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Science 11 July 1997:
Vol. 277. no. 5323, pp. 228 - 231
DOI: 10.1126/science.277.5323.228
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Reports

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

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

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.

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.
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.
D. B. Krizman, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
S. L. Sturley, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Y. A. Ioannou and M. E. Higgins, Mount Sinai School of Medicine, New York, NY 10029, USA.
E. J. Blanchette-Mackie, N. K. Dwyer, E. B. Neufeld, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
T.-Y. Chang, Dartmouth Medical School, Hanover, NH 03755, USA.
L. Liscum, Tufts University School of Medicine, Boston, MA 02111, USA.
J. F. Strauss III, University of Pennsylvania, Philadelphia, PA 19104, USA.
K. Ohno, Tottori University Faculty of Medicine, Yanago, Japan.
M. Zeigler, Hadassah University Hospital, Jerusalem, Israel.
R. Carmi, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
J. Sokol, Hillel Yaffe Medical Center, Hadera, Israel.
D. Markie, Dunedin School of Medicine, Dunedin, New Zealand.
O. P. van Diggelen, Erasmus University, Rotterdam, The Netherlands.
M. Elleder, Faculty of Medicine and University Hospital, Prague, Czech Republic.
M. C. Patterson, Mayo Clinic, Rochester, MN 55905, USA.
M. T. Vanier, INSERM U 189, Oullins, France.
*   These authors contributed equally to this study.

dagger    To whom correspondence should be addressed. E-mail: pentchev{at}codon.nih.gov

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   Abstract »    Full Text »    PDF »
The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking.
J. Zhang, N. Dudley-Rucker, J. R. Crowley, E. Lopez-Perez, M. Issandou, J. E. Schaffer, and D. S. Ory (2004)
J. Lipid Res. 45, 223-231
   Abstract »    Full Text »    PDF »
Hedgehog Signaling in the Drosophila Eye and Head: An Analysis of the Effects of Different patched Trans-heterozygotes.
C. Thomas and P. W. Ingham (2003)
Genetics 165, 1915-1928
   Abstract »    Full Text »    PDF »
NPC1 and NPC2 Regulate Cellular Cholesterol Homeostasis through Generation of Low Density Lipoprotein Cholesterol-derived Oxysterols.
A. Frolov, S. E. Zielinski, J. R. Crowley, N. Dudley-Rucker, J. E. Schaffer, and D. S. Ory (2003)
J. Biol. Chem. 278, 25517-25525
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Genetic aspects of susceptibility to air pollution.
S.R. Kleeberger (2003)
Eur. Respir. J. 21, 52S-56s
   Abstract »    Full Text »    PDF »
The Transport of Low Density Lipoprotein-derived Cholesterol to the Plasma Membrane Is Defective in NPC1 Cells.
K. M. Wojtanik and L. Liscum (2003)
J. Biol. Chem. 278, 14850-14856
   Abstract »    Full Text »    PDF »
How a Hedgehog might see holoprosencephaly.
E. Roessler and M. Muenke (2003)
Hum. Mol. Genet. 12, R15-25
   Abstract »    Full Text »    PDF »
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)
Development 129, 5753-5765
   Abstract »    Full Text »    PDF »
Structure of a cholesterol-binding protein deficient in Niemann-Pick type C2 disease.
N. Friedland, H.-L. Liou, P. Lobel, and A. M. Stock (2003)
PNAS 100, 2512-2517
   Abstract »    Full Text »    PDF »
Inaugural Article: The integrity of a cholesterol-binding pocket in Niemann-Pick C2 protein is necessary to control lysosome cholesterol levels.
D. C. Ko, J. Binkley, A. Sidow, and M. P. Scott (2003)
PNAS 100, 2518-2525
   Abstract »    Full Text »    PDF »
Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease.
T. S. Blom, M. D. Linder, K. Snow, H. Pihko, M. W. Hess, E. Jokitalo, V. Veckman, A.-C. Syvanen, and E. Ikonen (2003)
Hum. Mol. Genet. 12, 257-272
   Abstract »    Full Text »    PDF »
Telomerase immortalization upregulates Rab9 expression and restores LDL cholesterol egress from Niemann-Pick C1 late endosomes.
M. Walter, J. P. Davies, and Y. A. Ioannou (2003)
J. Lipid Res. 44, 243-253
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
MENTHO, a MLN64 Homologue Devoid of the START Domain.
F. Alpy, C. Wendling, M.-C. Rio, and C. Tomasetto (2002)
J. Biol. Chem. 277, 50780-50787
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Niemann-Pick type C disease: mutations of NPC1 gene and evidence of abnormal expression of some mutant alleles in fibroblasts.
P. Tarugi, G. Ballarini, B. Bembi, C. Battisti, S. Palmeri, F. Panzani, E. Di Leo, C. Martini, A. Federico, and S. Calandra (2002)
J. Lipid Res. 43, 1908-1919
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Yeast Cells Lacking the ARV1 Gene Harbor Defects in Sphingolipid Metabolism. COMPLEMENTATION BY HUMAN ARV1.
E. Swain, J. Stukey, V. McDonough, M. Germann, Y. Liu, S. L. Sturley, and J. T. Nickels Jr. (2002)
J. Biol. Chem. 277, 36152-36160
   Abstract »    Full Text »    PDF »
Modulation of Cellular Cholesterol Transport and Homeostasis by Rab11.
M. Holtta-Vuori, K. Tanhuanpaa, W. Mobius, P. Somerharju, and E. Ikonen (2002)
Mol. Biol. Cell 13, 3107-3122
   Abstract »    Full Text »    PDF »
MLN64 Mediates Mobilization of Lysosomal Cholesterol to Steroidogenic Mitochondria.
M. Zhang, P. Liu, N. K. Dwyer, L. K. Christenson, T. Fujimoto, F. Martinez, M. Comly, J. A. Hanover, E. J. Blanchette-Mackie, and J. F. Strauss III (2002)
J. Biol. Chem. 277, 33300-33310
   Abstract »    Full Text »    PDF »
Sterol-dependent Regulation of Sphingolipid Metabolism in Saccharomyces cerevisiae.
E. Swain, K. Baudry, J. Stukey, V. McDonough, M. Germann, and J. T. Nickels Jr. (2002)
J. Biol. Chem. 277, 26177-26184
   Abstract »    Full Text »    PDF »
Niemann-Pick C1 protein regulates cholesterol transport to the trans-Golgi network and plasma membrane caveolae.
W. S. Garver, K. Krishnan, J. R. Gallagos, M. Michikawa, G. A. Francis, and R. A. Heidenreich (2002)
J. Lipid Res. 43, 579-589
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Inhibition of Intracellular Cholesterol Transport Alters Presenilin Localization and Amyloid Precursor Protein Processing in Neuronal Cells.
H. Runz, J. Rietdorf, I. Tomic, M. de Bernard, K. Beyreuther, R. Pepperkok, and T. Hartmann (2002)
J. Neurosci. 22, 1679-1689
   Abstract »    Full Text »    PDF »
Porcine Niemann Pick-C1 Protein Is Expressed in Steroidogenic Tissues and Modulated by cAMP.
N. Gevry, D. Lacroix, J.-H. Song, N. Pescador, M. Dobias, and B. D. Murphy (2002)
Endocrinology 143, 708-716
   Abstract »    Full Text »    PDF »


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