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.