title: A novel mouse model of Niemann-Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations.
abstract: We have identified a point mutation in Npc1 that creates a novel mouse model (Npc1(nmf164)) of Niemann-Pick type C1 (NPC) disease: a single nucleotide change (A to G at cDNA bp 3163) that results in an aspartate to glycine change at position 1005 (D1005G). This change is in the cysteine-rich luminal loop of the NPC1 protein and is highly similar to commonly occurring human mutations. Genetic and molecular biological analyses, including sequencing the Npc1(spm) allele and identifying a truncating mutation, confirm that the mutation in Npc1(nmf164) mice is distinct from those in other existing mouse models of NPC disease (Npc1(nih), Npc1(spm)). Analyses of lifespan, body and spleen weight, gait and other motor activities, as well as acoustic startle responses all reveal a more slowly developing phenotype in Npc1(nmf164) mutant mice than in mice with the null mutations (Npc1(nih), Npc1(spm)). Although Npc1 mRNA levels appear relatively normal, Npc1(nmf164) brain and liver display dramatic reductions in Npc1 protein, as well as abnormal cholesterol metabolism and altered glycolipid expression. Furthermore, histological analyses of liver, spleen, hippocampus, cortex and cerebellum reveal abnormal cholesterol accumulation, glial activation and Purkinje cell loss at a slower rate than in the Npc1(nih) mouse model. Magnetic resonance imaging studies also reveal significantly less demyelination/dysmyelination than in the null alleles. Thus, although prior mouse models may correspond to the severe infantile onset forms of NPC disease, Npc1(nmf164) mice offer many advantages as a model for the late-onset, more slowly progressing forms of NPC disease that comprise the large majority of human cases.
authors: Department of Physiology and Neurobiology, Dartmouth Medical School, Hanover, NH 03755, USA.
authors: Robert A
authors: RA
authors: Maue
authors: Robert W
authors: RW
authors: Burgess
authors: Bing
authors: B
authors: Wang
authors: Christine M
authors: CM
authors: Wooley
authors: Kevin L
authors: KL
authors: Seburn
authors: Marie T
authors: MT
authors: Vanier
authors: Maximillian A
authors: MA
authors: Rogers
authors: Catherine C
authors: CC
authors: Chang
authors: Ta-Yuan
authors: TY
authors: Chang
authors: Brent T
authors: BT
authors: Harris
authors: David J
authors: DJ
authors: Graber
authors: Carlos A A
authors: CA
authors: Penatti
authors: Donna M
authors: DM
authors: Porter
authors: Benjamin S
authors: BS
authors: Szwergold
authors: Leslie P
authors: LP
authors: Henderson
authors: John W
authors: JW
authors: Totenhagen
authors: Theodore P
authors: TP
authors: Trouard
authors: Ivan A
authors: IA
authors: Borbon
authors: Robert P
authors: RP
authors: Erickson
mesh_terms: D017668:Age of Onset; D000483:Alleles; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress; D005732:Gangliosides / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008168:Lung / Q000166:cytology; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000473:pathology; D009186:Myelin Sheath; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D057165:Proteostasis Deficiencies; D011689:Purkinje Cells / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D013216:Reflex, Startle; D015996:Survival Rate
chemical_list: D002352:Carrier Proteins; D005732:Gangliosides; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D012333:RNA, Messenger; D002784:Cholesterol