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GENATLAS PHENOTYPE
last update : 03-03-2015
Symbol NPC1
Location 18q11.2
Name Niemann-Pick disease type C1
Corresponding gene NPC1
Main clinical features
  • a fatal neurovisceral disorder, characterized by ataxic gait, hepato splenomegaly progression to dementia, dysarthria, dystonia, seizures and death at teenage, due to an error in cellular trafficking of exogenous cholesterol with lysosomal accumulation of unesterified cholesterol, accounting for 95% of NPC
  • mutation resulting in accumulation of unesterified cholesterol in late endosomes and lysosomes (PMID: 22179027))
    • Genetic determination autosomal recessive
    Prevalence . responsible for 95p100 of the cases (PMID: 21075073)
    Function/system disorder metabolism/lysosomal
    neurology
    Type disease
    Gene product
    Name regulator of cholesterol trafficking (NPC1), approximatively 100 mutations identified and a possible influence of the haplotypic background or expression of missense mutation
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    various types     only three occuring quite frequently, I1061T, juvenile form, G992R, P1007A, leading to sphingomyelin accumulation with cholesterol, to concomitant acid sphingomyelinase deficiency and to an identical subcellular distribution of both lipids
    Remark(s)
  • NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells (sphingosine storage as the earliest measurable event after induction of an NPC disease phenotype inducing a novel calcium homeostatic defect characterized by low calcium levels in acidic stores)
  • alterations in MAPT mediated by its hyperphosphorylation may similarly act through a loss-of-function mechanism to exacerbate the phenotype of NPC1 patients, implicating autophagy in pathogenesis(Pacheco 2009)
  • NPC1 deficiency leads to cell autonomous, selective neurodegeneration and suggest that the ataxic symptoms of NPC disease arise from Purkinje cell death rather than cellular dysfunction (Elrick (2010)
  • NPC1 mutant proteins misfold in the endoplasmic reticulum, and it is misfolding rather than true loss of function that is responsible for the disease phenotype (PMID: 22065762))
  • expression of ABCA1 is impaired in NPC1(-/-) fibroblasts, resulting in reduced HDL particle formation and providing a mechanism for the reduced plasma HDL cholesterol seen in the majority of NPC1 patients (PMID: 22179027))
  • clearance of autophagosomes in NPC1 deficiency is impaired due to inhibition of lysosomal protease activity by stored lipids (PMID: 22872701))