Kinton, Lucy; (2003) The role of genetic factors in neuronal migration disorders and epilepsy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis studies two aspects of epilepsy genetics. Firstly a Brazilian family with a novel idiopathic autosomal dominant partial epilepsy, Partial Epilepsy with Peri-central Spikes (PEPS) is studied. It is differentiated clinically, electrophysiologically and genetically from previously described idiopathic partial epilepsy syndromes. A genome screen on members of the family was then performed to map the condition. Although PEPS epilepsy within the family appears inherited in an autosomal dominant manner, there are several consanguinity loops within the family which reduces the power of the family for linkage analysis. In order to map the condition, several models of linkage analysis were analysed together with construction of overlapping haplotypes for each chromosome followed up with a multipoint analysis over the areas unexcluded by this method. Analysis of further markers and typing of two unaffected individuals in these regions excluded all areas except 4p16-15. A multipoint LOD score of 3.3 was obtained at D4S2311. Examination of the genes within the region has identified several possible candidates for PEPS. Secondly, the role of genes involved in neuronal migration has been studied in a model system, the zebrafish. Mutations in two genes, LIS1 and DCX, have been found in patients with lissencephaly, a neuronal migration disorder which causes intractable epilepsy. The zebrafish orthologues of LIS1 and a gene closely related to DCX, DCLK, were cloned and the expression patterns during embryogenesis described. The technique of morpholino oligonucleotide injection to create targeted gene knock-down was used for both these genes. Whereas dclk knock-down gave no discernible phenotype, knockdown of lis1 expression in the zebrafish resulted in a disturbance of neuronal organisation, failure of neuronal migration increased cell death and cranio-facial abnormalities, providing a model system for the study of the action of this gene.

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