| First Author | Harris BS | Year | 2016 |
| Journal | MGI Direct Data Submission | Mgi Jnum | J:235637 |
| Mgi Id | MGI:5796923 | Citation | Harris BS, et al. (2016) A Viable Mouse Model of Hyperekplexia 3. MGI Direct Data Submission |
| abstractText | The recessive mutation tremor with stiff legged walk (trsl) presents in homozygotes by three weeks of age when homozygotes are discernably smaller and display tonic seizures of varying intensities when the cage lid is lifted or the mice are touched. Some seizures are severe enough that the mouse lies prone on its side with stiffened limbs and a whole body tremor, while other seizures are more subtle. After a seizure, homozygotes often walk with a stiffened gait. The majority of homozygotes die prematurely at approximately three to five weeks of age, with the greatest mortality occurring at three weeks of age, but some homozygotes survive into adulthood and even breed. The phenotype of the surviving adults is less severe than what is found pre-wean, with adults more prone to display a stiffened gait and not the seizures that leave them prone on their side. Rare homozygotes have survived over 1 year of age, the oldest living to nineteen months. Although both female and male homozygotes can breed, the majority of homozygous females fail to do so. The percentage of mutants obtained is slightly less than that predicted by Mendelian inheritance. Most homozygotes develop malocclusion and require tooth trimming. The trsl mutation was identified in a coisogenic subline of C57BL/6J having a short-nosed craniofacial mutation, which appears to have been bred out of the trsl subline before phenotypic assessment. A mapping cross to CAST/EiJ found no recombinants with D7Mit272, D7Mit69, D7Mit29, or D7Mit230 among 21 homozygotes and only 1 recombinant with D7Mit145, D7Mit82, D7Mit232, D7Mit83, or D7Mit229, placing this mutation on Chromosome 7 between positions 45,686,980 bp and 51,403,277 bp (GRCm38/mm10). Exome sequencing identified a single nucleotide (from G to A) variant in Slc6a5 on Chromosome 7: position 49,917,609 (GRCm38/mm10). This is predicted to result in the codon change of atG to atA and the subsequent amino acid change of methionine to isoleucine in a transmembrane domain (M278I in NP_001139485.1 and M2701I in NP_683733.2). In humans, mutation in SLC6A5 causes hyperekplexia 3, consistent with the phenotype presented by trsl homozygotes. Other published mouse alleles of Slc6a5 cause complete lethality by either 2 weeks of age or before wean. Thus, this single nucleotide point substitution may provide a viable model for recessive hyperekplexia 3. |
