| First Author | Harris BS | Year | 2016 |
| Journal | MGI Direct Data Submission | Mgi Jnum | J:229377 |
| Mgi Id | MGI:5751705 | Citation | Harris BS, et al. (2016) A spontaneous model for neuronal ceroid lipofuscinosis 10. MGI Direct Data Submission |
| abstractText | The recessive Ctsd<m1J> mutation arose spontaneously in a colony of C3HeB/FeJ inbred mice at The Jackson Laboratory when that inbred was at generation F174+15. By three weeks of age homozygotes become thinner overall with a sunken stomach and general weakness. Most die by 3 weeks of age while some survive to almost 4 weeks of age, but none have survived longer. Homozygotes are completely deaf with no auditory brainstem response found in two homozygotes assessed at two weeks of age or three homozygotes assessed at three weeks of age. Cross sections of the inner ear showed a normal organ of Corti and enlarged spiral ganglion. Histological assessment of one female at 3.5 weeks of age found extensive dead neurons in the cerebral cortex, hippocampus, and hypothalamus, and large and small dystrophic axons in many places. A second 3.5 week old female was found to have hyperkeratosis in the stomach, wavy colonic crypts, edematous villi in the small intestine and bubbly cytoplasm of transitional epithelium, thymic atrophy, hair follicles that were all in catagen, and ballooned neurons with lipofuscin. Of 1,175 pups born from heterozygous intercrosses only 109 were mutant, 22 were born dead and 18 were subsequently found dead, a rate of 9.8% mutants born, or, assuming the dead to have all been homozygotes a rate of 16.8% mutants born, still much lower than the 25% expected. The average litter size is approximately 5 pups per litter. A mapping cross to CAST/EiJ found three recombinants in 16 mutants with rs3716088 at Chromosome 7 position 132,998,156 bp and no recombinants with rs3664224 at 144,579,810 bp (GRCm38). Whole exome sequencing identified a C to T transition at Chromosome 7 position 142,385,619 bp in a splice acceptor site of cathepsin D (Ctsd), a key lysosomal aspartyl protease important in autophagy and apoptosis, and known to underlie neuronal ceroid lipofuscinosis 10 in humans and other species including other mouse alleles. The phenotype and molecular defect of this spontaneous point mutation make it a model for neuronal ceroid lipofuscinosis 10. |
