NPC1
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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]
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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 virus glycoprotein from binding to NPC1.[8][9]
References
- ^ a b "Entrez Gene: NPC1 Niemann-Pick disease, type C1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4864.
- ^ 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. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8446622.
- ^ 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.
- ^ 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 (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.
- ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2715784.
- ^ 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. PMID 22273177.
- ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3175325. Lay summary – New York Times.
- ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3230319. Lay summary – New York Times.
- ^ Flemming A (October 2011). "Achilles heel of Ebola viral entry". Nat Rev Drug Discov 10 (10): 731. doi:10.1038/nrd3568. PMID 21959282.
Further reading
- Vanier MT, Suzuki K (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 (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 (1999). "Niemann-Pick C disease: cholesterol handling gone awry". Molecular medicine today 4 (12): 525–31. doi:10.1016/S1357-4310(98)01374-4. PMID 9866822.
- Garver WS, Heidenreich RA (2003). "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.
- Carstea ED, Polymeropoulos MH, Parker CC et al (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=46008.
- Carstea ED, Morris JA, Coleman KG et al (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.
- Greer WL, Riddell DC, Byers DM et al (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1715879.
- Greer WL, Riddell DC, Gillan TL et al (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1377252.
- Watari H, Blanchette-Mackie EJ, Dwyer NK et al (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=15306.
- Patel SC, Suresh S, Kumar U et al (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=15549.
- Morris JA, Zhang D, Coleman KG et al (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 et al (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 et al (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1288277.
- Millat G, Marçais C, Rafi MA et al (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1288284.
- Davies JP, Ioannou YA (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 et al (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1226124.
- Sun X, Marks DL, Park WD et al (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1226123.
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