title: Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene.
abstract: 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.
authors.affiliation: Laboratory of Genetic Disease Research, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Loftus
authors.forename: J A
authors.initials: JA
authors.lastname: Morris
authors.forename: E D
authors.initials: ED
authors.lastname: Carstea
authors.forename: J Z
authors.initials: JZ
authors.lastname: Gu
authors.forename: C
authors.initials: C
authors.lastname: Cummings
authors.forename: A
authors.initials: A
authors.lastname: Brown
authors.forename: J
authors.initials: J
authors.lastname: Ellison
authors.forename: K
authors.initials: K
authors.lastname: Ohno
authors.forename: M A
authors.initials: MA
authors.lastname: Rosenfeld
authors.forename: D A
authors.initials: DA
authors.lastname: Tagle
authors.forename: P G
authors.initials: PG
authors.lastname: Pentchev
authors.forename: W J
authors.initials: WJ
authors.lastname: Pavan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D006706:Homeostasis; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D021382:Protein Sorting Signals / Q000737:chemistry; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D017386:Sequence Homology, Amino Acid
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D021382:Protein Sorting Signals; D011506:Proteins; C102196:SREBP cleavage-activating protein; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases