MOLECULAR ANALYSIS OF HUMAN CHROMOSOME 17

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Miller-Dieker syndrome (MDS) is s contiguous gene syndrome comprised of a severe neuronal migration disorder producing type I lissencephaly (smooth brain, argyria), characteristic dysmorphic features, and other congenital abnormalities. It is caused by a cytogenetic microdeletion in about half of cases, while the other half have recently been shown by us to have submicroscopic deletions detected by anonymous DNA probes. MDS thus offers a model system for the reverse genetics cloning of genes involved in the pathogenesis of a complex disease phenotype, and a more basic understanding of mechanisms of cytogenetic disorders and normal corticogenesis. Specific goals of the project include: 1) improved diagnostic ability in MDS by identification of new DNA probes in the critical region, additional RFLPs, and development of rapid RFLP analysis by the polymerase chain reaction (PCR). We will also determine whether patients with isolated lissencephaly syndrome (ILS), without the dysmorphic features of MDS, also have deletions or other alterations of a locus on 17p. 2) Study of mechanisms of chromosome rearrangement by determination of parental origin of rearrangements, pulsed-field detection of deletion and translocation breakpoints, followed by strategies to clone and sequence the breakpoint junctions. 3) Search for candidate genes by identification of evolutionarily conserved sequences and HTF islands, followed by search for RNA transcripts and identification of corresponding cDNA clones. 4) Contribute to human genome project and comparative mapping in man and mouse. A high- resolution regional mapping panel for 17p is being developed by addition of new patient breakpoints isolated in somatic cell hybrids, a long-range restriction map is being developed by pulsed- field gel analysis, and mapping in the mouse is being conducted by somatic cell hybrid techniques and by analysis of interspecific backcrosses between mus spretus and mus domesticus. We will determine whether MDS probes map close to known mouse neurological mutations, which may provide an animal model for MDS.