NPC1
Template:PBB Niemann-Pick disease, type C1 also known as NPC1 is a protein that in humans is encoded by the NPC1 gene.[1][2]
Function
NPC1 was identified as the gene that when mutated, results in Niemann-Pick disease, type C. Niemann-Pick disease, type C (NPC) 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.
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 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.
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 their research, 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.
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).[5] 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.
A small molecule has been identified that inhibits Ebola virus infection by preventing the the virus glycoprotein from binding to NPC1.[6][7]
References
- ^ a b "Entrez Gene: NPC1 Niemann-Pick disease, type C1".
- ^ 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) - ^ 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) - ^ Meyre D; Delplanque J; Chèvre JC; et al. (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|author-separator=ignored (help); Unknown parameter|month=ignored (help) - ^ 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) - ^ 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) - ^ Flemming A (2011). "Achilles heel of Ebola viral entry". Nat Rev Drug Discov. 10 (10): 731. doi:10.1038/nrd3568. PMID 21959282.
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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.
{{cite journal}}: Unknown parameter|author-separator=ignored (help) - 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.
{{cite journal}}: Unknown parameter|author-separator=ignored (help) - 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.
{{cite journal}}: Unknown parameter|author-separator=ignored (help) - 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.
{{cite journal}}: Unknown parameter|author-separator=ignored (help) - 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.
{{cite journal}}: Unknown parameter|author-separator=ignored (help)CS1 maint: numeric names: authors list (link) - 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.
{{cite journal}}: Unknown parameter|author-separator=ignored (help) - 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.
{{cite journal}}: Unknown parameter|author-separator=ignored (help) - 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.
{{cite journal}}: Unknown parameter|author-separator=ignored (help) - 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.
{{cite journal}}: Unknown parameter|author-separator=ignored (help) - 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.
{{cite journal}}: Unknown parameter|author-separator=ignored (help) - 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.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - 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.
{{cite journal}}: Unknown parameter|author-separator=ignored (help) - 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.
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External links
- NPC1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Hide & Seek Foundation for Lysosomal Disease Research
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