Epistasis between Pax6 Sey and genetic background reinforces the value of defined hybrid mouse models for therapeutic trials

• Published in: Gene therapy 2018-12, Vol.25 (8), p.524-537
• Main Authors: Hickmott, Jack W, Gunawardane, Uvini, Jensen, Kimberly, Korecki, Andrea J, Simpson, Elizabeth M
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Aniridia; Aniridia - genetics; Aniridia - pathology; Blood glucose; Chimera - genetics; Clinical trials; Cornea; Disease Models, Animal; Embryos; Epistasis; Epistasis, Genetic; Eye; Eye - pathology; Genes; Genetic Therapy - methods; Genetic variability; Genotype; Genotypes; Hyperglycemia; Inbreeding; Loss of Function Mutation; Mice; Mice, Inbred C57BL; Mutation; Pax6 protein; PAX6 Transcription Factor - genetics; PAX6 Transcription Factor - metabolism; Phenotype; Phenotypes; Retina; Rodents; Strains (organisms)
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/s41434-018-0043-6

The small eye (Sey) mouse is a model of PAX6-aniridia syndrome (aniridia). Aniridia, a congenital ocular disorder caused by heterozygous loss-of-function mutations in PAX6, needs new vision saving therapies. However, high phenotypic variability in Sey mice makes development of such therapies challenging. We hypothesize that genetic background is a major source of undesirable variability in Sey mice. Here we performed a systematic quantitative examination of anatomical, histological, and molecular phenotypes on the inbred C57BL/6J, hybrid B6129F1, and inbred 129S1/SvImJ backgrounds. The Sey allele significantly reduced eye weight, corneal thickness, PAX6 mRNA and protein levels, and elevated blood glucose levels. Surprisingly, Pax6 brains had significantly elevated Pax6 transcripts compared to Pax6 embryos. Genetic background significantly influenced 12/24 measurements, with inbred strains introducing severe ocular and blood sugar phenotypes not observed in hybrid mice. Additionally, significant interactions (epistasis) between Pax6 genotype and genetic background were detected in measurements of eye weight, cornea epithelial thickness and cell count, retinal mRNA levels, and blood glucose levels. The number of epistatic interactions was reduced in hybrid mice. In conclusion, severe phenotypes in the unnatural inbred strains reinforce the value of more naturalistic F1 hybrid mice for the development of therapies for aniridia and other disorders.