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Science 11 July 1997:
Vol. 277. no. 5323, pp. 232 - 235
DOI: 10.1126/science.277.5323.232
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Reports

Murine Model of Niemann-Pick C Disease: Mutation in a Cholesterol Homeostasis Gene

Stacie K. Loftus, Jill A. Morris, Eugene D. Carstea, Jessie Z. Gu, Christiano Cummings, Anthony Brown, Jane Ellison, Kousaku Ohno, Melissa A. Rosenfeld, Danilo A. Tagle, Peter G. Pentchev, William J. Pavan *

An integrated human-mouse positional candidate approach was used to identify the gene responsible for the phenotypes observed in a mouse model of Niemann-Pick type C (NP-C) disease. The predicted murine NPC1 protein has sequence homology to the putative transmembrane domains of the Hedgehog signaling molecule Patched, to the cholesterol-sensing regions of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and SREBP cleavage-activating protein (SCAP), and to the NPC1 orthologs identified in human, the nematode Caenorhabditis elegans, and the yeast Saccharomyces cerevisiae. The mouse model may provide an important resource for studying the role of NPC1 in cholesterol homeostasis and neurodegeneration and for assessing the efficacy of new drugs for NP-C disease.

S. K. Loftus, J. Ellison, W. J. Pavan, Laboratory of Genetic Disease Research, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
J. A. Morris, Laboratory of Gene Transfer, National Human Genome Research Institute, and Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
E. D. Carstea, C. Cummings, A. Brown, P. G. Pentchev, Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
J. Z. Gu, M. A. Rosenfeld, D. A. Tagle, Laboratory of Gene Transfer, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
K. Ohno, Department of Neurobiology, School of Life Sciences, Tottori University Faculty of Medicine, Yonago, 683, Japan.
*   To whom correspondence should be addressed. E-mail: bpavan{at}nhgri.nih.gov

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W. Yu, J.-S. Gong, M. Ko, W. S. Garver, K. Yanagisawa, and M. Michikawa (2005)
J. Biol. Chem. 280, 11731-11739
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Varied Mechanisms Underlie the Free Sialic Acid Storage Disorders.
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J. Biol. Chem. 280, 1408-1416
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Secretion of Sterols and the NPC2 Protein from Primary Astrocytes.
A.-L. Mutka, S. Lusa, M. D. Linder, E. Jokitalo, O. Kopra, M. Jauhiainen, and E. Ikonen (2004)
J. Biol. Chem. 279, 48654-48662
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NCR-1 and NCR-2, the C. elegans homologs of the human Niemann-Pick type C1 disease protein, function upstream of DAF-9 in the dauer formation pathways.
J. Li, G. Brown, M. Ailion, S. Lee, and J. H. Thomas (2004)
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Cyclin-Dependent Kinase Inhibitors Attenuate Protein Hyperphosphorylation, Cytoskeletal Lesion Formation, and Motor Defects in Niemann-Pick Type C Mice.
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T. Kishida, I. Kostetskii, Z. Zhang, F. Martinez, P. Liu, S. U. Walkley, N. K. Dwyer, E. J. Blanchette-Mackie, G. L. Radice, and J. F. Strauss III (2004)
J. Biol. Chem. 279, 19276-19285
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Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport.
D. E. Sleat, J. A. Wiseman, M. El-Banna, S. M. Price, L. Verot, M. M. Shen, G. S. Tint, M. T. Vanier, S. U. Walkley, and P. Lobel (2004)
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A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain.
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J. Lipid Res. 45, 582-591
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R. A. Nixon (2004)
Am. J. Pathol. 164, 757-761
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Suppression of Macrophage Eicosanoid Synthesis by Atherogenic Lipoproteins Is Profoundly Affected by Cholesterol-Fatty Acyl Esterification and the Niemann-Pick C Pathway of Lipid Trafficking.
A. R. Leventhal, C. C. Leslie, and I. Tabas (2004)
J. Biol. Chem. 279, 8084-8092
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Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption.
S. W. Altmann, H. R. Davis Jr., L.-j. Zhu, X. Yao, L. M. Hoos, G. Tetzloff, S. P. N. Iyer, M. Maguire, A. Golovko, M. Zeng, et al. (2004)
Science 303, 1201-1204
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J. Cell Biol. 164, 547-556
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Genetics 165, 1915-1928
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Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis.
B. Feng, D. Zhang, G. Kuriakose, C. M. Devlin, M. Kockx, and I. Tabas (2003)
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Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration.
C. Xie, E. G. Lund, S. D. Turley, D. W. Russell, and J. M. Dietschy (2003)
J. Lipid Res. 44, 1780-1789
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Presenilin Redistribution Associated with Aberrant Cholesterol Transport Enhances {beta}-Amyloid Production In Vivo.
M. Burns, K. Gaynor, V. Olm, M. Mercken, J. LaFrancois, L. Wang, P. M. Mathews, W. Noble, Y. Matsuoka, and K. Duff (2003)
J. Neurosci. 23, 5645-5649
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Trafficking defects in endogenously synthesized cholesterol in fibroblasts, macrophages, hepatocytes, and glial cells from Niemann-Pick type C1 mice.
P. C. Reid, S. Sugii, and T.-Y. Chang (2003)
J. Lipid Res. 44, 1010-1019
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How a Hedgehog might see holoprosencephaly.
E. Roessler and M. Muenke (2003)
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Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling.
T. Kawakami, T'N. Kawcak, Y.-J. Li, W. Zhang, Y. Hu, and P.-T. Chuang (2003)
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J. Lipid Res. 44, 243-253
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Trafficking of Cholesterol from Cell Bodies to Distal Axons in Niemann Pick C1-deficient Neurons.
B. Karten, D. E. Vance, R. B. Campenot, and J. E. Vance (2003)
J. Biol. Chem. 278, 4168-4175
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Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene.
S. K. Loftus, R. P. Erickson, S. U. Walkley, M. A. Bryant, A. Incao, R. A. Heidenreich, and W. J. Pavan (2002)
Hum. Mol. Genet. 11, 3107-3114
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J. Biol. Chem. 277, 43271-43280
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Identification of a pharmaceutical compound that partially corrects the Niemann-Pick C phenotype in cultured cells.
L. Liscum, E. Arnio, M. Anthony, A. Howley, S. L. Sturley, and M. Agler (2002)
J. Lipid Res. 43, 1708-1717
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M. Watarai, S.-i. Makino, M. Michikawa, K. Yanagisawa, S. Murakami, and T. Shirahata (2002)
Infect. Immun. 70, 4818-4825
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B. Bu, J. Li, P. Davies, and I. Vincent (2002)
J. Neurosci. 22, 6515-6525
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N. Gevry, D. Lacroix, J.-H. Song, N. Pescador, M. Dobias, and B. D. Murphy (2002)
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Control of Cholesterol Turnover in the Mouse.
J. M. Dietschy and S. D. Turley (2002)
J. Biol. Chem. 277, 3801-3804
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Accumulation of cholera toxin and GM1 ganglioside in the early endosome of Niemann-Pick C1-deficient cells.
Y. Sugimoto, H. Ninomiya, Y. Ohsaki, K. Higaki, J. P. Davies, Y. A. Ioannou, and K. Ohno (2001)
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The hedgehog pathway and basal cell carcinomas.
A. E. Bale and K.-p. Yu (2001)
Hum. Mol. Genet. 10, 757-762
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How Cells Handle Cholesterol.
K. Simons and E. Ikonen (2000)
Science 290, 1721-1726
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Receptor-mediated endocytosis of soluble and membrane-tethered Sonic hedgehog by Patched-1.
J. P. Incardona, J. H. Lee, C. P. Robertson, K. Enga, R. P. Kapur, and H. Roelink (2000)
PNAS
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Centripetal cholesterol flow from the extrahepatic organs through the liver is normal in mice with mutated Niemann-Pick type C protein (NPC1).
C. Xie, S. D. Turley, and J. M. Dietschy (2000)
J. Lipid Res. 41, 1278-1289
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A C. elegans patched gene, ptc-1, functions in germ-line cytokinesis.
P. E. Kuwabara, M.-H. Lee, T. Schedl, and G. S.X.E. Jefferis (2000)
Genes & Dev. 14, 1933-1944
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Models of Luteinization.
B. D. Murphy (2000)
Biol Reprod 63, 2-11
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Localization of the murine Niemann-Pick C1 protein to two distinct intracellular compartments.
W. S. Garver, R. A. Heidenreich, R. P. Erickson, M. A. Thomas, and J. M. Wilson (2000)
J. Lipid Res. 41, 673-687
   Abstract »    Full Text »
Alleviation of neuronal ganglioside storage does not improve the clinical course of the Niemann-Pick C disease mouse.
Y. Liu, Y.-P. Wu, R. Wada, E. B. Neufeld, K. A. Mullin, A. C. Howard, P. G. Pentchev, M. T. Vanier, K. Suzuki, and R. L. Proia (2000)
Hum. Mol. Genet. 9, 1087-1092
   Abstract »    Full Text »    PDF »
Role of Niemann-Pick Type C1 Protein in Intracellular Trafficking of Low Density Lipoprotein-derived Cholesterol.
J. C. Cruz, S. Sugii, C. Yu, and T.-Y. Chang (2000)
J. Biol. Chem. 275, 4013-4021
   Abstract »    Full Text »    PDF »
Genetic and Teratogenic Approaches To Craniofacial Development.
D.L. Young, R.A. Schneider, D. Hu, and J.A. Helms (2000)
Critical Reviews in Oral Biology & Medicine 11, 304-317
   Abstract »    Full Text »    PDF »
Cholesterol accumulation in tissues of the Niemann-Pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coated-pit pathway in each organ.
C. Xie, S. D. Turley, and J. M. Dietschy (1999)
PNAS 96, 11992-11997
   Abstract »    Full Text »    PDF »
Failure to Cleave Sterol Regulatory Element-binding Proteins (SREBPs) Causes Cholesterol Auxotrophy in Chinese Hamster Ovary Cells with Genetic Absence of SREBP Cleavage-activating Protein.
R. B. Rawson, R. DeBose-Boyd, J. L. Goldstein, and M. S. Brown (1999)
J. Biol. Chem. 274, 28549-28556
   Abstract »    Full Text »    PDF »
A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood.
M. S. Brown and J. L. Goldstein (1999)
PNAS 96, 11041-11048
   Abstract »    Full Text »    PDF »
Mutations in the Leucine Zipper Motif and Sterol-sensing Domain Inactivate the Niemann-Pick C1 Glycoprotein.
H. Watari, E. J. Blanchette-Mackie, N. K. Dwyer, M. Watari, E. B. Neufeld, S. Patel, P. G. Pentchev, and J. F. Strauss III (1999)
J. Biol. Chem. 274, 21861-21866
   Abstract »    Full Text »    PDF »
Oligomerization State Influences the Degradation Rate of 3-Hydroxy-3-methylglutaryl-CoA Reductase.
H. H. Cheng, L. Xu, H. Kumagai, and R. D. Simoni (1999)
J. Biol. Chem. 274, 17171-17178
   Abstract »    Full Text »    PDF »
Cholesterol Biosynthesis from Lanosterol. MOLECULAR CLONING, TISSUE DISTRIBUTION, EXPRESSION, CHROMOSOMAL LOCALIZATION, AND REGULATION OF RAT 7-DEHYDROCHOLESTEROL REDUCTASE, A SMITH-LEMLI-OPITZ SYNDROME-RELATED PROTEIN.
S.-H. Bae, J. N. Lee, B. U. Fitzky, J. Seong, and Y.-K. Paik (1999)
J. Biol. Chem. 274, 14624-14631
   Abstract »    Full Text »    PDF »
A Mammalian Lysosomal Membrane Protein Confers Multidrug Resistance upon Expression in Saccharomyces cerevisiae.
D. L. Hogue, L. Kerby, and V. Ling (1999)
J. Biol. Chem. 274, 12877-12882
   Abstract »    Full Text »    PDF »
The Niemann-Pick C1 Protein Resides in a Vesicular Compartment Linked to Retrograde Transport of Multiple Lysosomal Cargo.
E. B. Neufeld, M. Wastney, S. Patel, S. Suresh, A. M. Cooney, N. K. Dwyer, C. F. Roff, K. Ohno, J. A. Morris, E. D. Carstea, et al. (1999)
J. Biol. Chem. 274, 9627-9635
   Abstract »    Full Text »    PDF »
Localization of Niemann-Pick C1 protein in astrocytes: Implications for neuronal degeneration in Niemann- Pick type C disease.
S. C. Patel, S. Suresh, U. Kumar, C. Y. Hu, A. Cooney, E. J. Blanchette-Mackie, E. B. Neufeld, R. C. Patel, R. O. Brady, Y. C. Patel, et al. (1999)
PNAS 96, 1657-1662
   Abstract »    Full Text »    PDF »
Niemann-Pick C1 protein: Obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization.
H. Watari, E. J. Blanchette-Mackie, N. K. Dwyer, J. M. Glick, S. Patel, E. B. Neufeld, R. O. Brady, P. G. Pentchev, and J. F. Strauss III (1999)
PNAS 96, 805-810
   Abstract »    Full Text »    PDF »
Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.
C. Xie, S. D. Turley, P. G. Pentchev, and J. M. Dietschy (1999)
Am J Physiol Endocrinol Metab 276, E336-E344
   Abstract »    Full Text »    PDF »
Centripetal cholesterol flux to the liver is dictated by events in the peripheral organs and not by the plasma high density lipoprotein or apolipoprotein A-I concentration.
C. D. Jolley, L. A. Woollett, S. D. Turley, and J. M. Dietschy (1998)
J. Lipid Res. 39, 2143-2149
   Abstract »    Full Text »
Sterols regulate processing of carbohydrate chains of wild-type SREBP cleavage-activating protein (SCAP), but not sterol-resistant mutants Y298C or D443N.
A. Nohturfft, M. S. Brown, and J. L. Goldstein (1998)
PNAS 95, 12848-12853
   Abstract »    Full Text »    PDF »
Isolation of Cholesterol-requiring Mutant Chinese Hamster Ovary Cells with Defects in Cleavage of Sterol Regulatory Element-binding Proteins at Site 1.
R. B. Rawson, D. Cheng, M. S. Brown, and J. L. Goldstein (1998)
J. Biol. Chem. 273, 28261-28269
   Abstract »    Full Text »    PDF »


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