| First Author | Harris BS | Year | 2016 |
| Journal | MGI Direct Data Submission | Mgi Jnum | J:229662 |
| Mgi Id | MGI:5752885 | Citation | Harris BS, et al. (2016) Two viable spontaneous mutation in Kif1a. MGI Direct Data Submission |
| abstractText | The recessive mutation leg dragger (lgdg) causes homozygotes to be slightly smaller than their unaffected littermates and to lose most of the use of their rear legs such that they drag their rear legs and pull themselves along with their front legs to move. This phenotype can be detected as early as 2 weeks of age and is evident by 3 weeks of age. A few homozygotes nearing wean age are found to roll over and over in a struggle to right themselves. When raised by their tails they do not splay their legs outward but rather cross the front pair and the rear pair. Auditory brainstem response analysis of one homozygous animal at 18 days of age showed severe hearing loss and no others were tested. Heterozygotes appear normal and fertile and live a normal lifespan. Of 743 pups born from heterozygous intercrosses 139 were mutant, 6 were born dead, 2 were found dead after birth, and 12 were missing before wean age. This is a yield of approximately 21% assuming all dead and missing were mutant, less than the 25% expected. Leg dragger arose spontaneously at The Jackson Laboratory in a mutant subline of the C3.NB-H2<p>/SnJ strain. A linkage testing cross to FVB/NJ mapped the mutation to Chromosome 1 between rs4222328 at 51,465,002 bp and rs3663366 at 112,352,573 bp (GRCm38). Exome sequencing identified a C to T point transition at Chromosome 1 position 93,076,218 bp (GRCm38/mm10), which causes a L181F mutation (Ctc to Ttc) in Kif1a. A second spontaneous mutation showing a similar hind-leg paralysis was later identified in a C57BL/6J mouse and was found to have a G to A point transition at Chromosome 1 position 93,056,245 bp (GRCm38/mm10) predicted to result in the missense mutation R593W. This is the leg dragger 2 Jackson allele (lgdg-2J). A complementation intercross between heterozygotes for each of the two leg dragger alleles produced 3 pups of 36 that had the leg dragger phenotype and one compound heterozygote that only developed a tremor as it aged. While a targeted null allele of Kif1a results in perinatal death, these spontaneous recessive alleles provide models for autosomal recessive spastic paraplegia 30. |
