Disease relevance of NPC1

• Niemann-Pick type C1 (NPC1) disease is a fatal neurodegenerative disease characterized by neuronal lipid storage and progressive Purkinje cell loss in the cerebellum [1].
• Taken together, these results demonstrate that there are multiple defects in sperms from mice lacking a functional NPC1 protein, and these observed sperm defects may result in sterility [2].
• A synthetic fluorescent alpha-glycosylceramide analog of the Sphingomonas Ag trafficked to the lysosome of wild-type cells but accumulated in the late endosome of NPC1-deficient cells [3].
• Mutations in NPC1 in two Brazilian patients with Niemann-Pick disease type C and progressive supranuclear palsy-like presentation [4].
• We investigated whether therapeutic approaches to bypass the cholesterol trafficking defect in NPC1 disease might delay disease progression in the npc1(-/-) mouse model [1].

Psychiatry related information on NPC1

• This is a well-known NPC1 gene mutation that causes a unique phenotype of NPC, which has been limited to a single Acadian ancestor in Nova Scotia, Canada. Our patient characteristically started presenting with cataplexy at the age of 9 years [5].
• PURPOSE: The purpose of this study was to investigate the roles of cigarette use and alcohol consumption as risk factors for NPC in the United States. METHODS: We conducted a case-control study using data from the National Mortality Followback Survey based on information from death certificates [6].
• We conducted a case-control study of nasopharyngeal carcinoma (NPC) in Tunisia, on diet, dietary patterns and life style, the characteristics of which had been defined by an anthropological study [7].
• Epstein-Barr virus (EBV) activation of latent infection and traditional life styles, especially food habits, have been strongly associated with an increased risk of nasopharyngeal carcinoma (NPC) in humans [8].
• CONCLUSION: Use of FDG-PET was found to influence the salvage treatment decision making for locally persistent NPC by identifying patients who were not likely to benefit from additional treatment and by improving accuracy of GTV definition in salvage treatment planning [9].

High impact information on NPC1

• Our findings provide evidence of a major susceptibility locus for NPC on chromosome 4 in a subset of families [10].
• In areas with high incidence, NPC clusters in families, which suggests that both geography and genetics may influence disease risk [10].
• Here we report the results of a genome-wide search carried out in families at high risk of NPC from Guangdong Province, China. Parametric analyses provide evidence of linkage to the D4S405 marker on chromosome 4 with a logarithm of odds for linkage (lod) score of 3.06 and a heterogeneity-adjusted lod (hlod) score of 3.21 [10].
• Epstein-Barr virus (EBV) has been associated with nasopharyngeal carcinoma, some lymphomas, and lymphoproliferative disease after organ transplantation [11].
• The presence of EBV in metastases from an occult primary tumor is predictive of the development of overt nasopharyngeal carcinoma [12].

Chemical compound and disease context of NPC1

• Niemann-Pick type C1 (NPC1) is a late endosomal/lysosomal transmembrane protein involved in the cellular transport of glycosphingolipids and cholesterol that is mutated in a majority of patients with Niemann-Pick C neurodegenerative disease [3].
• The EBV thymidine kinase was the most sensitive predictor of nasopharyngeal carcinoma; all such samples showed both IgG and IgA antibody responses to this protein and all gave clearly distinct titres from those of the EBV-seropositive donors in the IgA test [13].
• Phase II study of neoadjuvant carboplatin and paclitaxel followed by radiotherapy and concurrent cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: therapeutic monitoring with plasma Epstein-Barr virus DNA [14].
• Major toxicity of cisplatin, fluorouracil, and leucovorin following chemoradiotherapy in patients with nasopharyngeal carcinoma [15].
• In contrast, the 3 NPC cell lines were all negative for Epstein-Barr virus and contained G----C transversions in the p53 gene, with cell lines CNE-1 and CNE-2 harboring identical AGA (arginine) to ACA (threonine) changes at codon 280 [16].

Biological context of NPC1

• Consistent with its role in the proteolytic processing of prosaposin, inactivation of CTSD function resulted in the accumulation of glycosphingo-lipid and free cholesterol in late endosomes/lysosomes, a phenotype similar to NPC1 deficiency [17].
• We have investigated alterations that occur in hepatic lipid homeostasis using primary hepatocytes isolated from NPC1-deficient mice [18].
• The NPC1 gene on chromosome 18 was recently identified but its physiological function remains unknown [19].
• Eight men and two women (19-40 years of age) harbouring mutations in the gene coding for the cholesterol trafficking protein NPC1 were put through the same test battery independently of their disease stage [20].
• Earlier studies have suggested that an increased risk of nasopharyngeal carcinoma is associated with specific haplotypes in the HLA region: relative risks slightly over twofold were found for haplotypes A2, Bw46 and the antigen B17 [21].

Anatomical context of NPC1

• We have now investigated whether this NO-dependent Gpc-1 autoprocessing is active in fibroblasts from NPC1 disease [22].
• Exit of recycling cholesterol from late endosomes is defective in Niemann-Pick C1 (NPC1) and Niemann-Pick C2 (NPC2) diseases [22].
• The presence of NPC1 in endosomal structures in nerve terminals, and the finding of aberrant synaptic vesicles, suggest that defects in synaptic vesicle recycling contribute to neurological abnormalities characteristic of NPC disease [23].
• We found that NPC1-deficient mice lacked Valpha14-Jalpha18 NKT cells, a major population of CD1d-restricted T cells that is conserved in humans [3].
• Most cases of NP-C are associated with inactivating mutations of the NPC1 gene [2], which encodes a protein implicated in the retrograde transport of sterols and other cargo from lysosomes [3] [24].

Associations of NPC1 with chemical compounds

• The synthesis of phosphatidylcholine, cholesteryl esters, and cholesterol in hepatocytes was increased by NPC1 deficiency and the amount of the mature form of sterol response element-binding protein-1 was also increased [18].
• We report a Japanese patient with NPC caused by a homozygous c.2974 G > T mutation of the NPC1 gene, which predicts a glycine (GGG) to tryptophan (TGG) change at codon 992 (designated as p.G992W) [5].
• We show that the neurosteroid allopregnanolone (ALLO) and T0901317, a synthetic oxysterol ligand, act in concert to delay onset of neurological symptoms and prolong the lifespan of npc1(-/-) mice [1].
• In 56 day old npc1(-/-) mice that had been fed from 35 days of age a rodent diet or the same diet containing either cholesterol (1.0%, w/w) or ezetimibe (a sterol absorption inhibitor; 0.0125%, w/w), whole liver cholesterol content averaged 33.5 +/- 1.1, 87.9 +/- 1.7, and 20.8 +/- 0.9 mg, respectively [25].
• LXR agonist treatment prior to and during apoA-I incubation resulted in reduction in filipin staining of unesterified cholesterol in late endosomes/lysosomes, as well as cholesterol mass, in NPC1(-/-) cells [26].

Physical interactions of NPC1

• Activation of nuclear factor-kappaB p50 homodimer/Bcl-3 complexes in nasopharyngeal carcinoma [27].
• Expression of E-cadherin/catenin complex in nasopharyngeal carcinoma: correlation with clinicopathological parameters [28].

Regulatory relationships of NPC1

• Furthermore, the expression of LOC344967 was significantly up-regulated at both mRNA and protein levels in nasopharyngeal carcinoma cells sharing the -32G/A genotype compared with nasopharyngeal carcinoma cells with the -32G/G genotype [29].
• EGFR tyrosine kinase inhibitor AG1478 inhibits cell proliferation and arrests cell cycle in nasopharyngeal carcinoma cells [30].
• We show that Tpl-2 is expressed in primary biopsies from patients with nasopharyngeal carcinoma and Hodgkin's disease, where LMP1 is also found [31].
• SPLUNC1 was differentially expressed in nasopharyngeal carcinoma [32].
• E-, P-, and N-cadherin are co-expressed in the nasopharyngeal carcinoma cell line TW-039 [33].

Other interactions of NPC1

• A functional variant in the transcriptional regulatory region of gene LOC344967 cosegregates with disease phenotype in familial nasopharyngeal carcinoma [29].
• THY1 is a candidate tumour suppressor gene with decreased expression in metastatic nasopharyngeal carcinoma [34].
• Induction of interleukin-8 by Epstein-Barr virus latent membrane protein-1 and its correlation to angiogenesis in nasopharyngeal carcinoma [35].
• Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival [36].
• Chemokine receptor expression profiles in nasopharyngeal carcinoma and their association with metastasis and radiotherapy [37].

Analytical, diagnostic and therapeutic context of NPC1

• METHODOLOGY/PRINCIPAL FINDINGS: Using cDNA microarrays, we analyzed the genome-wide expression patterns of human fibroblasts homozygous for the I1061T NPC1 mutation that is characterized by a severe defect in the intracellular processing of low density lipoprotein-derived cholesterol [38].
• European Organization for Research on Treatment of Cancer (E.O.R.T.C.). Controlled trials of chemotherapy as an adjuvant or palliative treatment of nasopharyngeal carcinoma [39].
• The decreased sperm number in Npc1(-/-) mice is due, at least in part, to partial arrest of spermatogenesis in the testes, as revealed by histological analysis [2].
• Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration [12].
• METHODS: One hundred seventy NPC patients, without metastatic disease at presentation, were treated with a uniform radiotherapy protocol [40].

References