NPC1

NPC1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNPC1, NPC, NPC intracellular cholesterol transporter 1, SLC65A1, POGZ
External IDsOMIM: 607623 MGI: 1097712 HomoloGene: 228 GeneCards: NPC1
Gene location (Human)
Chr.Chromosome 18 (human)[1]
Band18q11.2Start23,506,184 bp[1]
End23,586,898 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

4864

18145

Ensembl

ENSG00000141458

ENSMUSG00000024413

UniProt

O15118

O35604

RefSeq (mRNA)

NM_000271

NM_008720

RefSeq (protein)

NP_000262

NP_032746

Location (UCSC)Chr 18: 23.51 – 23.59 MbChr 18: 12.19 – 12.24 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
NPC1 gene is located on the long (q) arm of chromosome 18 at position 11.2.

Niemann-Pick disease, type C1 (NPC1) is a disease of a membrane protein that mediates intracellular cholesterol trafficking in mammals. In humans the protein is encoded by the NPC1 gene (chromosome location 18q11).[5][6]

Function

NPC1 was identified as the gene that when mutated, results in Niemann-Pick disease, type C. Niemann-Pick disease, type C is a rare neurovisceral lipid storage disorder resulting from autosomal recessively inherited loss-of-function mutations in either NPC1 or NPC2. This disrupts intracellular lipid transport, leading to the accumulation of lipid products in the late endosomes and lysosomes. Approximately 95% of NPC patients are found to have mutations in the NPC1 gene.

NPC1 encodes a putative integral membrane protein containing sequence motifs consistent with a role in intracellular transport of cholesterol to post-lysosomal destinations.[5][7]

Clinical significance

Obesity

Mutations in the NPC1 gene have been strongly linked with obesity.[8] A genome-wide association study identified NPC1 mutations as a risk factor in childhood obesity and adult morbid obesity, and 1,416 age-matched normal weight controls.[8] Mutations in NPC1 were also correlated with ordinary weight gain in the population. Previous studies in mice have suggested that the NPC1 gene has a role in controlling appetite, as mice with a non-functioning NPC1 gene suffer late-onset weight loss and have poor food intake. NPC1 gene variant could account for around 10 per cent of all childhood obesity and about 14 per cent of adult morbid obesity cases.[8]

HIV-AIDS

Cholesterol pathways play an important role at multiple stages during the HIV-1 infection cycle. HIV-1 fusion, entry, assembly, and budding occur at cholesterol-enriched microdomains called lipid rafts. The HIV-1 accessory protein, Nef, has been shown to induce many genes involved in cholesterol biosynthesis and homeostasis. Intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production.[9][10]

Ebola virus

The human Niemann–Pick C1 (NPC1) cholesterol transporter appears to be essential for Ebola virus infection: a series of independent studies have presented evidence that Ebola virus enters human cells after binding to NPC1.[11][12] When cells from Niemann Pick Type C patients lacking this transporter were exposed to Ebola virus in the laboratory, the cells survived and appeared impervious to the virus, further indicating that Ebola relies on NPC1 to enter cells.[12] The same studies described similar results with Marburg virus, another filovirus, showing that it too needs NPC1 to enter cells.[11][12] In one of the studies, NPC1 was shown to be critical to filovirus entry because it mediates infection by binding directly to the viral envelope glycoprotein.[12] A later study confirmed the findings that NPC1 is a critical filovirus receptor that mediates infection by binding directly to the viral envelope glycoprotein and that the second lysosomal domain of NPC1 mediates this binding.[13]

In one of the original studies, a small molecule was shown to inhibit Ebola virus infection by preventing the virus glycoprotein from binding to NPC1.[12][14] In the other study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse adapted Ebola virus.[11] Together, these studies suggest NPC1 may be potential therapeutic target for an Ebola anti-viral drug.

Mechanisms in pathology

In a mouse model carrying the underlying mutation for Niemann-Pick type C1 disease in the NPC1 protein, the expression of Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased.[15] MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths.[16] A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.[15]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000141458 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024413 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. 1 2 "Entrez Gene: NPC1 Niemann-Pick disease, type C1".
  6. ↑ Carstea ED, Polymeropoulos MH, Parker CC, Detera-Wadleigh SD, O'Neill RR, Patterson MC, Goldin E, Xiao H, Straub RE, Vanier MT (March 1993). "Linkage of Niemann-Pick disease type C to human chromosome 18". Proc. Natl. Acad. Sci. U.S.A. 90 (5): 2002–4. doi:10.1073/pnas.90.5.2002. PMC 46008. PMID 8446622.
  7. ↑ Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, Gu J, Rosenfeld MA, Pavan WJ, Krizman DB, Nagle J, Polymeropoulos MH, Sturley SL, Ioannou YA, Higgins ME, Comly M, Cooney A, Brown A, Kaneski CR, Blanchette-Mackie EJ, Dwyer NK, Neufeld EB, Chang TY, Liscum L, Strauss JF 3rd, Ohno K, Zeigler M, Carmi R, Sokol J, Markie D, O'Neill RR, van Diggelen OP, Elleder M, Patterson MC, Brady RO, Vanier MT, Pentchev PG, Tagle DA (July 1997). "Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis". Science. 277 (5323): 228–31. doi:10.1126/science.277.5323.228. PMID 9211849.
  8. 1 2 3 Meyre D, Delplanque J, Chèvre JC, Lecoeur C, Lobbens S, Gallina S, Durand E, Vatin V, Degraeve F, Proença C, Gaget S, Körner A, Kovacs P, Kiess W, Tichet J, Marre M, Hartikainen AL, Horber F, Potoczna N, Hercberg S, Levy-Marchal C, Pattou F, Heude B, Tauber M, McCarthy MI, Blakemore AI, Montpetit A, Polychronakos C, Weill J, Coin LJ, Asher J, Elliott P, Järvelin MR, Visvikis-Siest S, Balkau B, Sladek R, Balding D, Walley A, Dina C, Froguel P (February 2009). "Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations". Nat. Genet. 41 (2): 157–9. doi:10.1038/ng.301. PMID 19151714.
  9. ↑ Tang Y, Leao IC, Coleman EM, Broughton RS, Hildreth JE (August 2009). "Deficiency of niemann-pick type C-1 protein impairs release of human immunodeficiency virus type 1 and results in Gag accumulation in late endosomal/lysosomal compartments". J. Virol. 83 (16): 7982–95. doi:10.1128/JVI.00259-09. PMC 2715784. PMID 19474101.
  10. ↑ Coleman EM, Walker TN, Hildreth JE (January 2012). "Loss of Niemann Pick type C proteins 1 and 2 greatly enhances HIV infectivity and is associated with accumulation of HIV Gag and cholesterol in late endosomes/lysosomes". Virol J. 9 (1): 31. doi:10.1186/1743-422X-9-31. PMC 3299633. PMID 22273177.
  11. 1 2 3 Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, Kuehne AI, Kranzusch PJ, Griffin AM, Ruthel G, Dal Cin P, Dye JM, Whelan SP, Chandran K, Brummelkamp TR (September 2011). "Ebola virus entry requires the cholesterol transporter Niemann-Pick C1". Nature. 477 (7364): 340–3. doi:10.1038/nature10348. PMC 3175325. PMID 21866103. Lay summary – New York Times.
  12. 1 2 3 4 5 Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, Hensley L, Li Q, Ory D, Chandran K, Cunningham J (September 2011). "Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection". Nature. 477 (7364): 344–8. doi:10.1038/nature10380. PMC 3230319. PMID 21866101. Lay summary – New York Times.
  13. ↑ Miller EH, Obernosterer G, Raaben M, Herbert AS, Deffieu MS, Krishnan A, Ndungo E, Sandesara RG, Carette JE, Kuehne AI, Ruthel G, Pfeffer SR, Dye JM, Whelan SP, Brummelkamp TR, Chandran K (March 2012). "Ebola virus entry requires the host-programmed recognition of an intracellular receptor". EMBO Journal. 31 (8): 1947–60. doi:10.1038/emboj.2012.53. PMC 3343336. PMID 22395071.
  14. ↑ Flemming A (October 2011). "Achilles heel of Ebola viral entry". Nat Rev Drug Discov. 10 (10): 731. doi:10.1038/nrd3568. PMID 21959282.
  15. 1 2 Yan X, Lukas J, Witt M, Wree A, Hübner R, Frech M, Köhling R, Rolfs A, Luo J (December 2011). "Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse". Metab Brain Dis. 26 (4): 299–306. doi:10.1007/s11011-011-9263-9. PMID 21938520.
  16. ↑ Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M, Emery B (September 2012). "Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS". J. Neurosci. 32 (36): 12528–42. doi:10.1523/JNEUROSCI.1069-12.2012. PMC 3752083. PMID 22956843.

Further reading

  • Vanier MT, Suzuki K (January 1998). "Recent advances in elucidating Niemann-Pick C disease". Brain Pathol. 8 (1): 163–74. doi:10.1111/j.1750-3639.1998.tb00143.x. PMID 9458174.
  • Liscum L, Klansek JJ (April 1998). "Niemann-Pick disease type C". Curr. Opin. Lipidol. 9 (2): 131–5. doi:10.1097/00041433-199804000-00009. PMID 9559270.
  • Morris JA, Carstea ED (December 1998). "Niemann-Pick C disease: cholesterol handling gone awry". Mol Med Today. 4 (12): 525–31. doi:10.1016/S1357-4310(98)01374-4. PMID 9866822.
  • Garver WS, Heidenreich RA (August 2002). "The Niemann-Pick C proteins and trafficking of cholesterol through the late endosomal/lysosomal system". Curr. Mol. Med. 2 (5): 485–505. doi:10.2174/1566524023362375. PMID 12125814.
  • Greer WL, Riddell DC, Byers DM, Welch JP, Girouard GS, Sparrow SM, Gillan TL, Neumann PE (July 1997). "Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C". Am. J. Hum. Genet. 61 (1): 139–42. doi:10.1086/513899. PMC 1715879. PMID 9245994.
  • Greer WL, Riddell DC, Gillan TL, Girouard GS, Sparrow SM, Byers DM, Dobson MJ, Neumann PE (July 1998). "The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097-->T transversion in NPC1". Am. J. Hum. Genet. 63 (1): 52–4. doi:10.1086/301931. PMC 1377252. PMID 9634529.
  • Watari H, Blanchette-Mackie EJ, Dwyer NK, Glick JM, Patel S, Neufeld EB, Brady RO, Pentchev PG, Strauss JF (February 1999). "Niemann-Pick C1 protein: obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization". Proc. Natl. Acad. Sci. U.S.A. 96 (3): 805–10. doi:10.1073/pnas.96.3.805. PMC 15306. PMID 9927649.
  • Patel SC, Suresh S, Kumar U, Hu CY, Cooney A, Blanchette-Mackie EJ, Neufeld EB, Patel RC, Brady RO, Patel YC, Pentchev PG, Ong WY (February 1999). "Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease". Proc. Natl. Acad. Sci. U.S.A. 96 (4): 1657–62. doi:10.1073/pnas.96.4.1657. PMC 15549. PMID 9990080.
  • Morris JA, Zhang D, Coleman KG, Nagle J, Pentchev PG, Carstea ED (August 1999). "The genomic organization and polymorphism analysis of the human Niemann-Pick C1 gene". Biochem. Biophys. Res. Commun. 261 (2): 493–8. doi:10.1006/bbrc.1999.1070. PMID 10425213.
  • Yamamoto T, Nanba E, Ninomiya H, Higaki K, Taniguchi M, Zhang H, Akaboshi S, Watanabe Y, Takeshima T, Inui K, Okada S, Tanaka A, Sakuragawa N, Millat G, Vanier MT, Morris JA, Pentchev PG, Ohno K (1999). "NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C". Hum. Genet. 105 (1–2): 10–6. doi:10.1007/s004390051057. PMID 10480349.
  • Greer WL, Dobson MJ, Girouard GS, Byers DM, Riddell DC, Neumann PE (November 1999). "Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain". Am. J. Hum. Genet. 65 (5): 1252–60. doi:10.1086/302620. PMC 1288277. PMID 10521290.
  • Millat G, Marçais C, Rafi MA, Yamamoto T, Morris JA, Pentchev PG, Ohno K, Wenger DA, Vanier MT (November 1999). "Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype". Am. J. Hum. Genet. 65 (5): 1321–9. doi:10.1086/302626. PMC 1288284. PMID 10521297.
  • Davies JP, Ioannou YA (August 2000). "Topological analysis of Niemann-Pick C1 protein reveals that the membrane orientation of the putative sterol-sensing domain is identical to those of 3-hydroxy-3-methylglutaryl-CoA reductase and sterol regulatory element binding protein cleavage-activating protein". J. Biol. Chem. 275 (32): 24367–74. doi:10.1074/jbc.M002184200. PMID 10821832.
  • Millat G, Marçais C, Tomasetto C, Chikh K, Fensom AH, Harzer K, Wenger DA, Ohno K, Vanier MT (June 2001). "Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop". Am. J. Hum. Genet. 68 (6): 1373–85. doi:10.1086/320606. PMC 1226124. PMID 11333381.
  • Sun X, Marks DL, Park WD, Wheatley CL, Puri V, O'Brien JF, Kraft DL, Lundquist PA, Patterson MC, Pagano RE, Snow K (June 2001). "Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1". Am. J. Hum. Genet. 68 (6): 1361–72. doi:10.1086/320599. PMC 1226123. PMID 11349231.

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