C57BL/6J-Npc1^nmf164/J

Stock number: 004817
Research areas: Mouse/Human Gene Homologs, Neurobiology Research

Description

These mice carry an ENU-induced mutation characterized by ataxia, sphingomyelinosis, and abnormal cholesterol levels in liver. Degeneration of the purkinje cell layer in the cerebellum is also seen.

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Detailed description

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 Npc1^spm (Stock #002760) and Npc1^m1N (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.

Development

This phenotypic deviant was identified following multidose ethylnitrosourea (ENU) treatments to induce mutations in male founder C57BL/6J mice during a forward genetic screen for recessive neurological phenotypes at the Neuroscience Mutagenesis Facility at The Jackson Laboratory. Mutagenized males were outcrossed to C57BL/6J females. The mutation results in a A to G transversion in exon 20 of 25 exons. The mutation alters the corresponding amino acid from aspartate to glycine at codon 1005 (D1005G) in loop I of the protein between the eighth and ninth (of 13) transmembrane domains.

Allele

Symbol: Npc1^nmf164
Name: neuroscience mutagenesis facility, 164
MGI accession ID: MGI:2686741
Generation method: Chemically induced (ENU)
Attributes: Hypomorph
Synonyms: Npc1^spm-J; sphingomyelinosis Jackson
Marker symbol: Npc1
Marker name: NPC intracellular cholesterol transporter 1
Marker synonyms: A430089E03Rik; C85354; Cdig2; D18Ertd139e; D18Ertd723e; lcsd; nmf164; NPC; POGZ; SLC65A1; SLC66A1
Chromosome: 18
Strain of origin: C57BL/6J
Molecular note: This phenotypic mutant was identified in an ENU mutagenesis screen. A noncomplementation test with other Npc1 alleles showed that nmf164 represents an allele of Npc1. The mutation is an A to G transversion at coding nucleoide 3014 (c.3014A>G) in exon 20 of 25 exons, altering the corresponding amino acid from aspartate to glycine at codon 1005 (p.D1005G) in loop I of the protein between the eighth and ninth (of 13) transmembrane domains. Western blot analysis reveals that protein levels reduced to 10-15% of wild type.