Niemann Pick Disease Type C2 (NPC2)

HE1; NP-C2; EDDM1; Epididymal Protein 1; Human epididymis-specific protein 1; Epididymal secretory protein E1

SPN	N248
HGNC	14537
MGI	1915213
PubMed	23791309
RGD	628756
UniProt	P61916
Wiki	NPC2

Mutations in the NPC2 gene associated with Niemann-Pick disease type C2 cause abnormally high cholesterol accumulation in cells. NPC2, a secreted soluble protein, binds cholesterol specifically with a much higher affinity than previously reported. Genetic and biochemical studies identified single amino acid changes that prevent both cholesterol binding and the restoration of normal cholesterol levels in mutant cells.

The amino acids that affect cholesterol binding surround a hydrophobic pocket in the NPC2 protein structure, identifying a candidate sterol-binding location. On the basis of evolutionary analysis and mutagenesis, 3 other regions of the NPC2 protein emerged as important, including 1 required for efficient secretion.

Reference

"Region-specific variation of gene expression in the human epididymis as revealed by in situ hybridization with tissue-specific cDNAs."
Mol. Reprod. Dev. 34:16-24(1993) [PubMed] [Europe PMC] [Abstract]

"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]

"The DNA sequence and analysis of human chromosome 14."
Nature 421:601-607(2003) [PubMed] [Europe PMC] [Abstract]

"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]

"NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols."
J. Biol. Chem. 281:36710-36723(2006) [PubMed] [Europe PMC] [Abstract]

"Identification of HE1 as the second gene of Niemann-Pick C disease."
Science 290:2298-2301(2000) [PubMed] [Europe PMC] [Abstract]

"In vivo interaction between the human dehydrodolichyl diphosphate synthase and the Niemann-Pick C2 protein revealed by a yeast two-hybrid system."
Biochem. Biophys. Res. Commun. 318:198-203(2004) [PubMed] [Europe PMC] [Abstract]

"Transcriptomic and proteomic analyses of rhabdomyosarcoma cells reveal differential cellular gene expression in response to enterovirus 71 infection."
Cell. Microbiol. 8:565-580(2006) [PubMed] [Europe PMC] [Abstract]

"Regulation of sterol transport between membranes and NPC2."
Biochemistry 47:11134-11143(2008) [PubMed] [Europe PMC] [Abstract]

"NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes."
Proc. Natl. Acad. Sci. U.S.A. 105:15287-15292(2008) [PubMed] [Europe PMC] [Abstract]

"Identification of NPC2 protein as interaction molecule with C2 domain of human Nedd4L."
Biochem. Biophys. Res. Commun. 388:290-296(2009) [PubMed] [Europe PMC] [Abstract]

"Nogo-B receptor stabilizes Niemann-Pick type C2 protein and regulates intracellular cholesterol trafficking."
Cell Metab. 10:208-218(2009) [PubMed] [Europe PMC] [Abstract]

"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry."
J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract]

"Initial characterization of the human central proteome."
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]

"Novel function of Niemann-Pick C1-like 1 as a negative regulator of Niemann-Pick C2 protein."
Hepatology 55:953-964(2012) [PubMed] [Europe PMC] [Abstract]

"NPC1/NPC2 function as a tag team duo to mobilize cholesterol."
Proc. Natl. Acad. Sci. U.S.A. 105:15223-15224(2008) [PubMed] [Europe PMC] [Abstract]

"Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking."
Biochim. Biophys. Acta 1791:671-678(2009) [PubMed] [Europe PMC] [Abstract]

"Transfer of cholesterol by the NPC team."
Cell Metab. 12:105-106(2010) [PubMed] [Europe PMC] [Abstract]

"Function of the Niemann-Pick type C proteins and their bypass by cyclodextrin."
Curr. Opin. Lipidol. 22:204-209(2011) [PubMed] [Europe PMC] [Abstract]

"An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome."
J. Proteomics 96:253-262(2014) [PubMed] [Europe PMC] [Abstract]

"Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group."
Am. J. Hum. Genet. 69:1013-1021(2001) [PubMed] [Europe PMC] [Abstract]

"Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2."
Ann. Neurol. 52:743-749(2002) [PubMed] [Europe PMC] [Abstract]

"Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1."
Hum. Mutat. 22:313-325(2003) [PubMed] [Europe PMC] [Abstract]

"Niemann-Pick type C disease: subcellular location and functional characterization of NPC2 proteins with naturally occurring missense mutations."
Hum. Mutat. 26:20-28(2005) [PubMed] [Europe PMC] [Abstract]

"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."
Mol. Genet. Metab. 86:220-232(2005) [PubMed] [Europe PMC] [Abstract]