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These data support the hypothesis that cholesterol is transported through interactions between two or more NPC1 molecules.
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Mutation in the NPC1 gene is associated with Niemann-Pick type C.
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pronounced alterations in several proteins linked to autophagy and lysosomal catabolism reflecting vesicular transport obstruction and defective lysosomal turnover resulting from NPC1 deficiency, were observed.
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Niemann-Pick C1 (NPC1) protein structures suggest mapping of all of the disease-causing mutations for future molecular insights into the pathogenesis of Niemann-Pick type C disease (NPC) disease.
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This study demonistrated that heterozygous mutations of NPC1 genes could contribute to dementia plus, at least in a subset of patients.
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Docking of the NPC1-NPC2 complex onto the full-length NPC1 structure reveals a direct cholesterol transfer tunnel between NPC2 and N-terminal domain cholesterol binding pockets, supporting the "hydrophobic hand-off" cholesterol transfer model.
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Taken together, these studies suggest that Ebola virus requires phosphatidylinositol (3,5) bisphosphate production in cells to promote efficient delivery to NPC1.
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identification of NPC1 and/or NPC2 mutations combined with descriptions of clinical phenotype, will improve our knowledge of pathogenic mutations and our understanding of genotype-phenotype correlations.
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Here we report a crystal structure of a large fragment of human NPC1 at 3.6 A resolution, which reveals internal twofold pseudosymmetry along TM 2-13 and two structurally homologous domains that protrude 60 A into the endosomal lumen, and we propose a model for NPC1 function in cholesterol sensing and transport.
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Sequencing of genomic DNA from GM03123 Led to the identification of a mutation in NPC1 GENE, g.41940G>C (c.1947 + 5G>C; rs770321568) (Fig. 1A), with a minor allele frequency of 0.0000082
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this case provides support for the V950M variant being sufficient for adult-onset Niemann-Pick type C disease.
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We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism's fitness.
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The mutant NPC1 did not significantly reduce cholesterol accumulation, but approximately 85% of the mutants showed reduced cholesterol accumulation when treated with vorinostat or panobinostat.
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knockdown of TMEM97 also increases levels of residual NPC1 in NPC1-mutant patient fibroblasts and reduces cholesterol storage in an NPC1-dependent manner. Our findings propose TMEM97 inhibition as a novel strategy to increase residual NPC1 levels in cells and a potential therapeutic target for Niemann-Pick type C disease (NP-C).
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The splicing mutation IVS23 + 3insT was associated in homozygocity with a severe biochemical and clinical phenotype. A possible founder effect for this mutation was demonstrated in the Greek Island, as well as a different origin for each novel mutation
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Rare loss-of-function NPC1 mutations were identified as being associated with human adiposity with a high penetrance in a Chinese population.
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Furthermore saturation and intracellular distribution of alpha-Toc seem to be strongly dependent on the availability of this vitamin as well as on the presence of the lysosomal protein NPC1
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Two mutations were identified in the NPC1 gene, one of which was novel and its pathogenetic nature was unknown
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Our data suggest an incidence rate for NPC1 and NPC2 of 1/92,104 and 1/2,858,998, respectively. Evaluation of common NPC1 variants, however, suggests that there may be a late-onset NPC1 phenotype with a markedly higher incidence.
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Fibroblasts from Niemann-Pick type C (NPC) disease patients with low levels of NPC1 protein have high amounts of procathepsin D but reduced quantities of the mature protein, thus showing a diminished cathepsin D activity.
