DOI: 10.1126/science.277.5323.228. Niemann-Pick C1 Disease Gene: Homology to Mediators of Cholesterol Homeostasis

Niemann-Pick C1 Disease Gene: Homology to Mediators of Cholesterol Homeostasis

10.1126/science.277.5323.228

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)–derived cholesterol. By positional cloning methods, a gene ( NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients. Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. The 1278–amino acid NPC1 protein has sequence similarity to the morphogen receptor PATCHED and the putative sterol-sensing regions of SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase.

Authors 38

Eugene D. Carstea (first)
Jill A. Morris (additional)
Katherine G. Coleman (additional)
Stacie K. Loftus (additional)
Dana Zhang (additional)
Christiano Cummings (additional)
Jessie Gu (additional)
Melissa A. Rosenfeld (additional)
William J. Pavan (additional)
David B. Krizman (additional)
James Nagle (additional)
Mihail H. Polymeropoulos (additional)
Stephen L. Sturley (additional)
Yiannis A. Ioannou (additional)
Maureen E. Higgins (additional)
Marcella Comly (additional)
Adele Cooney (additional)
Anthony Brown (additional)
Christine R. Kaneski (additional)
E. Joan Blanchette-Mackie (additional)
Nancy K. Dwyer (additional)
Edward B. Neufeld (additional)
Ta-Yuan Chang (additional)
Laura Liscum (additional)
Jerome F. Strauss (additional)
Kousaku Ohno (additional)
Marsha Zeigler (additional)
Rivka Carmi (additional)
Jacob Sokol (additional)
David Markie (additional)
Raymond R. O'Neill (additional)
O. P. van Diggelen (additional)
Milan Elleder (additional)
Marc C. Patterson (additional)
Roscoe O. Brady (additional)
Marie T. Vanier (additional)
Peter G. Pentchev (additional)
Danilo A. Tagle (additional)

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]. For evaluation 8 to 11 fields each consisting of ∼200 cells were randomly selected and viewed with a 25× objective. Intense filipin fluorescence staining of cholesterol in perinuclear vacuoles was used as a marker of the lysosomal cholesterol accumulation characteristic of NP-C cells. Individual cells free of this intense fluorescence were scored as “corrected.” Frequently the corrected cells appeared in patches of two or more cells and their lysosomes were often seen scattered throughout the cytoplasm. In untransfected vector-only transfected and antisense NPC1 transfected cultures 1.9 0.4 and 2.4% respectively of the mutant NPC1 cells showed no filipin staining of perinuclear vesicles. By contrast in cultures transfected with the NPC1 vectors 5-4 8-1 and 1-1 23 22 and 19% respectively of the mutant cells showed no filipin staining.
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We thank D. Mosbrook and N. Dietrich for nucleotide sequencing F. S. Collins for advice E. A. Dawidowicz for many helpful discussions D. Schoenberg for assistance in the preparation of the manuscript and J. M. Trent for encouragement and mentoring. We thank the Ara Parseghian Medical Research Foundation and the National Niemann-Pick Disease Foundation for research support and the United Kingdom Niemann-Pick Foundation for helpful interactions. We foremost acknowledge the wisdom courage understanding and faith of the Niemann-Pick C patients and their families who have made this work possible.

Dates

Type	When
Created	23 years, 1 month ago (July 27, 2002, 5:37 a.m.)
Deposited	1 year, 7 months ago (Jan. 13, 2024, 12:46 a.m.)
Indexed	10 hours, 12 minutes ago (Aug. 29, 2025, 6:09 a.m.)
Issued	28 years, 1 month ago (July 11, 1997)
Published	28 years, 1 month ago (July 11, 1997)
Published Print	28 years, 1 month ago (July 11, 1997)

Funders 0

None

BibTeX

@article{Carstea_1997, title={Niemann-Pick C1 Disease Gene: Homology to Mediators of Cholesterol Homeostasis}, volume={277}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.277.5323.228}, DOI={10.1126/science.277.5323.228}, number={5323}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Carstea, Eugene D. and Morris, Jill A. and Coleman, Katherine G. and Loftus, Stacie K. and Zhang, Dana and Cummings, Christiano and Gu, Jessie and Rosenfeld, Melissa A. and Pavan, William J. and Krizman, David B. and Nagle, James and Polymeropoulos, Mihail H. and Sturley, Stephen L. and Ioannou, Yiannis A. and Higgins, Maureen E. and Comly, Marcella and Cooney, Adele and Brown, Anthony and Kaneski, Christine R. and Blanchette-Mackie, E. Joan and Dwyer, Nancy K. and Neufeld, Edward B. and Chang, Ta-Yuan and Liscum, Laura and Strauss, Jerome F. and Ohno, Kousaku and Zeigler, Marsha and Carmi, Rivka and Sokol, Jacob and Markie, David and O’Neill, Raymond R. and van Diggelen, O. P. and Elleder, Milan and Patterson, Marc C. and Brady, Roscoe O. and Vanier, Marie T. and Pentchev, Peter G. and Tagle, Danilo A.}, year={1997}, month=jul, pages={228–231} }

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  "abstract": "<jats:p>\n            Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)\u2013derived cholesterol. By positional cloning methods, a gene (\n            <jats:italic>NPC1)</jats:italic>\n            with insertion, deletion, and missense mutations has been identified in NP-C patients. Transfection of NP-C fibroblasts with wild-type\n            <jats:italic>NPC1</jats:italic>\n            cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. The 1278\u2013amino acid NPC1 protein has sequence similarity to the morphogen receptor PATCHED and the putative sterol-sensing regions of SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase.\n          </jats:p>",
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  "title": "Niemann-Pick C1 Disease Gene: Homology to Mediators of Cholesterol Homeostasis",
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          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
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        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
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          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
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        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
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        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
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        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
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          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
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          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
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        },
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          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
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          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
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          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
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      "family": "Nagle",
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      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Mihail H.",
      "family": "Polymeropoulos",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Stephen L.",
      "family": "Sturley",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Yiannis A.",
      "family": "Ioannou",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Maureen E.",
      "family": "Higgins",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Marcella",
      "family": "Comly",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Adele",
      "family": "Cooney",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Anthony",
      "family": "Brown",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Christine R.",
      "family": "Kaneski",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "E. Joan",
      "family": "Blanchette-Mackie",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Nancy K.",
      "family": "Dwyer",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Edward B.",
      "family": "Neufeld",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Ta-Yuan",
      "family": "Chang",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Laura",
      "family": "Liscum",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "suffix": "III",
      "given": "Jerome F.",
      "family": "Strauss",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Kousaku",
      "family": "Ohno",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Marsha",
      "family": "Zeigler",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Rivka",
      "family": "Carmi",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Jacob",
      "family": "Sokol",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "David",
      "family": "Markie",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Raymond R.",
      "family": "O'Neill",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "O. P.",
      "family": "van Diggelen",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Milan",
      "family": "Elleder",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Marc C.",
      "family": "Patterson",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Roscoe O.",
      "family": "Brady",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Marie T.",
      "family": "Vanier",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Peter G.",
      "family": "Pentchev",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    },
    {
      "given": "Danilo A.",
      "family": "Tagle",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "E. D. Carstea, J. A. Morris, K. G. Coleman, D. Zhang, C. Cummings, J. Nagle, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, R. R. O'Neill, R. O. Brady, P. G. Pentchev, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA."
        },
        {
          "name": "S. K. Loftus, J. Gu, M. A. Rosenfeld, W. J. Pavan, M. H. Polymeropoulos, D. A. Tagle, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA."
        },
        {
          "name": "S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA."
        },
        {
          "name": "Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA."
        }
      ]
    }
  ],
  "member": "221",
  "reference": [
    {
      "key": "e_1_3_1_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.3513311"
    },
    {
      "key": "e_1_3_1_3_2",
      "doi-asserted-by": "crossref",
      "first-page": "8487",
      "DOI": "10.1016/S0021-9258(19)40786-2",
      "volume": "250",
      "author": "Goldstein J. L.",
      "year": "1975",
      "unstructured": "Goldstein J. L., Dana S. E., Faust J. R., Beaudet A. L., Brown M. S., J. Biol. Chem. 250, 8487 (1975).",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_1_4_2",
      "unstructured": "P. G. Pentchev M. T. Vanier K. Suzuki M. C. Patterson in Metabolic and Molecular Bases of Inherited Disease C. R. Scriver A. L. Beaudet W. S. Sly D. D. Valle Eds. (McGraw-Hill New York 1995) pp. 2625\u20132639."
    },
    {
      "key": "e_1_3_1_5_2",
      "first-page": "118",
      "volume": "58",
      "author": "Vanier M. T.",
      "year": "1996",
      "unstructured": "Vanier M. T., et al., Am. J. Hum. Genet. 58, 118 (1996).",
      "journal-title": "Am. J. Hum. Genet."
    },
    {
      "key": "e_1_3_1_6_2",
      "doi-asserted-by": "crossref",
      "first-page": "40",
      "DOI": "10.1096/fasebj.1.1.3609608",
      "volume": "1",
      "author": "Pentchev P. G.",
      "year": "1987",
      "unstructured": "Pentchev P. G., et al., FASEB J. 1, 40 (1987);",
      "journal-title": "FASEB J."
    },
    {
      "key": "e_1_3_1_6_3",
      "doi-asserted-by": "crossref",
      "first-page": "17002",
      "DOI": "10.1016/S0021-9258(18)45483-X",
      "volume": "262",
      "author": "Liscum L.",
      "year": "1987",
      "unstructured": "Liscum L., Faust J., J. Biol. Chem. 262, 17002 (1987).",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_1_7_2",
      "doi-asserted-by": "crossref",
      "unstructured": "E. D. Carstea et al. Proc. Natl . Acad. Sci . U.S.A. 90 2002 (1993).",
      "DOI": "10.1073/pnas.90.5.2002"
    },
    {
      "key": "e_1_3_1_8_2",
      "unstructured": "E. D. Carstea et al. unpublished data."
    },
    {
      "key": "e_1_3_1_9_2",
      "unstructured": "Patient DNA samples consist of a pan-ethnic selection from more than 40 NPC1 families whose genotype ( 4) and phenotype (3) were established. All patient and control DNA samples were obtained under the guidelines approved by clinical and research committees of the National Institutes of Health."
    },
    {
      "key": "e_1_3_1_10_2",
      "unstructured": "J. Z. Gu et al. Proc. Natl. Acad. Sci. U.S.A. in press."
    },
    {
      "key": "e_1_3_1_11_2",
      "unstructured": "BAC DNA was subcloned into exon-trapping vectors pSPL3 and pTAG4 as described ["
    },
    {
      "key": "e_1_3_1_11_3",
      "first-page": "167",
      "volume": "68",
      "author": "Krizman D. B.",
      "year": "1997",
      "unstructured": "Krizman D. B., et al., Methods Mol. Biol. 68, 167 (1997)].",
      "journal-title": "Methods Mol. Biol."
    },
    {
      "key": "e_1_3_1_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.274.5287.540"
    },
    {
      "key": "e_1_3_1_13_2",
      "unstructured": "Long-range polymerase chain reaction (PCR) was performed on a human fetal brain Marathon-Ready cDNA library with Advantage Klentaq Polymerase Mix (Clontech). An antisense primer 5\u2032-TATTCTGCACAGACACTGCATCGTG-3\u2032 was designed on the basis of the 5\u2032 sequence of EST clone  (GenBank) and its reverse primer was provided by the manufacturer. Amplification products were subcloned into TA-vector (Invitrogen) and sequenced. For further 5\u2032 extension from human Marathon-Ready cDNA libraries additional antisense primers (5\u2032-CGCTTGTTCCATCTTCAGCACCTCTGACAC-3\u2032 5\u2032-CAGAAAGTGCGTGTGGTAATCGGCATACAC-3\u2032 5\u2032-GTGCAGTTCGTGTTATACGGTGAAAGAGGG-3\u2032) were designed from newly identified NPC1 sequence. Full-length NPC1 was generated by PCR amplification of human fibroblast and human ovary Marathon-Ready cDNA libraries performed with 5\u2032 untranslated region (UTR) primer 704F (5\u2032-TGCTCCTGCTCCTCCGCTC-3\u2032) or 87F (5\u2032-AACCAGCCGAACGCCGCC-3\u2032) paired with the 3\u2032 UTR primer G-60 (5\u2032-GTCCCTCATTTCATGCCACATC-3\u2032. PCR products were cloned into expression vector pCR3.1 (Invitrogen). Orientation was determined by digestion with Sac I."
    },
    {
      "key": "e_1_3_1_14_2",
      "unstructured": "Molecular mass determinations were made with the GCG program PEPTIDESORT ["
    },
    {
      "key": "e_1_3_1_14_3",
      "doi-asserted-by": "crossref",
      "first-page": "387",
      "DOI": "10.1093/nar/12.1Part1.387",
      "volume": "12",
      "author": "Deveraux J.",
      "year": "1984",
      "unstructured": "Deveraux J., Haeberil P., Smithies O., Nucleic Acids Res. 12, 387 (1984);",
      "journal-title": "Nucleic Acids Res."
    },
    {
      "key": "e_1_3_1_14_4",
      "unstructured": "]. PSORT {"
    },
    {
      "key": "e_1_3_1_14_5",
      "doi-asserted-by": "crossref",
      "first-page": "271",
      "DOI": "10.1016/0168-1702(85)90051-6",
      "volume": "3",
      "author": "McGeogh D. J.",
      "year": "1985",
      "unstructured": "McGeogh D. J., Virus Res. 3, 271 (1985).",
      "journal-title": "Virus Res."
    },
    {
      "key": "e_1_3_1_14_6",
      "unstructured": "modified by K. Nakai and M. Kanehisa [ Proteins Struct. Funct. Genet. 11 95 (1991)} was used to detect signal peptide sequence. The same sequence was predicted by GCG-MOTIFS. TM domains were predicted with TMbase ["
    },
    {
      "key": "e_1_3_1_14_7",
      "first-page": "166",
      "volume": "374",
      "author": "Hofmann K.",
      "year": "1993",
      "unstructured": "Hofmann K., Stoffel W., Biol. Chem. Hoppe-Seyler 374, 166 (1993);",
      "journal-title": "Biol. Chem. Hoppe-Seyler"
    },
    {
      "key": "e_1_3_1_14_8",
      "unstructured": "] and the method described by P. Klein M. Kanehisha and C. DeLisi [ Biochim. Biophys. Acta 815 468 (1985)]."
    },
    {
      "key": "e_1_3_1_15_2",
      "doi-asserted-by": "crossref",
      "first-page": "5210",
      "DOI": "10.1016/S0021-9258(17)37676-7",
      "volume": "269",
      "author": "Ortgata S.",
      "year": "1994",
      "unstructured": "Ortgata S., Fukuda M., J. Biol. Chem. 269, 5210 (1994);",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_1_15_3",
      "unstructured": "; I. V. Sandoval et al. ibid. p. 6622."
    },
    {
      "key": "e_1_3_1_16_2",
      "doi-asserted-by": "crossref",
      "first-page": "2963",
      "DOI": "10.1002/j.1460-2075.1994.tb06594.x",
      "volume": "13",
      "author": "Hunziker W.",
      "year": "1994",
      "unstructured": "Hunziker W., Fumey C., EMBO J. 13, 2963 (1994);",
      "journal-title": "EMBO J."
    },
    {
      "key": "e_1_3_1_16_3",
      "doi-asserted-by": "crossref",
      "first-page": "1143",
      "DOI": "10.1016/0092-8674(92)90636-Q",
      "volume": "69",
      "author": "Letourneur F.",
      "year": "1992",
      "unstructured": "Letourneur F., Klausner R. D., Cell 69, 1143 (1992).",
      "journal-title": "Cell"
    },
    {
      "key": "e_1_3_1_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.277.5323.232"
    },
    {
      "key": "e_1_3_1_18_2",
      "first-page": "1681",
      "volume": "243",
      "author": "Landschultz W. H.",
      "year": "1988",
      "unstructured": "Landschultz W. H., Johnson P. F., McKnight S. L., ibid. 243, 1681 (1988).",
      "journal-title": "ibid."
    },
    {
      "key": "e_1_3_1_19_2",
      "doi-asserted-by": "crossref",
      "first-page": "7835",
      "DOI": "10.1016/S0021-9258(17)42869-9",
      "volume": "259",
      "author": "Cooper J. A.",
      "year": "1984",
      "unstructured": "Cooper J. A., Esch F. S., Taylor S. S., Hunter T., J. Biol. Chem. 259, 7835 (1984).",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_1_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.272.5268.1668"
    },
    {
      "key": "e_1_3_1_21_2",
      "doi-asserted-by": "crossref",
      "first-page": "415",
      "DOI": "10.1016/S0092-8674(00)81362-8",
      "volume": "87",
      "author": "Hua X.",
      "year": "1996",
      "unstructured": "Hua X., Nohturfft A., Goldstein J. L., Brown M. S., Cell 87, 415 (1996).",
      "journal-title": "Cell"
    },
    {
      "key": "e_1_3_1_22_2",
      "doi-asserted-by": "crossref",
      "first-page": "613",
      "DOI": "10.1038/308613a0",
      "volume": "308",
      "author": "Chin D. J.",
      "year": "1984",
      "unstructured": "Chin D. J., et al., Nature 308, 613 (1984).",
      "journal-title": "Nature"
    },
    {
      "key": "e_1_3_1_23_2",
      "unstructured": "SSCP analysis was carried out on both cDNA and genomic DNA samples. cDNA was generated from cultured fibroblast RNA with Superscript II RNase H Reverse Transcriptase (Gibco-BRL). For genomic DNA intron-exon boundaries were identified for 19 exons of NPC1 (constituting 72% of the ORF) thus permitting PCR-based SSCP analysis from genomic DNA with primers designed from intron sequences. DNA was isolated from blood with the Puregene kit (GentraSystem Minneapolis MN). PCR was performed in 10-\u03bcl reactions containing 0.5 U of Taq (Perkin-Elmer) 50 ng of DNA and 0.25 mM each of dATP dGTP dTTP and [ 32 P]dCTP. Samples were subjected to electrophoresis on 0.6\u00d7 tris-borate EDTA\u2013buffered Mutation Detection Enhancement (MDE) (FMC Products Rockland ME) SSCP at 4 W for 14 hours. SSCP conformers were excised from the gel and reamplified by means of the original primer set. Reamplification products were sequenced (Applied Biosystems Foster City CA) and compared to normal controls."
    },
    {
      "key": "e_1_3_1_24_2",
      "unstructured": "For transient transfection DNA vectors 5-4 (704F/G60) 8-1 (87F/G60) 1-1 (704F/G60) and antisense 7-5 (704F/G60) were extracted by alkaline lysis and CsCl gradient centrifugation. On day 0 NPC1 fibroblasts (GM-3123) were plated (70 000 cells per well) in Lab-Tek Chamber Slides (Nunc Napeeville IL). On day 1 lipofectamine transfection was done according to the manufacturer's recommendations (Gibco-BRL). On day 2 cells were rinsed once with phosphate-buffered saline and Eagle's minimum essential medium containing 10% lipoprotein-deficient serum (LPDS) was then added to the cells for 36 hours and then replaced with LPDS medium with or without LDL (50 \u03bcg/ml) for 24 hours. The NPC1 -genotyped cells were fixed stained with filipin and cytochemically viewed ["
    },
    {
      "key": "e_1_3_1_24_3",
      "doi-asserted-by": "crossref",
      "first-page": "8022",
      "DOI": "10.1073/pnas.85.21.8022",
      "volume": "85",
      "author": "Blanchette-Mackie E. J.",
      "year": "1988",
      "unstructured": "Blanchette-Mackie E. J., et al., Proc. Natl. Acad. Sci. U.S.A. 85, 8022 (1988);",
      "journal-title": "Proc. Natl. Acad. Sci. U.S.A."
    },
    {
      "key": "e_1_3_1_24_4",
      "unstructured": "]. For evaluation 8 to 11 fields each consisting of \u223c200 cells were randomly selected and viewed with a 25\u00d7 objective. Intense filipin fluorescence staining of cholesterol in perinuclear vacuoles was used as a marker of the lysosomal cholesterol accumulation characteristic of NP-C cells. Individual cells free of this intense fluorescence were scored as \u201ccorrected.\u201d Frequently the corrected cells appeared in patches of two or more cells and their lysosomes were often seen scattered throughout the cytoplasm. In untransfected vector-only transfected and antisense NPC1 transfected cultures 1.9 0.4 and 2.4% respectively of the mutant NPC1 cells showed no filipin staining of perinuclear vesicles. By contrast in cultures transfected with the NPC1 vectors 5-4 8-1 and 1-1 23 22 and 19% respectively of the mutant cells showed no filipin staining."
    },
    {
      "key": "e_1_3_1_25_2",
      "doi-asserted-by": "crossref",
      "first-page": "10379",
      "DOI": "10.1074/jbc.271.17.10379",
      "volume": "271",
      "author": "Hua X.",
      "year": "1996",
      "unstructured": "Hua X., Sakai J., Brown M. S., Goldstein J. L., J. Biol. Chem. 271, 10379 (1996);",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_1_25_3",
      "doi-asserted-by": "crossref",
      "first-page": "1037",
      "DOI": "10.1016/S0092-8674(00)81304-5",
      "volume": "85",
      "author": "Sakai J.",
      "year": "1996",
      "unstructured": "Sakai J., et al., Cell 85, 1037 (1996).",
      "journal-title": "Cell"
    },
    {
      "key": "e_1_3_1_26_2",
      "doi-asserted-by": "crossref",
      "first-page": "52",
      "DOI": "10.1016/0092-8674(94)90234-8",
      "volume": "77",
      "author": "Wang X.",
      "year": "1994",
      "unstructured": "Wang X., Sato R., Brown M. S., Hua X., Goldstein J. L., Cell 77, 52 (1994).",
      "journal-title": "Cell"
    },
    {
      "key": "e_1_3_1_27_2",
      "unstructured": "We thank D. Mosbrook and N. Dietrich for nucleotide sequencing F. S. Collins for advice E. A. Dawidowicz for many helpful discussions D. Schoenberg for assistance in the preparation of the manuscript and J. M. Trent for encouragement and mentoring. We thank the Ara Parseghian Medical Research Foundation and the National Niemann-Pick Disease Foundation for research support and the United Kingdom Niemann-Pick Foundation for helpful interactions. We foremost acknowledge the wisdom courage understanding and faith of the Niemann-Pick C patients and their families who have made this work possible."
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