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Human Genetics

, Volume 109, Issue 1, pp 24–32 | Cite as

Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations

  • Isaura Ribeiro
  • Ana Marcão
  • Olga Amaral
  • Maria Sá Miranda
  • Marie T. Vanier
  • Gilles Millat
Original Investigation

Abstract.

Niemann-Pick type C disease (NPC) is a rare neurodegenerative disorder characterised by lysosomal/late endosomal accumulation of endocytosed unesterified cholesterol and delayed induction of cholesterol homeostatic reactions. The large majority of mutations in the NPC1 gene described thus far have been associated with severe cellular cholesterol trafficking impairment (classic biochemical phenotype, present in about 85% of NPC patients). In our population of 13 unrelated NP-C1 patients, among which 12 were of Portuguese extraction, we observed an unusually large proportion of families presenting mild alterations of intracellular cholesterol transport (variant biochemical phenotype), without strict correlation between the biochemical phenotype and the clinical expression of the disease. Mutational studies were carried out to compare molecular lesions associated with severe and mild cholesterol traffic impairment. Levels of NPC1 protein were studied by Western blot in cultured fibroblasts of four patients with homozygous mutant alleles. Ten novel mutations were identified (Q92R, C177Y, R518W, W942C, R978C, A1035V, 2129delA, 3662delT, IVS23+1 G>A and IVS16–82 G>A). The mutational profile appeared to be correlated with the biochemical phenotype. Splicing mutations, I1061T and A1035V, corresponded to "classic" alleles, while three missense mutations, C177Y, R978C and P1007A, could be defined as "variant" alleles. All "variant" mutations described so far appear to be clustered within the cysteine-rich luminal loop between TM 8 and 9, with the remarkable exception of C177Y. The latter mutant allele, at variance with P1007A, was correlated to a decreased level of NPC1 protein and a severe course of the disease, and disclosed a new location for "variant" mutations, the luminal loop located at the N-terminal end of the protein.

Keywords

Biochemical Phenotype NPC1 Protein Neurological Onset NPC1 Mutation Cholesteryl Ester Formation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • Isaura Ribeiro
    • 1
  • Ana Marcão
    • 1
  • Olga Amaral
    • 1
  • Maria Sá Miranda
    • 1
  • Marie T. Vanier
    • 2
  • Gilles Millat
    • 2
  1. 1.Genetic Neurobiology, IBMC University of Porto, 4150-180 Porto, Portugal and Enzymology Unit, Institute of Medical Genetics Jacinto de Magalhães, 4050-466 Porto, PortugalPortugal
  2. 2.INSERM U189, Lyon-Sud Medical School, 69921 Oullins and Fondation Gillet-Mérieux, Lyon-Sud Hospital, 69495 Pierre Bénite, FranceFrance

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