Abstract
Niemann-Pick type C2 disease (NP-C2) is a fatal hereditary disorder of unknown etiology characterized by defective egress of cholesterol from lysosomes. Here we show that the disease is caused by a deficiency in HE1, a ubiquitously expressed lysosomal protein identified previously as a cholesterol-binding protein. HE1 was undetectable in fibroblasts from NP-C2 patients but present in fibroblasts from unaffected controls and NP-C1 patients. Mutations in the HE1 gene, which maps to chromosome 14q24.3, were found in NP-C2 patients but not in controls. Treatment of NP-C2 fibroblasts with exogenous recombinant HE1 protein ameliorated lysosomal accumulation of low density lipoprotein-derived cholesterol.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Biological Transport
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CHO Cells
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Carrier Proteins*
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Cell Membrane / metabolism
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Cells, Cultured
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Cholesterol / metabolism*
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Cricetinae
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Culture Media, Conditioned
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Fibroblasts / metabolism
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Glycoproteins / chemistry
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Glycoproteins / genetics*
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Glycoproteins / metabolism*
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Glycoproteins / pharmacology
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Humans
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Lysosomes / metabolism*
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Molecular Sequence Data
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Mutation
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Niemann-Pick Diseases / genetics*
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Niemann-Pick Diseases / metabolism
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Rats
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Receptor, IGF Type 2 / metabolism
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Transfection
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Vesicular Transport Proteins
Substances
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Carrier Proteins
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Culture Media, Conditioned
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Glycoproteins
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NPC2 protein, human
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Receptor, IGF Type 2
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Recombinant Proteins
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Vesicular Transport Proteins
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Cholesterol