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http://purl.uniprot.org/citations/11349231http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/11349231http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/11349231http://www.w3.org/2000/01/rdf-schema#comment"Niemann-Pick disease type C (NPC) is a fatal, autosomal recessive lipidosis characterized by lysosomal accumulation of unesterified cholesterol and multiple neurological symptoms, such as vertical supranuclear ophthalmoplegia, progressive ataxia, and dementia. More than 90% of cases of NPC are due to a defect in Niemann-Pick C1 (NPC1), a late endosomal, integral membrane protein that plays a role in cholesterol transport or homeostasis. Biochemical diagnosis of NPC has relied on the use of patient skin fibroblasts in an assay to demonstrate delayed low-density lipoprotein (LDL)-derived cholesterol esterification and a cytological technique-filipin staining-to demonstrate the intracellular accumulation of cholesterol. A small percentage of patients, referred to as "NPC variants," present with clinical symptoms of NPC but show near-normal results of these biochemical tests, making laboratory confirmation of NPC disease problematic. Here, we demonstrate that NPC-variant fibroblast samples can be detected as sphingolipid storage disease cells, using a fluorescent sphingolipid analog, BODIPY-lactosylceramide. This lipid accumulated in endosomes/lysosomes in variant cells preincubated with LDL cholesterol but targeted to the Golgi complex in normal cells under these conditions. The reproducibility of this technique was validated in a blinded study. In addition, we performed mutation analysis of the NPC1 gene in NPC variant and "classical" NPC cell samples and found a high incidence of specific mutations within the cysteine-rich region of NPC1 in variants. We also found that 5 of the 12 variant cell samples had no apparent defect in NPC1 but were otherwise indistinguishable from other variant cells. This is a surprising result, since, in general, approximately 90% of patients with NPC possess defects in NPC1. Our findings should be useful for the detection of NPC variants and also may provide significant new insight regarding NPC1 genotype/phenotype correlations."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.org/dc/terms/identifier"doi:10.1086/320599"xsd:string
http://purl.uniprot.org/citations/11349231http://purl.org/dc/terms/identifier"doi:10.1086/320599"xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Sun X."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Sun X."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Puri V."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Puri V."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Patterson M.C."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Patterson M.C."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"O'Brien J.F."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"O'Brien J.F."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Park W.D."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Park W.D."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Marks D.L."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Marks D.L."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Pagano R.E."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Pagano R.E."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Kraft D.L."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Kraft D.L."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Lundquist P.A."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Lundquist P.A."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Snow K."xsd:string
http://purl.uniprot.org/citations/11349231http://purl.uniprot.org/core/author"Snow K."xsd:string
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