C57BLKS/J-Npc1^spm/J

Stock number: 002760
Product name: sphingomyelinosis
Research areas: Internal/Organ Research, Metabolism Research, Mouse/Human Gene Homologs, Neurobiology Research

Description

This spontaneous mutation provides a model for Niemann-Pick disease types C1 and D, with severe Purkinje cell loss. Homozygotes on this C57BLKS/J background live longer than mice homozygous for this mutation on a DBA/2J or C57BL/6J background but develop a massive hepatomegaly not seen on these other backgrounds.

Detailed description

NPC1 is a transmembrane protein involved in the transport and export of LDL-derived cholesterol and other lipids from late endosomes and lysosomes. NPC1 Defects cause Niemann-Pick disease types C1 and D, lysosomal storage diseases in which cholesterol and other lipids accumulate in lysosomes of many organs. On this C57BLKS/J background sphingomyelinosis (spm) homozygotes begin to display weight loss and progressive neurological symptoms, such as tremor and ataxia, at approximately 7 weeks of age and die between 11 and 15 weeks of age with mean longevity of approximately 85 days for females and 90 days for males. Hepatosplenomegaly is found as early as 4 weeks of age, and peaks at 6 weeks of age just before noticeable weight loss. Massive foam cell clusters are found in the liver and spleen, and the liver has irregularly shaped white areas while the spleen has a whitish color. The lymph nodes are enlarged, including the mesenteric, inguinal and submandiubular lymph nodes. (Miyawaki et al., 1982, 1986)

Beginning at 4 weeks of age, neuronal swelling is found in the neocortex, piriform cortex, hippocampus and basal ganglia and this spreads with age to include the thalamus, midbrain, cerebellum and brainstem by 11 to 12 weeks of age. Neuronal cell loss is restricted to the Purkinje cell layer and the ventral posterior medial and lateral nuclei of the thalamus, with the thalamic neurons degenerating between 4 and 13 weeks of age and the Purkinje cell loss delayed to 5 weeks of age and nearly complete loss by 9 weeks oaf age (Yamada et al., 2001). Purkinje cell loss begins with zebrin II negative Purkinje cells, which results in a striping pattern of cell loss. At 45 days of age there is significant loss in both the posterior lobe, and anterior lobe, by 60 days of age there is further loss, especially in the posterior lobe hemispheres, and by 90 days of age most Purkinje cells are gone, but some remain in the flocculus/paraflocculus, lobules IX and X of the nodular zone, and 3 stripes remain in the anterior zone. These sphingomyelinosis homozygotes have a faster, more severe Purkinje cell loss than do Npc1^m1N homozygotes on a BALB/c background, but survive approximately 15 days longer (Sarna et al, 2003).

Genetic background impacts the phenotype for this mutation. On this C57BLKS/J background the foam cells stain slightly reddish with H&E stain, but on a DBA/2J congenic background the foam cells appear vacuolated, the massive hepatomegaly is not seen, weight loss begins just after 6 weeks of age and is faster with most dying between 9 and 10 weeks of age and the mean longevity for females and males is approximately 66 days. On a C57BL/6J congenic background homozygotes have a phenotype closer to that found in DBA/2J than in C57BLKS/J. (Miyawaki et al., 1986)

Sphingomyelinosis homozygotes fail to breed, but homozygous ovarian transplants and in vitro fertilization using sperm from homozygotes have each been used successfully for this strain.

Development

This spontaneous mutation was identified in two sibling C57BL/KsJ mice held at the Research Laboratories, Nippon Shinyaku Co.,Ltd in 1975. The mutation is an A to C substitution in the third base pair of intron 19, which destroys the splice donor site and retains 43 bases into the intron before a cryptic splice site splices to exon 20. The 43 base pair insertion generates a frame shift resulting in 30 novel amino acids followed by a premature termination codon. There is no evidence of wild-type splicing in spm transcripts. The strain was transferred to The Jackson Laboratory in 1996 and cryopreserved in 1998.

Allele

Symbol: Npc1^spm
Name: sphingomyelinosis
MGI accession ID: MGI:1857051
Generation method: Spontaneous
Synonyms: spm
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: C57BLKS/J
Molecular note: This spontaneous mutation is an A-to-C substitution in the third base pair of intron 19, which destroys the splice donor site, leading to the retention of 43 intronic bases before a cryptic splice site splices to exon 20. The 43 base pair insertion generates a frame shift resulting in 30 novel amino acids followed by a premature termination codon. There is no evidence of wild-type splicing in spm transcripts.