View source for NPC1

{{Infobox_gene}}
[[File:NPC1 location.png|thumb|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).<ref name="entrez">{{cite web | title = Entrez Gene: NPC1 Niemann-Pick disease, type C1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4864| accessdate = }}</ref><ref name="pmid8446622">{{cite journal |vauthors=Carstea ED, Polymeropoulos MH, Parker CC, Detera-Wadleigh SD, O'Neill RR, Patterson MC, Goldin E, Xiao H, Straub RE, Vanier MT | title = Linkage of Niemann-Pick disease type C to human chromosome 18 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 90 | issue = 5 | pages = 2002–4 |date=March 1993 | pmid = 8446622 | pmc = 46008 | doi = 10.1073/pnas.90.5.2002 }}</ref>

== 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 motif]]s consistent with a role in intracellular transport of [[cholesterol]] to post-[[lysosome|lysosomal]] destinations.<ref name="entrez"/><ref name="pmid9211849">{{cite journal | vauthors = 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| title = Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis | journal = Science | volume = 277 | issue = 5323 | pages = 228–31 |date=July 1997 | pmid = 9211849 | doi = 10.1126/science.277.5323.228  }}</ref>

== Clinical significance ==

=== Obesity ===

Mutations in the NPC1 gene have been strongly linked with [[obesity]].<ref name="pmid19151714"/>  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.<ref name="pmid19151714">{{cite journal |vauthors=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 | title = Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations | journal = Nat. Genet. | volume = 41 | issue = 2 | pages = 157–9 |date=February 2009 | pmid = 19151714 | doi = 10.1038/ng.301 }}</ref> 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.<ref name="pmid19151714"/>

=== HIV-AIDS ===

Cholesterol pathways play an important role at multiple stages during the [[Subtypes of HIV#HIV-1|HIV-1]] infection cycle. HIV-1 fusion, entry, assembly, and budding occur at cholesterol-enriched microdomains called [[lipid raft]]s. The HIV-1 accessory protein, [[Nef (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.<ref name="pmid19474101">{{cite journal |vauthors=Tang Y, Leao IC, Coleman EM, Broughton RS, Hildreth JE | title = 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 | journal = J. Virol. | volume = 83 | issue = 16 | pages = 7982–95 |date=August 2009 | pmid = 19474101 | pmc = 2715784 | doi = 10.1128/JVI.00259-09 }}</ref><ref name="pmid22273177">{{cite journal |vauthors=Coleman EM, Walker TN, Hildreth JE | title = 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 | journal = Virol J | volume = 9 | issue = 1 | pages = 31 |date=January 2012 | pmid = 22273177 | doi = 10.1186/1743-422X-9-31 | pmc=3299633}}</ref>

=== 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.<ref name="Carette_2011">{{cite journal |vauthors=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 | title = Ebola virus entry requires the cholesterol transporter Niemann-Pick C1 | journal = Nature | volume = 477 | issue = 7364 | pages = 340–3 |date=September 2011 | pmid = 21866103 | pmc = 3175325 | doi = 10.1038/nature10348 | laysummary = https://www.nytimes.com/2012/01/17/health/npc1-protein-may-give-ebola-its-opening.html | laysource = New York Times }}</ref><ref name="Côté_2011">{{cite journal |vauthors=Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, Hensley L, Li Q, Ory D, Chandran K, Cunningham J | title = Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection | journal = Nature | volume = 477 | issue = 7364 | pages = 344–8 |date=September 2011 | pmid = 21866101 | pmc = 3230319 | doi = 10.1038/nature10380 | laysummary = https://www.nytimes.com/2012/01/17/health/npc1-protein-may-give-ebola-its-opening.html | laysource = New York Times }}</ref> When cells from [[Niemann-Pick disease, type C|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.<ref name="Côté_2011"></ref> The same studies described similar results with [[Marburg virus]], another [[filovirus]], showing that it too needs NPC1 to enter cells.<ref name="Carette_2011"></ref><ref name="Côté_2011"></ref> 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.<ref name="Côté_2011"></ref> 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.<ref name="pmid22395071">{{cite journal |vauthors=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 | title = Ebola virus entry requires the host-programmed recognition of an intracellular receptor | journal = EMBO Journal | volume = 31 | issue = 8 | pages = 1947–60 |date=March 2012 | pmid = 22395071 | pmc = 3343336 | doi = 10.1038/emboj.2012.53 }}</ref>

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.<ref name="Côté_2011"></ref><ref name="pmid21959282">{{cite journal | author = Flemming A | title = Achilles heel of Ebola viral entry | journal = Nat Rev Drug Discov | volume = 10 | issue = 10 | pages = 731 |date=October 2011 | pmid = 21959282 | doi = 10.1038/nrd3568 }}</ref> In the other study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse adapted Ebola virus.<ref name="Carette_2011"></ref> 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.<ref name="Yan_2011">{{cite journal |vauthors=Yan X, Lukas J, Witt M, Wree A, Hübner R, Frech M, Köhling R, Rolfs A, Luo J | title = Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse | journal = Metab Brain Dis | volume = 26 | issue = 4 | pages = 299–306 |date=December 2011 | pmid = 21938520 | doi = 10.1007/s11011-011-9263-9 | url = }}</ref> [[Myelin gene Regulatory Factor|MRF]] is a [[transcription factor]] of critical importance in the development and maintenance of [[myelin sheath]]s.<ref name="Koenning_2012">{{cite journal |vauthors=Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M, Emery B | title = Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS | journal = J. Neurosci. | volume = 32 | issue = 36 | pages = 12528–42 |date=September 2012 | pmid = 22956843 | doi = 10.1523/JNEUROSCI.1069-12.2012 | url = | pmc = 3752083 }}</ref> A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.<ref name="Yan_2011"/>

==References==
{{reflist|35em}}

==Further reading==
{{refbegin|35em}}
* {{cite journal |vauthors=Vanier MT, Suzuki K | title = Recent advances in elucidating Niemann-Pick C disease | journal = Brain Pathol. | volume = 8 | issue = 1 | pages = 163–74 |date=January 1998 | pmid = 9458174 | doi = 10.1111/j.1750-3639.1998.tb00143.x }}
* {{cite journal |vauthors=Liscum L, Klansek JJ | title = Niemann-Pick disease type C | journal = Curr. Opin. Lipidol. | volume = 9 | issue = 2 | pages = 131–5 |date=April 1998 | pmid = 9559270 | doi = 10.1097/00041433-199804000-00009 }}
* {{cite journal |vauthors=Morris JA, Carstea ED | title = Niemann-Pick C disease: cholesterol handling gone awry | journal = Mol Med Today | volume = 4 | issue = 12 | pages = 525–31 |date=December 1998 | pmid = 9866822 | doi = 10.1016/S1357-4310(98)01374-4 }}
* {{cite journal |vauthors=Garver WS, Heidenreich RA | title = The Niemann-Pick C proteins and trafficking of cholesterol through the late endosomal/lysosomal system | journal = Curr. Mol. Med. | volume = 2 | issue = 5 | pages = 485–505 |date=August 2002 | pmid = 12125814 | doi = 10.2174/1566524023362375 }}
* {{cite journal |vauthors=Greer WL, Riddell DC, Byers DM, Welch JP, Girouard GS, Sparrow SM, Gillan TL, Neumann PE | title = Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C | journal = Am. J. Hum. Genet. | volume = 61 | issue = 1 | pages = 139–42 |date=July 1997 | pmid = 9245994 | pmc = 1715879 | doi = 10.1086/513899 | url = }}
* {{cite journal |vauthors=Greer WL, Riddell DC, Gillan TL, Girouard GS, Sparrow SM, Byers DM, Dobson MJ, Neumann PE | title = The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097-->T transversion in NPC1 | journal = Am. J. Hum. Genet. | volume = 63 | issue = 1 | pages = 52–4 |date=July 1998 | pmid = 9634529 | pmc = 1377252 | doi = 10.1086/301931 }}
* {{cite journal |vauthors=Watari H, Blanchette-Mackie EJ, Dwyer NK, Glick JM, Patel S, Neufeld EB, Brady RO, Pentchev PG, Strauss JF | title = Niemann-Pick C1 protein: obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 3 | pages = 805–10 |date=February 1999 | pmid = 9927649 | pmc = 15306 | doi = 10.1073/pnas.96.3.805 }}
* {{cite journal |vauthors=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 | title = Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 4 | pages = 1657–62 |date=February 1999 | pmid = 9990080 | pmc = 15549 | doi = 10.1073/pnas.96.4.1657 }}
* {{cite journal |vauthors=Morris JA, Zhang D, Coleman KG, Nagle J, Pentchev PG, Carstea ED | title = The genomic organization and polymorphism analysis of the human Niemann-Pick C1 gene | journal = Biochem. Biophys. Res. Commun. | volume = 261 | issue = 2 | pages = 493–8 |date=August 1999 | pmid = 10425213 | doi = 10.1006/bbrc.1999.1070 }}
* {{cite journal |vauthors=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 | title = NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C | journal = Hum. Genet. | volume = 105 | issue = 1-2 | pages = 10–6 | year = 1999 | pmid = 10480349 | doi = 10.1007/s004390051057 }}
* {{cite journal |vauthors=Greer WL, Dobson MJ, Girouard GS, Byers DM, Riddell DC, Neumann PE | title = Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain | journal = Am. J. Hum. Genet. | volume = 65 | issue = 5 | pages = 1252–60 |date=November 1999 | pmid = 10521290 | pmc = 1288277 | doi = 10.1086/302620 }}
* {{cite journal |vauthors=Millat G, Marçais C, Rafi MA, Yamamoto T, Morris JA, Pentchev PG, Ohno K, Wenger DA, Vanier MT | title = 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 | journal = Am. J. Hum. Genet. | volume = 65 | issue = 5 | pages = 1321–9 |date=November 1999 | pmid = 10521297 | pmc = 1288284 | doi = 10.1086/302626 }}
* {{cite journal |vauthors=Davies JP, Ioannou YA | title = 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 | journal = J. Biol. Chem. | volume = 275 | issue = 32 | pages = 24367–74 |date=August 2000 | pmid = 10821832 | doi = 10.1074/jbc.M002184200 }}
* {{cite journal |vauthors=Millat G, Marçais C, Tomasetto C, Chikh K, Fensom AH, Harzer K, Wenger DA, Ohno K, Vanier MT | title = 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 | journal = Am. J. Hum. Genet. | volume = 68 | issue = 6 | pages = 1373–85 |date=June 2001 | pmid = 11333381 | pmc = 1226124 | doi = 10.1086/320606 }}
* {{cite journal |vauthors=Sun X, Marks DL, Park WD, Wheatley CL, Puri V, O'Brien JF, Kraft DL, Lundquist PA, Patterson MC, Pagano RE, Snow K | title = Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1 | journal = Am. J. Hum. Genet. | volume = 68 | issue = 6 | pages = 1361–72 |date=June 2001 | pmid = 11349231 | pmc = 1226123 | doi = 10.1086/320599 }}
{{refend}}

==External links==
{{commons category}}
* {{MeshName|NPC1+protein,+human}}
* [http://fightnpc.com/en/ Fight NPC, a website dedicated to providing information and resources on treating Niemann–Pick type C disease]
* [http://www.hideandseek.org Hide & Seek Foundation for Lysosomal Disease Research]
{{NLM content}}

[[Category:Genes on human chromosome 18]]