A novel mouse model of Niemann-Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations

Robert A. Maue, Robert W. Burgess, Bing Wang, Christine M. Wooley, Kevin L. Seburn, Marie T. Vanier, Maximillian A. Rogers, Catherine C. Chang, Ta Yuan Chang, Brent T. Harris, David J. Graber, Carlos A.A. Penatti, Donna M. Porter, Benjamin S. Szwergold, Leslie P. Henderson, John W. Totenhagen, Theodore P. Trouard, Ivan A. Borbon, Robert P. Erickson

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


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.

Original languageEnglish (US)
Article numberddr505
Pages (from-to)730-750
Number of pages21
JournalHuman molecular genetics
Issue number4
StatePublished - Feb 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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