GENOMIC ORGANIZATION OF THE MURINE MILLER-DIEKER LISSENCEPHALY REGION- CONSERVATION OF LINKAGE WITH THE HUMAN REGION/

Several human syndromes are associated with haploinsufficiency of chro mosomal regions secondary to microdeletions. Isolated lissencephaly se quence (ILS), a human developmental disease characterized by a smooth cerebral surface (classical lissencephaly) and microscopic evidence of incomplete neuronal migration, is often associated with small deletio ns or translocations at chromosome 17p13.3. Miller-Dieker syndrome (MD S) is associated with larger deletions of 17p13.3 and consists of clas sical lissencephaly with additional phenotypes including facial abnorm alities. We have isolated the murine homologs of three genes located i nside and outside the MDS region: Lis1, Mnt/Rox, and 14-3-3 epsilon. T hese genes are all located on mouse chromosome 11B2, as determined by metaphase FISH, and the relative order and approximate gene distance w as determined by interphase FISH analysis. The transcriptional orienta tion and intergenic distance of Lis1 and Mnt/Rox were ascertained by F ragmentation analysis of a mouse yeast artificial chromosome containin g both genes. To determine the distance and orientation of 14-3-3 epsi lon with respect to Lis1 and Mnt/Rox, we introduced a super-rare cutte r site (VDE) that is unique in the mouse genome into 14-3-3 epsilon by gene targeting. Using the introduced VDE site, the orientation of thi s gene was determined by pulsed field gel electrophoresis and Southern blot analysis. Our results demonstrate that the MDS region is conserv ed between human and mouse. This conservation of linkage suggests that the mouse can be used to model microdeletions that occur in ILS and M DS.