+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease

Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease

Human Molecular Genetics 12(3): 257-272

Niemann-Pick type C (NPC) disease is a fatal recessively inherited lysosomal cholesterol-sphingolipidosis. Mutations in the NPC1 gene cause approximately 95% of the cases, the rest being caused by NPC2 mutations. Here the molecular basis of a severe infantile form of the disease was dissected. The level of NPC1 protein in the patient fibroblasts was similar to that in control cells. However, the protein was partially mislocalized from late endocytic organelles diffusely to the cell periphery. In contrast, NPC2 was upregulated and accumulated in cholesterol storing late endocytic organelles. Two point mutations and a four-nucleotide deletion were identified in the NPC1 gene, leading to the amino acid substitutions C113R, P237S and deletion of 37 C-terminal amino acids (delC). Overexpression of individual NPC1 mutations revealed that delC produced an unstable protein, wild-type and NPC1-P237S colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to the ER, Rab7-negative endosomes and the cell surface. Expression of wild-type or NPC1-P237S cleared the lysosomal cholesterol accumulation in NPC1-deficient cells whereas C113R or delC did not. In the Finnish and Swedish population samples, alleles carrying C113R or delC were not identified, whereas approximately 5% of the alleles carried P237S. Our studies identify P237S as a prevalent NPC1 polymorphism and delC and C113R as deleterious NPC1 mutations. Moreover, they show that delC leads to rapid degradation of NPC1 and C113R to endocytic missorting of the protein. These changes are accompanied by lysosomal accumulation of NPC2, suggesting that NPC1 governs the endocytic transport of NPC2.

(PDF emailed within 0-6 h: $19.90)

Accession: 010420500

Download citation: RISBibTeXText

PMID: 12554680

DOI: 10.1093/hmg/ddg025

Related references

Pulmonary abnormalities in animal models due to Niemann-Pick type C1 (NPC1) or C2 (NPC2) disease. Plos One 8(7): E67084, 2014

Niemann-Pick type C disease: a QM/MM study of conformational changes in cholesterol in the NPC1(NTD) and NPC2 binding pockets. Biochemistry 53(41): 6603-6614, 2015

Diagnosis of Niemann-Pick disease type C with 7-ketocholesterol screening followed by NPC1/NPC2 gene mutation confirmation in Chinese patients. Orphanet Journal of Rare Diseases 9: 82, 2014

Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations. Human Genetics 109(1): 24-32, 2001

FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts. Faseb Journal 31(4): 1719-1730, 2017

The new obesity-associated protein, neuronal growth regulator 1 (NEGR1), is implicated in Niemann-Pick disease Type C (NPC2)-mediated cholesterol trafficking. Biochemical and Biophysical Research Communications 482(4): 1367-1374, 2016

Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells. Human Molecular Genetics 25(16): 3588-3599, 2016

Selective screening of Niemann-Pick type C Brazilian patients by cholestane-3β,5α,6β-triol and chitotriosidase measurements followed by filipin staining and NPC1/NPC2 gene analysis. Clinica Chimica Acta; International Journal of Clinical Chemistry 459: 57-62, 2017

Spermatozoa from mice deficient in Niemann-Pick disease type C2 (NPC2) protein have defective cholesterol content and reduced in vitro fertilising ability. Reproduction, Fertility, and Development 26(4): 609-621, 2014

Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. Molecular Genetics and Metabolism 86(1-2): 220-232, 2005

Ultrastructural Similarity of Storage Bodies in Neurons Lacking NPC1, NPC2, or Both Proteins Suggest NPC1-NPC2 Molecular Co-operativity in Lipid Trafficking. Microscopy and Microanalysis 10(S02): 1468-1469, 2004

Cholesterol overload promotes morphogenesis of a Niemann-Pick C (NPC)-like compartment independent of inhibition of NPC1 or HE1/NPC2 function. Journal of Biological Chemistry 276(49): 46414-46421, 2001

Molecular analysis of NPC1 and NPC2 gene in 34 Niemann-Pick C Italian patients: identification and structural modeling of novel mutations. Neurogenetics 10(3): 229-239, 2009

Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking. Biochimica et Biophysica Acta 1791(7): 671-678, 2009

Niemann-Pick C disease: functional characterization of three NPC2 mutations and clinical and molecular update on patients with NPC2. Clinical Genetics 71(4): 320-330, 2007