Neurodevelopmental Defects In Spinocerebellar Ataxia Type 13 Linked To The EGF-R Signaling Pathway (P2.034)

OBJECTIVE: To understand the neurodevelopmental effects of the p.Arg423His mutation in the Kv3.3 voltage gated K+ channel involved in spinocerebellar ataxia 13 (SCA13). BACKGROUND: SCA13 is a neurological disorder caused by a repertoire of mutations in the Kv3.3 voltage gated K+ channel. The p.Arg423His allelic form is known to cause early onset disease characterized by locomotor delay and cognitive impairment. Genetic tools with the Drosophila model have revealed insights regarding mechanism of action and discovery of developmental or degenerative pathologies. METHODS: Transgenic flies expressing human wild-type (WT) and p.Arg423His channels were created and photoneuronal morphology of larval eye discs was examined. Restricting expression of WT and p.Arg423His to the eyes and the wings, the resulting phenotypes were documented. Effects of co-expressing p.Arg423His and EGF-R in the eyes were also assessed. RESULTS: The p.Arg423His mutant larval eye discs demonstrated abnormal gaps and fusions in contrast to the normal morphology of photoneurons in the WT discs. Adult eyes of the p.Arg423His mutants had a phenotype with smaller, maldeveloped eyes and fused ommatidia also contrasting the fully developed WT eyes. The co-expression of p.Arg423His and EGF-R exhibited a partial rescue of the phenotype with the shape and size of the eyes similar to the controls. Expression of p.Arg423His in the wings led to abnormal patterning and vein formation. CONCLUSIONS: Our results indicate maldevelopment in Drosophila eyes and wings due to expression of p.Arg423His, with suggested involvement of the EGF-R signaling pathway. Further studies will determine rescues of the mutant phenotype investigating additional components of the EGF-R pathway along with the underlying biochemical effects. Disclosure: Dr. Khare has nothing to disclose. Dr. Salmasinia has nothing to disclose. Dr. Arbelaez has nothing to disclose. Dr. Nick has nothing to disclose. Dr. Rincon-Limas has nothing to disclose. Dr. Nick has nothing to disclose. Dr. Fernandez-Funez has nothing to disclose. Dr. Waters has nothing to disclose.