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Gene Review

NPC2  -  Niemann-Pick disease, type C2

Homo sapiens

Synonyms: EDDM1, Epididymal secretory protein E1, HE1, He1, Human epididymis-specific protein 1, ...
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Disease relevance of NPC2


High impact information on NPC2


Chemical compound and disease context of NPC2

  • Niemann-Pick disease type C (NPC), a neurovisceral disorder characterized by accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system, is due to mutations on either the NPC1 or the NPC2 genes [7].
  • The molecular isolation of NPC1 and NPC2, the genes defective in patients with Niemann-Pick disease type C (NP-C), has heralded in an exponential increase in our understanding of this syndrome and thus of human intracellular sterol transport [8].

Biological context of NPC2


Anatomical context of NPC2

  • The mature NPC2/HE1 protein is a ubiquitous soluble small 132-amino-acid glycoprotein, first characterized as a major secretory protein in the human epididymis, but also detected in most tissues [11].
  • Current data have led to the hypothesis that NPC2 would bind cholesterol from internal lysosomal membranes, enabling a physical interaction with NPC1 (or another protein) and allowing postlysosomal export of cholesterol [11].
  • In contrast, NPC2 was upregulated and accumulated in cholesterol storing late endocytic organelles [13].
  • The inherited disorder Niemann-Pick type C (NPC), in which abnormal LDL-cholesterol trafficking from the endo/lysosomal compartment leads to substantial cholesterol and glycolipid accumulation in lysosomes, is caused by defects in either of two genes that encode for proteins designated as NPC1 and NPC2 [14].
  • Both wild-type and NPC1-/- astrocytes secreted the NPC2 protein [15].

Associations of NPC2 with chemical compounds


Physical interactions of NPC2

  • These changes are accompanied by lysosomal accumulation of NPC2, suggesting that NPC1 governs the endocytic transport of NPC2 [13].

Other interactions of NPC2


Analytical, diagnostic and therapeutic context of NPC2


  1. Cholesterol depletion facilitates ubiquitylation of NPC1 and its association with SKD1/Vps4. Ohsaki, Y., Sugimoto, Y., Suzuki, M., Hosokawa, H., Yoshimori, T., Davies, J.P., Ioannou, Y.A., Vanier, M.T., Ohno, K., Ninomiya, H. J. Cell. Sci. (2006) [Pubmed]
  2. Pulmonary storage with emphysema as a sign of Niemann-Pick type C2 disease (second complementation group). Report of a case. Elleder, M., Houstková, H., Zeman, J., Ledvinová, J., Poupetová, H. Virchows Arch. (2001) [Pubmed]
  3. Structure of a cholesterol-binding protein deficient in Niemann-Pick type C2 disease. Friedland, N., Liou, H.L., Lobel, P., Stock, A.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. Two-dimensional complementary deoxyribonucleic acid electrophoresis revealing up-regulated human epididymal protein-1 and down-regulated CL-100 in thyroid papillary carcinoma. Asakawa, J., Kodaira, M., Ishikawa, N., Hirai, Y., Nagataki, S., Moatamed, F., Sugawara, M. Endocrinology (2002) [Pubmed]
  5. Identification of HE1 as the second gene of Niemann-Pick C disease. Naureckiene, S., Sleat, D.E., Lackland, H., Fensom, A., Vanier, M.T., Wattiaux, R., Jadot, M., Lobel, P. Science (2000) [Pubmed]
  6. Guilty until proven innocent: the case of NPC1 and cholesterol. Ioannou, Y.A. Trends Biochem. Sci. (2005) [Pubmed]
  7. Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. Millat, G., Baïlo, N., Molinero, S., Rodriguez, C., Chikh, K., Vanier, M.T. Mol. Genet. Metab. (2005) [Pubmed]
  8. The pathophysiology and mechanisms of NP-C disease. Sturley, S.L., Patterson, M.C., Balch, W., Liscum, L. Biochim. Biophys. Acta (2004) [Pubmed]
  9. Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. Klünemann, H.H., Elleder, M., Kaminski, W.E., Snow, K., Peyser, J.M., O'Brien, J.F., Munoz, D., Schmitz, G., Klein, H.E., Pendlebury, W.W. Ann. Neurol. (2002) [Pubmed]
  10. NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of low density lipoprotein cholesterol-derived oxysterols. Frolov, A., Zielinski, S.E., Crowley, J.R., Dudley-Rucker, N., Schaffer, J.E., Ory, D.S. J. Biol. Chem. (2003) [Pubmed]
  11. Structure and function of the NPC2 protein. Vanier, M.T., Millat, G. Biochim. Biophys. Acta (2004) [Pubmed]
  12. Cholesterol overload promotes morphogenesis of a Niemann-Pick C (NPC)-like compartment independent of inhibition of NPC1 or HE1/NPC2 function. Frolov, A., Srivastava, K., Daphna-Iken, D., Traub, L.M., Schaffer, J.E., Ory, D.S. J. Biol. Chem. (2001) [Pubmed]
  13. Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease. Blom, T.S., Linder, M.D., Snow, K., Pihko, H., Hess, M.W., Jokitalo, E., Veckman, V., Syvänen, A.C., Ikonen, E. Hum. Mol. Genet. (2003) [Pubmed]
  14. Mechanism of cholesterol transfer from the niemann-pick type c2 protein to model membranes supports a role in lysosomal cholesterol transport. Cheruku, S.R., Xu, Z., Dutia, R., Lobel, P., Storch, J. J. Biol. Chem. (2006) [Pubmed]
  15. Secretion of sterols and the NPC2 protein from primary astrocytes. Mutka, A.L., Lusa, S., Linder, M.D., Jokitalo, E., Kopra, O., Jauhiainen, M., Ikonen, E. J. Biol. Chem. (2004) [Pubmed]
  16. Neuronal localization and association of Niemann Pick C2 protein (HE1/NPC2) with the postsynaptic density. Ong, W.Y., Sundaram, R.K., Huang, E., Ghoshal, S., Kumar, U., Pentchev, P.G., Patel, S.C. Neuroscience (2004) [Pubmed]
  17. Genomic sequencing reveals a 5-methylcytosine-free domain in active promoters and the spreading of preimposed methylation patterns. Toth, M., Lichtenberg, U., Doerfler, W. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  18. Molecular cloning and characterization of HE1, a major secretory protein of the human epididymis. Kirchhoff, C., Osterhoff, C., Young, L. Biol. Reprod. (1996) [Pubmed]
  19. NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols. Liou, H.L., Dixit, S.S., Xu, S., Tint, G.S., Stock, A.M., Lobel, P. J. Biol. Chem. (2006) [Pubmed]
  20. Peroxisome proliferator-activated receptor alpha controls cellular cholesterol trafficking in macrophages. Chinetti-Gbaguidi, G., Rigamonti, E., Helin, L., Mutka, A.L., Lepore, M., Fruchart, J.C., Clavey, V., Ikonen, E., Lestavel, S., Staels, B. J. Lipid Res. (2005) [Pubmed]
  21. Effect of vasectomy on gene expression in the epididymis of cynomolgus monkey. Doiron, K., Légaré, C., Saez, F., Sullivan, R. Biol. Reprod. (2003) [Pubmed]
  22. Tissue-specific gene expression as an indicator of epididymis-specific functional status in the boar, bull and stallion. Uhlenbruck, F., Sinowatz, F., Amselgruber, W., Kirchhoff, C., Ivell, R. Int. J. Androl. (1993) [Pubmed]
  23. Function of human epididymal proteins in sperm maturation. Kirchhoff, C., Osterhoff, C., Pera, I., Schröter, S. Andrologia (1998) [Pubmed]
  24. HE1/NPC2 status in human reproductive tract and ejaculated spermatozoa: consequence of vasectomy. Légaré, C., Thabet, M., Gatti, J.L., Sullivan, R. Mol. Hum. Reprod. (2006) [Pubmed]
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