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== Function ==
== 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
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.
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 | author = 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 | year = 1997 | month = July | pmid = 9211849 | doi = 10.1126/science.277.5323.228 }}</ref>
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 | author = 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 | year = 1997 | month = July | pmid = 9211849 | doi = 10.1126/science.277.5323.228 }}</ref>
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=== Obesity ===
=== Obesity ===


Mutations in the NPC1 gene have been strongly linked with [[obesity]].<ref name="pmid19151714">{{cite journal |author=Meyre D |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 |year=2009 |month=February |pmid=19151714 |doi=10.1038/ng.301 |author-separator=, |author2=Delplanque J |author3=Chèvre JC |display-authors=3 |last4=Lecoeur |first4=Cécile |last5=Lobbens |first5=Stéphane |last6=Gallina |first6=Sophie |last7=Durand |first7=Emmanuelle |last8=Vatin |first8=Vincent |last9=Degraeve |first9=Franck}}</ref> A research group led by researcher Philippe Froguel of Imperial College London and Inserm researcher David Meyre published an obesity report in Nature Genetics in January 2009. The researchers conducting a genome-wide association study of 1,380 Europeans with early-onset childhood obesity and adult morbid obesity, and 1,416 age-matched normal weight controls.
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 | author = 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 | year = 2009 | month = February | 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 accounts for around 10 per cent of all childhood obesity and about 14 per cent of adult morbid obesity cases.<ref name="pmid19151714"/>

The obesity study led to the discovery of three new genes, including NPC1, that increased the risk not only of severe obesity but also 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. According to the report, the NPC1 gene variant could accounts for around 10 per cent of all childhood obesity and about 14 per cent of adult morbid obesity cases.


=== HIV-AIDS ===
=== 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 | author = 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 | year = 2009 | month = August | pmid = 19474101 | pmc = 2715784 | doi = 10.1128/JVI.00259-09 }}</ref><ref name="pmid22273177">{{cite journal | author = 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 | year = 2012 | month = January | pmid = 22273177 | doi = 10.1186/1743-422X-9-31 }}</ref>
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. Research led by Dr. James Hildreth of the University of California at Davis demonstrate that intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production.


=== Ebola virus ===
=== Ebola virus ===


On August 24, 2011, worked published in the journal Nature by researchers from several leading institutions and the [[United States Army Medical Research Institute of Infectious Diseases]] (USAMRIID) showed that [[Ebola virus]] cell entry and replication requires the cholesterol transporter protein Niemann–Pick C1 (NPC1).<ref name="pmid21866103">{{cite journal | author = 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 | year = 2011 | month = September | pmid = 21866103 | pmc = 3175325 | doi = 10.1038/nature10348 | laysummary = http://www.nytimes.com/2012/01/17/health/npc1-protein-may-give-ebola-its-opening.html | laysource = New York Times }}</ref> NPC1 appears to be essential for Ebola infection.
[[Ebola virus]] cell entry and replication requires the cholesterol transporter protein Niemann–Pick C1 (NPC1).<ref name="pmid21866103">{{cite journal | author = 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 | year = 2011 | month = September | pmid = 21866103 | pmc = 3175325 | doi = 10.1038/nature10348 | laysummary = http://www.nytimes.com/2012/01/17/health/npc1-protein-may-give-ebola-its-opening.html | laysource = New York Times }}</ref> NPC1 appears to be essential for Ebola infection.

Researchers made the critical discovery by studying human cell lines from patients with [[Niemann-Pick disease, type C]], a rare autosomal [[recessive]] [[lysosomal storage disease]] of [[cholesterol]] metabolism caused by genetic mutations in NPC1. When Niemann Pick Type C patients cells were exposed to the Ebola-like virus in the laboratory the cells survived and appeared immune to the [[virus]], further indicating that Ebola relies on NPC1 to enter cells. This might imply that genetic mutations in the NPC1 gene in humans could make some people resistant to one of the deadliest known viruses affecting humans.


It is not yet known whether this mutated NPC1 gene might offer similar protection against Ebola's cousin in the [[filovirus]] group, the [[Marburg virus]].
When [[Niemann-Pick disease, type C|Niemann Pick Type C]] patients cells were exposed to the Ebola-like virus in the laboratory the cells survived and appeared immune to the [[virus]], further indicating that Ebola relies on NPC1 to enter cells. This might imply that genetic mutations in the NPC1 gene in humans could make some people resistant to one of the deadliest known viruses affecting humans. It is not yet known whether this mutated NPC1 gene might offer similar protection against Ebola's cousin in the [[filovirus]] group, the [[Marburg virus]].


A [[small molecule]] has been identified that inhibits Ebola virus infection by preventing the the virus glycoprotein from binding to NPC1.<ref name="pmid21866101">{{cite journal | author = 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 | year = 2011 | month = September | pmid = 21866101 | pmc = 3230319 | doi = 10.1038/nature10380 | laysummary = http://www.nytimes.com/2012/01/17/health/npc1-protein-may-give-ebola-its-opening.html | laysource = New York Times }}</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 | year = 2011 | month = October | pmid = 21959282 | doi = 10.1038/nrd3568 }}</ref>
A [[small molecule]] has been identified that inhibits Ebola virus infection by preventing the the virus glycoprotein from binding to NPC1.<ref name="pmid21866101">{{cite journal | author = 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 | year = 2011 | month = September | pmid = 21866101 | pmc = 3230319 | doi = 10.1038/nature10380 | laysummary = http://www.nytimes.com/2012/01/17/health/npc1-protein-may-give-ebola-its-opening.html | laysource = New York Times }}</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 | year = 2011 | month = October | pmid = 21959282 | doi = 10.1038/nrd3568 }}</ref>

Revision as of 18:29, 26 January 2012

Template:PBB Niemann-Pick disease, type C1 also known as NPC1 is a protein that in humans is encoded by the NPC1 gene (chromosome location 18q11).[1][2]

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.[1][3]

Clinical significance

Obesity

Mutations in the NPC1 gene have been strongly linked with obesity.[4] 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.[4] 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 accounts for around 10 per cent of all childhood obesity and about 14 per cent of adult morbid obesity cases.[4]

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.[5][6]

Ebola virus

Ebola virus cell entry and replication requires the cholesterol transporter protein Niemann–Pick C1 (NPC1).[7] NPC1 appears to be essential for Ebola infection.

When Niemann Pick Type C patients cells were exposed to the Ebola-like virus in the laboratory the cells survived and appeared immune to the virus, further indicating that Ebola relies on NPC1 to enter cells. This might imply that genetic mutations in the NPC1 gene in humans could make some people resistant to one of the deadliest known viruses affecting humans. It is not yet known whether this mutated NPC1 gene might offer similar protection against Ebola's cousin in the filovirus group, the Marburg virus.

A small molecule has been identified that inhibits Ebola virus infection by preventing the the virus glycoprotein from binding to NPC1.[8][9]

References

  1. ^ a b "Entrez Gene: NPC1 Niemann-Pick disease, type C1".
  2. ^ Carstea ED, Polymeropoulos MH, Parker CC, Detera-Wadleigh SD, O'Neill RR, Patterson MC, Goldin E, Xiao H, Straub RE, Vanier MT (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ 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 (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  4. ^ a b c 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 (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Tang Y, Leao IC, Coleman EM, Broughton RS, Hildreth JE (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Coleman EM, Walker TN, Hildreth JE (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. PMID 22273177. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  7. ^ 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 (2011). "Ebola virus entry requires the cholesterol transporter Niemann-Pick C1". Nature. 477 (7364): 340–3. doi:10.1038/nature10348. PMC 3175325. PMID 21866103. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, Hensley L, Li Q, Ory D, Chandran K, Cunningham J (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. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Flemming A (2011). "Achilles heel of Ebola viral entry". Nat Rev Drug Discov. 10 (10): 731. doi:10.1038/nrd3568. PMID 21959282. {{cite journal}}: Unknown parameter |month= ignored (help)

Further reading

External links

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