Npc1 is a transmembrane protein involved in endosomal lipid sorting and trafficking. The nmf164 allele is a point mutation, which results in partial functional loss of the protein. In comparison to mice carrying Npc1spm (Stock #002760) and Npc1m1N (Stock #003092), the nmf164 phenotype has a delayed onset and models a more slowly progressing form of human Niemann-Pick C disease. Mice exhibit age-dependent ataxia, impaired motor and strength capabilities, shortened lifespan (112 +/- 4 days), weight loss, progressive accumulation of sphingomyelin and glycosphingolipids in the liver and spleen (sphingomyelinosis), and abnormal cholesterol levels in liver. In the brain, phenotypic characteristics include: loss of cerebellar Purkinje cells, an increase in the GM2 and GM3 gangliosides, abnormal astrocyte and microglial cell activation, abnormal cholesterol levels in neurons, and acoustic startle response abnormalities. This mutant mouse strain may be useful in studies of Niemann-Pick C disease.
Standard pathology work-up on two mutants (91 or 104 days of age) showed degeneration of the purkinje cell layer in the cerebellum. Lysosomal storage of lipid was also noted in macrophages present in the liver and spleen, as well as in the cytoplasm of neurons in the cerebral cortex. Apoptosis of the inner portion of the inner nuclear layer of the retina, and atrophic seminiferous tubules were also noted in one mutant.
