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The proposed program project (PP) will examine the basis of neuronal migration in the forebrain. The focal point of the PP will be the study of the molecular basis of classical lissencephaly and subcortical band heterotopia, which are now recognized to constitute a spectrum of brain malformations whose fundamental morphologic phenotype reflects disordered migration of cortical neurons. Recent data, derived from the laboratories of the PP investigators, have defined two specific molecular defects as the basis for these distinct malformations (LIS1 on chromosome 17p13.3 and XLIS/DBCN on Xq22.3-q23). The clinical consequences can be very substantial -- intractable epilepsy and severe mental retardation. The proposed PP, which emanates from the close collaborative efforts of the PP investigators over the past 10-15 years, consists of four individual projects and three Cores. Projects 1 and 2 deal mainly with LIS1 and Projects 3 and 4 mainly with XLIS/DBCN. Cores A and B are developed to provide the clinical and diagnostic services for Projects 1,3, and 4. Core C will provide transgenic animals for Projects 2, 3, and 4.
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