• DOI:10.3233/JND-160197
• Corpus ID: 5500331

Postnatal Development of Spasticity Following Transgene Insertion in the Mouse βIV Spectrin Gene (SPTBN4).

@article{Kichkin2017PostnatalDO,
  title={Postnatal Development of Spasticity Following Transgene Insertion in the Mouse $\beta$IV Spectrin Gene (SPTBN4).},
  author={Eva Kichkin and Archunan Visvanathan and Frank J. Lovicu and Daisy Y. Shu and Shannon J. Das and Stephen W Reddel and Emily P. McCann and Katharine Y. Zhang and Kelly L. Williams and Ian P. Blair and William D Phillips},
  journal={Journal of neuromuscular diseases},
  year={2017},
  volume={4 2},
  pages={
          159-164
        }
}

• Eva Kichkin, Archunan Visvanathan, +8 authors W. Phillips
• Published 2017
• Biology
• Journal of neuromuscular diseases

BACKGROUND
The L25 mouse line was generated by random genomic insertion of a lens-specific transgene. Inbreeding of L25 hemizygotes revealed an unanticipated spastic phenotype in the hind limbs.

OBJECTIVE
The goals were to characterize the motor phenotype in the L25 mice and to map the transgene insert site within the mouse genome.

METHODS
Six pairs of L25+/- mice were repeatedly mated. Beginning at weaning, all progeny were inspected for body weight and motor signs twice weekly until they displayed predefined ethical criteria for termination. The transgene insert site was determined by whole genome sequencing. Western blotting was used to compare the expression levels of beta-IV spectrin protein in the brain.

RESULTS
Matings of hemizygous L25+/- × L25+/- mice yielded 20% (29/148) affected weanlings, identified by an abnormal retraction of the hind limbs when lifted by the tail, and a fine tremor. Affected mice were less mobile and grew more slowly than wild-type littermates. All affected mice required termination due to >15% loss of body weight (50% survival age 92 days). At the endpoint, mice showed varying degrees of spastic paresis or spastic paralysis localised to the hind limbs. Motor endplates remained fully innervated. Genome sequencing confirmed that the transgene was inserted in the locus of βIV spectrin of L25 mice. Western blotting indicated that this random insertion had greatly reduced the expression of βIV spectrin protein in the affected L25 mice.

CONCLUSIONS
The results confirm the importance of βIV spectrin for maintaining central motor pathway control of the hind limbs, and provide a developmental time course for the phenotype.