree of similarity with the sequence of the human CAN protein. To confirm its homology and to determine its subcellular localization, Kraemer et al. (1994) expressed a 39-kD internal segment of the 213,790-Da CAN protein in Escherichia coli and raised monospecific antibodies that reacted with the putative rat nucleoporin. Immunofluorescence microscopy of HeLa cells gave a punctate nuclear surface staining pattern characteristic of nucleoporins, and immunoelectron microscopy yielded specific decoration of the cytoplasmic side of the nuclear pore complex. This suggested that the protein is part of the short fibers that emanate from the cytoplasmic aspect of the nuclear pore complex. In agreement with previously proposed nomenclature for nucleoporins, they proposed the alternative term NUP214 (nucleoporin of 214 kD) for the CAN protein.
Fornerod et al. (1997) demonstrated by coprecipitation that CAN forms a complex with NUP88 (602552) and CRM1 (602559).
By analyzing the virus capsid uncoating process during adenovirus infection in HeLa cells, Strunze et al. (2011) found that the incoming virus particle moved toward the nucleus via microtubules and docked to the NPC by interacting with Nup214. Adenovirus subsequently recruited kinesin-1 using viral capsid protein IX, which interacted with kinesin-1 light chain KLC1 (600025)/KLC2 (611729). Kinesin-1 then bound to NUP358 (601181), which was attached to the NUP214/NUP88 (602552) complex, through its heavy chain KIF5C (604593) and disrupted the viral capsid and dislocated NUP214, NUP358, and NUP62 (605815) from the central NPC to the periphery. Disruption of the NPC increased permeability of the nuclear envelope and facilitated entry of viral DNA into the nucleus.
By examining human head and neck tumor tissues and cancer cell lines, Bhattacharjya et al. (2015) found that expression of the microRNA MIR133B (610946) and NUP124 was negatively correlated, with low MIR133B levels and high NUP124 levels. Using transfected human squamous cell carcinoma cells, the authors showed that MIR133B downregulated expression of NUP214 by binding to its 3-prime UTR. Repression of NUP214 by MIR133B perturbed normal mitotic progression, resulting chromosomal abnormalities that led to apoptosis.
Acute Infection-Induced Encephalopathy 9, Susceptibility to
In 3 sisters, born of consanguineous Saudi parents, with acute infection-induced encephalopathy-9 (IIAE9; 618426), Shamseldin et al. (2019) identified a homozygous missense mutation in the NUP214 gene (D154G; 114350.0001). The mutation, which was found by a combination of linkage analysis and exon sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. Patient fibroblasts showed a dysmorphic phenotype of nuclei with an abnormal surface morphology and dramatic disruption of NUP214 localization similar to that observed in cells with knockdown of the NUP214 gene. These findings suggested that the mutation resulted in a loss of function.
In 4 patients from 2 unrelated families with IIAE9, Fichtman et al. (2019) identified homozygous or compound heterozygous mutations in the NUP214 gene (114350.0002-114350.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Analysis of patient fibroblasts showed about a 50% decrease in NUP214 and NUP88 levels compared to controls, and immunoblot analysis showed decreased nuclear rim localization of these proteins. The findings suggested that the mutations destabilize NUP protein interactions. Functional studies in patient fibroblasts showed impaired, although not abolished, activity of nuclear transport pathways, including protein import and mRNA export. Direct surface imaging of fibroblast nuclei by scanning electron microscopy revealed a large increase in the presence of central particles ('plugs') in the nuclear pore channels of affected cells. Treatment with a transcription inhibitor reduced these 'plugs,' suggesting that many of the particles may be messenger RNA complexes. Exposure of fibroblasts from affected individuals to heat shock resulted in a marked delay in their stress response, followed by increased apoptotic cell death. These abnormalities could be partially rescued with transfection of wildtype NUP214 and NUP88. The results suggested a mechanistic link between decreased cell survival in cell culture and severe fever-induced neurodegeneration in affected individuals.
T-cell acute lymphoblastic leukemia (T-ALL)
In T-cell acute lymphoblastic leukemia (T-ALL), transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified. Graux et al. (2004) described the extrachromosomal (episomal) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL. Molecular analyses delineated the amplicon as a 500-kb region from band 9q34, containing the oncogenes ABL1 and NUP214. Graux et al. (2004) reported a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1. They detected the NUP214/ABL1 transcript in 5 individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL, and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214/ABL1 was found to be sensitive to the tyrosine kinase inhibitor imatinib. The recurrent cryptic NUP214/ABL1 rearrangement was found to be associated with increased expression of HOX11 (186770) and HOX11L2 (604640) and deletion of CDKN2A (600160), consistent with a multistep pathogenesis of T-ALL.
Van Deursen et al. (1996) created Can knockout mice by targeted disruption and embryonic stem (ES) cell technology. No Can knockout mice were identified in heterozygous crosses, demonstrating that Can is essential for embryonic development. Lethality occurs between 4.0-4.5 days postcoitum, after the depletion of maternal Can sources. Homozygous Can -/- ES cells are not viable. In 3.5-day-old mutant embryos, cultured in vitro, progressive depletion of Can leads to cell cycle arrest in G2 phase, and eventually to blastocele collapse, impaired NLS-mediated protein uptake, and nuclear accumulation of polyadenylated RNA. The defective Can-depleted embryos did not display any gross morphologic abnormalities of the nuclear envelope or nuclear pore complex (NPC). The results suggested to the authors that Can is critical to cell cycle progression and required for both nuclear protein import and mRNA export.
In 3 sisters, born of consanguineous Saudi parents, with acute infection-induced encephalopathy-9 (IIAE9; 618426), Shamseldin et al. (2019) identified a homozygous c.461A-G transition (c.461A-G, NM_005085.3) in the NUP214 gene, resulting in an asp154-to-gly (D154G) substitution at a conserved residue. The mutation, which was found by a combination of linkage analysis and exon sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. Patient fibroblasts showed dysmorphic nuclei with an abnormal surface morphology and dramatic disruption of NUP214 localization from the nuclear rim similar to that observed in cells with knockdown of the NUP214 gene. These findings suggested that the mutation resulted in a loss of function.
In 2 affected members of a highly consanguineous Palestinian family (family A) with acute infection-induced encephalopathy-9 (IIAE9; 618426), Fichtman et al. (2019) identified a homozygous c.112C-T transition (c.112C-T, NM_005085.3) in the NUP214 gene, resulting in an arg38-to-cys (R38C) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a low frequency in heterozygous state in the gnomAD database, but was not found among 120 population-matched controls or in an in-house database of 3,000 individuals, including about 50% Palestinians.
In 2 sisters, born of unrelated parents of northern European descent (family B), with acute infection-induced encephalopathy-9 (IIAE9; 618426), Fichtman et al. (2019) identified compound heterozygous mutations in the NUP214 gene: a c.1159C-T transition (c.1159C-T, NM_0050085.3), resulting in a pro387-to-ser (P387S) substitution at a highly conserved residue, and a 1-bp deletion (c.1574delC; 114350.0004), resulting in a frameshift in exon 12 and premature termination (Pro525LeufsTer6). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The P387S variant was found once in heterozygous state in the gnomAD database, whereas c.1574delC was not present.
For discussion of the 1-bp deletion (c.1574delC, NM_005085.3) in the NUP214 gene, resulting in a frameshift and premature termination (Pro525LeufsTer6), that was found in compound heterozygous state in 2 sisters with acute infection-induced encephalopathy-9 (IIAE9; 618426) by Fichtman et al. (2019), see 114350.0003.
Bhattacharjya, S., Roy, K. S., Ganguly, A., Sarkar, S., Panda, C. K., Bhattacharyya, D., Bhattacharyya, N. P., Roychoudhury, S. Inhibition of nucleoporin member Nup124 expression by miR-133b perturbs mitotic timing and leads to cell death. Molec. Cancer 14: 42, 2015. Note: Electronic Article. [PubMed: 25743594] [Full Text: https://doi.org/10.1186/s12943-015-0299-z]
Fichtman, B., Harel, T., Biran, N., Zagairy, F., Applegate, C. D., Salzberg, Y., Gilboa, T., Salah, S., Shaag, A., Simanovsky, N., Ayoubieh, H., Sobreira, N., Punzi, G., Pierri, C. L., Hamosh, A., Elpeleg, O., Harel, A., Edvardson, S. Pathogenic variants in NUP214 cause 'plugged' nuclear pore channels and acute febrile encephalopathy. Am. J. Hum. Genet. 105: 48-64, 2019. [PubMed: 31178128] [Full Text: https://doi.org/10.1016/j.ajhg.2019.05.003]
Fornerod, M., van Deursen, J., van Baal, S., Reynolds, A., Davis, D., Murti, K. G., Fransen, J., Grosveld, G. The human homologue of yeast CRM1 is in a dynamic subcomplex with CAN/Nup214 and a novel nuclear pore component Nup88. EMBO J. 16: 807-816, 1997. [PubMed: 9049309] [Full Text: https://doi.org/10.1093/emboj/16.4.807]
Graux, C., Cools, J., Melotte, C., Quentmeier, H., Ferrando, A., Levine, R., Vermeesch, J. R., Stul, M., Dutta, B., Boeckx, N., Bosly, A., Heimann, P., and 12 others. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nature Genet. 36: 1084-1089, 2004. [PubMed: 15361874] [Full Text: https://doi.org/10.1038/ng1425]
Gross, M. B. Personal Communication. Baltimore, Md. 6/24/2019.
Kinoshita, Y., Kalir, T., Dottino, P., Kohtz, D. S. Nuclear distributions of NUP62 and NUP214 suggest architectural diversity and spatial patterning among nuclear pore complexes. PLoS One 7: e36137, 2012. Note: Electronic Article. [PubMed: 22558357] [Full Text: https://doi.org/10.1371/journal.pone.0036137]
Kraemer, D., Wozniak, R. W., Blobel, G., Radu, A. The human CAN protein, a putative oncogene product associated with myeloid leukemogenesis, is a nuclear pore complex protein that faces the cytoplasm. Proc. Nat. Acad. Sci. 91: 1519-1523, 1994. [PubMed: 8108440] [Full Text: https://doi.org/10.1073/pnas.91.4.1519]
Pilz, A., Woodward, K., Povey, S., Abbott, C. Comparative mapping of 50 human chromosome 9 loci in the laboratory mouse. Genomics 25: 139-149, 1995. [PubMed: 7774911] [Full Text: https://doi.org/10.1016/0888-7543(95)80119-7]
Shamseldin, H. E., Makhseed, N., Ibrahim, N., Al-Sheddi, T., Alobeid, E., Abdulwahab, F., Alkuraya, F. S. NUP214 deficiency causes severe encephalopathy and microcephaly in humans. Hum. Genet. 138: 221-229, 2019. [PubMed: 30758658] [Full Text: https://doi.org/10.1007/s00439-019-01979-w]
Strunze, S., Engelke, M. F., Wang, I-H., Puntener, D., Boucke, K., Schleich, S., Way, M., Schoenenberger, P., Burckhardt, C. J., Greber, U. F. Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection. Cell Host Microbe 10: 210-223, 2011. [PubMed: 21925109] [Full Text: https://doi.org/10.1016/j.chom.2011.08.010]
van Deursen, J., Boer, J., Kasper, L., Grosveld, G. G(2) arrest and impaired nucleocytoplasmic transport in mouse embryos lacking the proto-oncogene CAN/Nup214. EMBO J. 15: 5574-5583, 1996. [PubMed: 8896451]
von Lindern, M., Poustka, A., Lehrach, H., Grosveld, G. The (6;9) chromosome translocation, associated with a specific subtype of acute nonlymphocytic leukemia, leads to aberrant transcription of a target gene on 9q34. Molec. Cell. Biol. 10: 4016-4026, 1990. [PubMed: 2370860] [Full Text: https://doi.org/10.1128/mcb.10.8.4016-4026.1990]