Identification of
            <i>HE1</i>
            as the Second Gene of Niemann-Pick C Disease

Naureckiene, Saule; Sleat, David E.; Lackland, Henry; Fensom, Anthony H.; Vanier, Marie T.; Wattiaux, Robert; Jadot, Michel; Lobel, Peter

doi:10.1126/science.290.5500.2298

Cited by 766 publications

(629 citation statements)

References 26 publications

(17 reference statements)

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“…Two disease-causing genes, NPC1 (MIM#607623) and NPC2 (MIM#601015), have been identified (Vanier et al 1996;Carstea et al 1993;Naureckiene et al 2000). NPC1 gene, located on chromosome 18q11-q12, encodes a large membrane glycoprotein of 1,278 aminoacids containing 13 transmembrane domains and located predominantly in late endosomes (Davies and Ioannou 2000).…”

Section: Introductionmentioning

confidence: 99%

“…NPC1 gene, located on chromosome 18q11-q12, encodes a large membrane glycoprotein of 1,278 aminoacids containing 13 transmembrane domains and located predominantly in late endosomes (Davies and Ioannou 2000). NPC2 gene is mapped to chromosome 14q24.3 and encodes a small soluble protein present in the lumen of the lysosomes (Naureckiene et al 2000;Vanier and Millat 2004). Although it is known that both NPC1 and NPC2 bind unesterified cholesterol and both are involved in the egress of cholesterol and other lipids from the lysosomes, the precise mechanisms by which these proteins exert this function is not clear.…”

Section: Introductionmentioning

confidence: 99%

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Treatment of Human Fibroblasts Carrying NPC1 Missense Mutations with MG132 Leads to an Improvement of Intracellular Cholesterol Trafficking

et al. 2011

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Niemann Pick type C (NPC) disease is an autosomal recessive disorder characterized by the lysosomal/ late endosomal (LE) accumulation of unesterified cholesterol and other lipids due to a defect in the intracellular lipid trafficking. About 95% of patients present mutations in the NPC1 gene. Among the 290 mutations reported in the NPC1 gene, about 70% are missense. However, little information is available regarding the impact of missense mutations on NPC1 protein stability and function. In this study, we in vitro characterized the pathogenic effect of 7 NPC1 missense mutations. In all cases, the basal levels of mutant NPC1 expression were reduced with respect to wild type. Treatment of fibroblasts carrying NPC1 missense mutations in homo or hemizygosity, with the proteasome inhibitor MG132 or glycerol 10%, a chemical chaperone known to stabilize misfolded proteins, resulted in a significant increase of NPC1 protein levels in all cell lines, indicating that these mutants are subjected to proteasomal degradation due to protein misfolding The increment of NPC1 mutant protein induced by the proteasome inhibitor was associated with a localization of NPC1 protein within lysosomal/LE compartment. In cell lines carrying mutations p.N1156S, p.L1191F, p.V1165M, and p.I1061T, the increment of NPC1 mutant protein resulted in an improvement of the intracellular trafficking of cholesterol and GM1. These findings showed that it is possible to correct the NPC cellular phenotype by increasing the amount of endogenous NPC1 mutated protein, suggesting that at least some NPC1 mutations might be potentially rescued by small molecules-based chaperone therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Treatment of Human Fibroblasts Carrying NPC1 Missense Mutations with MG132 Leads to an Improvement of Intracellular Cholesterol Trafficking

et al. 2011

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“…Most patients have mutations in the NPC1 gene that encodes a membrane protein involved in intracellular cholesterol transport (Ory 2004). Other patients have mutations in the NPC2 gene that encodes a soluble lysosomal cholesterol-binding protein (Naureckiene et al 2000). These mutations point to a defect in cholesterol transport in NPC, but the lipid accumulation is complex and the primary offending metabolite in the brain is disputed (Lloyd-Evans and Platt 2010).…”

Section: Introductionmentioning

confidence: 99%

Miglustat Treatment May Reduce Cerebrospinal Fluid Levels of the Axonal Degeneration Marker Tau in Niemann–Pick Type C

et al. 2011

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Introduction: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that leads to progressive neurodegeneration. The glucosylceramide synthase blocker miglustat is being used to treat NPC, but monitoring of disease progression and treatment response is difficult. NPC patients have elevated cerebrospinal fluid (CSF) levels of total-tau (T-tau) indicating axonal degeneration, and increased CSF amyloid b (Ab) indicating abnormal brain amyloid metabolism, but it is unknown if start of miglustat treatment affects these biomarker levels.Methods: Biomarkers were measured in serial CSF samples from NPC patients who started miglustat between samplings (N ¼ 5), were untreated at both samplings (N ¼ 5) or received treatment during the whole study (N ¼ 6) (median time between samplings 309 days [range 175-644]). CSF was analyzed for Ab 38 , Ab 40 , Ab 42 , a-cleaved soluble APP, b-cleaved soluble APP, T-tau and phospho-tau.Results: T-tau levels decreased in patients who started miglustat treatment (median 955 [range 338-1,271] ng/L at baseline vs. 382 ng/L at follow-up, p ¼ 0.043). Untreated patients and continuously treated patients had stable levels (p > 0.05). No changes were seen in the other biomarkers.Conclusion: Reduced CSF T-tau suggests that miglustat treatment might affect axonal degeneration in NPC. However, the results must be interpreted with caution and verified in future studies, since this pilot study was small, treatment was not randomized, and patients starting treatment had higher baseline CSF T-tau than untreated patients.

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“…To date, mutations in two genes have been identified: NPC1 (OMIM 607623), in ~ 95% of NPC patients, and NPC2 (OMIM 601015) in 5% 3, 4. Although the functions of NPC1 and NPC2 proteins have not been completely elucidated, their critical involvement in cholesterol export from the lysosome/late endosomal cellular compartment has been recognized 5, 6, 7, 8.…”

mentioning

confidence: 99%

Identification of novel bile acids as biomarkers for the early diagnosis of Niemann‐Pick C disease

Mazzacuva¹,

Mills²,

Mills³

et al. 2016

FEBS Letters

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This article describes a rapid UPLC‐MS/MS method to quantitate novel bile acids in biological fluids and the evaluation of their diagnostic potential in Niemann‐Pick C (NPC). Two new compounds, NPCBA1 (3β‐hydroxy,7β‐N‐acetylglucosaminyl‐5‐cholenoic acid) and NPCBA2 (probably 3β,5α,6β‐trihydroxycholanoyl‐glycine), were observed to accumulate preferentially in NPC patients: median plasma concentrations of NPCBA1 and NPCBA2 were 40‐ and 10‐fold higher in patients than in controls. However, NPCBA1 concentrations were normal in some patients because they carried a common mutation inactivating the GlcNAc transferase required for the synthesis of this bile acid. NPCBA2, not containing a GlcNAc moiety, is thus a better NPC biomarker.

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Identification of HE1 as the Second Gene of Niemann-Pick C Disease

Cited by 766 publications

References 26 publications

Treatment of Human Fibroblasts Carrying NPC1 Missense Mutations with MG132 Leads to an Improvement of Intracellular Cholesterol Trafficking

Treatment of Human Fibroblasts Carrying NPC1 Missense Mutations with MG132 Leads to an Improvement of Intracellular Cholesterol Trafficking

Miglustat Treatment May Reduce Cerebrospinal Fluid Levels of the Axonal Degeneration Marker Tau in Niemann–Pick Type C

Identification of novel bile acids as biomarkers for the early diagnosis of Niemann‐Pick C disease

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