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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]

Protein NPC1 PDB 3GKH.png
Available structures
PDBOrtholog search: PDBe RCSB
AliasesNPC1, NPC, NPC intracellular cholesterol transporter 1, SLC65A1, POGZ
External IDsOMIM: 607623 MGI: 1097712 HomoloGene: 228 GeneCards: NPC1
Gene location (Human)
Chromosome 18 (human)
Chr.Chromosome 18 (human)[1]
Chromosome 18 (human)
Genomic location for NPC1
Genomic location for NPC1
Band18q11.2Start23,506,184 bp[1]
End23,586,506 bp[1]
RNA expression pattern
PBB GE NPC1 202679 at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



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


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 significanceEdit


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]


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 virusEdit

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 pathologyEdit

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]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000141458 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024413 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: NPC1 Niemann-Pick disease, type C1".
  6. ^ Carstea ED, Polymeropoulos MH, Parker CC, Detera-Wadleigh SD, O'Neill RR, Patterson MC, et al. (March 1993). "Linkage of Niemann-Pick disease type C to human chromosome 18". Proceedings of the National Academy of Sciences of the United States of America. 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, et al. (July 1997). "Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis" (PDF). Science. 277 (5323): 228–31. doi:10.1126/science.277.5323.228. PMID 9211849.
  8. ^ a b c Meyre D, Delplanque J, Chèvre JC, Lecoeur C, Lobbens S, Gallina S, et al. (February 2009). "Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations". Nature Genetics. 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". Journal of Virology. 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". Virology Journal. 9 (1): 31. doi:10.1186/1743-422X-9-31. PMC 3299633. PMID 22273177.
  11. ^ a b c Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, et al. (August 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 summaryNew York Times.
  12. ^ a b c d e Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, et al. (August 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 summaryNew York Times.
  13. ^ Miller EH, Obernosterer G, Raaben M, Herbert AS, Deffieu MS, Krishnan A, et al. (April 2012). "Ebola virus entry requires the host-programmed recognition of an intracellular receptor". The EMBO Journal. 31 (8): 1947–60. doi:10.1038/emboj.2012.53. PMC 3343336. PMID 22395071.
  14. ^ Flemming A (September 2011). "Achilles heel of Ebola viral entry". Nature Reviews. Drug Discovery. 10 (10): 731. doi:10.1038/nrd3568. PMID 21959282.
  15. ^ a b Yan X, Lukas J, Witt M, Wree A, Hübner R, Frech M, et al. (December 2011). "Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse". Metabolic Brain Disease. 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". The Journal of Neuroscience. 32 (36): 12528–42. doi:10.1523/JNEUROSCI.1069-12.2012. PMC 3752083. PMID 22956843.

Further readingEdit

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