| First Author | Harris BS | Year | 2015 |
| Journal | MGI Direct Data Submission | Mgi Jnum | J:223790 |
| Mgi Id | MGI:5660352 | Citation | Harris BS, et al. (2015) Lilting walker, a spontaneous mutation that causes ataxia. MGI Direct Data Submission |
| abstractText | A recessive spontaneous mutation causing an extreme leaning gait was identified by Becky Durgin in the C57BL/6J colony at The Jackson Laboratory. Homozygotes have difficulty righting themselves as early as 12 days of age. Adults exhibit a pronounced leaning gait in which they briefly walk upright, then tilt their head and then their body, firmly over to one side before righting themselves and leaning severely to the other side. While this phenotype suggests a cerebellar defect, H&E staining of serial sections of the cerebellum from one 21-week-old female did not reveal any abnormalities. We have named this mutation lilting walker (lltw). Standard pathology of one homozygous female at 4 weeks of age revealed deficient peripheral myelin, however assessment of two homozygous females at 12 weeks of age revealed no abnormalities other than mild otitis in one ear of one mutant and one ear of one heterozygous control. No abnormalities were found in the heart or blood vessels. Ophthalmoscopy of two male homozygotes at approximately 12 weeks of age and ABR assessment of two homozygotes at approximately 8 weeks of age did not reveal abnormal vision or hearing. The lltw mutation is recessive and the phenotype shows the expected Mendelian ratio for a recessive mutation while maintained on a C57BL/6J background. When lilting walker (lltw) was outcrossed to C3H/HeSnJ for genetic mapping, only 11 (7%; n=157) of the F2 progeny were affected, significantly less than the expected 25%. These results suggest embryonic lethality or the presence of modifying alleles inherited from the C3H/HeSnJ causing reduced penetrance on the mixed B6;C3H background. Using the 11 affected F2 animals from the C3H mapping cross, lltw was mapped to a genetic interval on Chromosome 11 flanked by rs3705233 at 63,615,690 bp and rs3663879 at 82,863,758 bp. Exome sequencing and whole genome sequencing were used to identify lltw candidate mutations. Two variants were found. The first, an A to T transversion at Chromosome 11 position 61,493,802 bp, is predicted to result in the missense mutation V26D in Mapk7; and, the second, a C to T transition at Chromosome 11 position 69,556,152 bp, is predicted to result in the missense mutation G244E in Efnb3. Preliminary genotyping of a small number of samples from the colony revealed that these mutations were potentially linked to the phenotype. To further investigate, a subset of DNA samples from the mapping cross were genotyped for the Mapk7 and Efnb3 variants. Although Mapk7 was concordant with the marker defining the proximal end of the critical interval, it was discordant with lltw itself and was eliminated from consideration as the causative variant. In contrast, Efnb3 was entirely concordant with lltw. Thus, our data are consistent with the lltw phenotype being caused by the G244E point mutation in Efnb3. |
