The genetic dissection of a complex trait involves identifying a group of genes that contribute to the expression of a given phenotype. Our group has initiated a genetic analysis of two common neurologic traits, epilepsy and multiple sclerosis (MS). Defining a collection of genes, each of which is able to influence a complex trait such as epilepsy, will enable the construction of a wall chart of genetic interactions that may provide insights as to the mechanisms underlying normal communication between neurons. Our strategy includes both a candidate gene and a positional cloning approach, and the experimental systems include mouse and man. In order to identify genes that result in or predispose to epilepsy, one of the candidate genes will first be knocked out in transgenic mice. The gene encoding the GABA synthetic enzyme, glutamic acid decarboxylase (GAD), is being targeted for elimination because GABAergic inhibitory mechanisms normally restrict development of firing bursts typical of epileptic seizures. Embryonic stem cells are currently being screened for homologous recombination at the GAD locus. Any transgenic mice that display seizures will be employed to isolate """"""""modifier"""""""" genes that influence this phenotype. This will be carried out by crossing the GAD knock-out onto a number of inbred mouse strains and performing linkage analysis to close in on other genes that affect the epileptic phenotype. The cognate human genes for these loci that contribute to an epileptic phenotype can then be cloned. In a second approach to defining epilepsy genes in man, families with an inherited, defined pattern of seizures are undergoing clinical evaluation in preparation for positional cloning. The focus is on families with Rolandic epilepsy, a type which is inherited as an autosomal dominant with a characteristic wave form of seizures. A candidate gene approach is also underway for MS. The inability to synthesize or maintain the myelin sheath in this demyelinating disorder could arise from defects in any of a number of oligodendrocyte proteins or in cytokines thought to be critical for myelination. The existence of a number of families with a high incidence of MS has allowed us to screen for linkage of the disease trait to the myelin basic protein (MBP) gene, the proteolipid protein (PLP) gene and other candidate genes.
