Abstracts

Rationale: Jeavons syndrome (JS) is an uncommon form of epilepsy that affects children of around 6 to 8 years old. JS patients display three main characteristics: eyelid myoclonia with or without absences, eye closure-induced seizures and sensitivity to light. In some families of patients with absence epilepsy and eyelid myoclonia, including JS, mutations have been observed in the gene encoding for importin-8 (IPO8) a member of karyopherin superfamily of proteins. Karyopherin are known to regulate nucleo-cytoplasmic transport of many proteins critical for cell physiology: division, differentiation, migration and adaptation to external environment. IPO8, a member of the β-karyopherin sub-family, is reported to control the transport Ago-2, c-Jun and Smad-4 for example, three proteins important for brain development. IPO8 could be at the origin of JS via its role in the transport of these proteins. Methods: In Situ Hybridization (ISH) at various embryonic (E12, E14, E18) and post-natal ages (P5, P60) were performed using dig-labeled riboprobes. In Utero Electroporation (IUE) of plasmids (either expressing an shRNA against mIPO8 or a pathological mutant form of hIPO8) was performed in the brain of E14 embryos and neuroblast migration was analyzed three days later by immunocytochemistry using an anti-EGFP antibody. Results: Using ISH, mIPO8 mRNA was observed in brains of various ages and with different levels. At E14, mRNA is expressed in the sub-ventricular/ventricular zone (SVZ/VZ), the cortical plate (CP) and the ganglionic eminences. Using two different shRNA directed against mIPO8, we observed that neuroblasts accumulated in the IZ and did not reach the CP in contrast to the control condition. This effect can be corrected by the co-expression of a form of IPO8 that is resistant to the shRNA, demonstrating the specificity of the effect. When overexpressing the pathological forms of hIPO8, but not a variant, radial migration of neuroblasts was also impaired as they accumulate in the SVZ/VZ. Conclusions: IPO8 is expressed in mouse brain during both embryogenesis and postnatal ages. Both IPO8 shRNA and IPO8 pathological forms affect neuroblasts migration in the developing brain. So, abnormal brain development due to IPO8 mutations could be at the origin of Jeavons Syndrome. Funding: FNRS, Belgium ; FRIA, Belgium; University of Liège.