Parkinson, Nicholas James; (1998) Genetic and physical mapping of the murine epilepsy locus lethargic (lh) and investigation of voltage-dependent calcium channel beta subunits in human absence seizure predisposition. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Lethargic (lh) is one of six spontaneously occurring single-locus spike-wave epilepsy mutants known in the mouse. It is an autosomal recessive disorder characterised by ataxia and frequent absence seizures. It was anticipated that identification of the lh gene would provide an insight into the mechanisms underlying seizure generation in the mammalian brain and also allows the role of homologous human genes to be investigated in inherited epilepsy. A genetic map with a theoretical resolution of 0.1cM was constructed using a panel of over 1000 informative meioses taken from separate M.m.castaneus x M.m.domesticus B6C3HF1-lh/lh N2 and F2 crosses. A critical region spanning 1.98cM of chromosome 2 was determined and a physical mapping strategy initiated using markers defining the flanks. Chromosome walking techniques developed two contigs containing 52 YAC clones estimated to cover a physical distance greater than 5.0Mb. The elucidation of the lh mutation (Burgess et al., 1997) as a null allele of the gene encoding the voltage-dependant calcium channel β4 subunit, Cacnb4, suggests a potential role for this and related subunit genes in human epilepsy. A linkage based analysis was undertaken in a resource of families displaying childhood absence epilepsy. Polymorphic markers were selected to provide haplotypes encompassing the cytogenetic regions to which both the human CACNB2 and CACNB4 genes had been mapped. No evidence for involvement of either gene in this phenotype was found. A genomic structure analysis was initiated for CACNB2 to allow direct mutation analysis to be performed on patients exhibiting a much broader range of absence seizure phenotypes in which the mode of inheritance is complex or unclear. Mutational analysis was also performed on CACNB4 subunit mRNA isolated from a group of patients displaying the combined phenotype of absence seizures and ataxia similar to that displayed by the lethargic mouse.

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