title: Genomic organization of the murine Miller-Dieker/lissencephaly region: conservation of linkage with the human region.
abstract: Several human syndromes are associated with haploinsufficiency of chromosomal regions secondary to microdeletions. Isolated lissencephaly sequence (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 deletions or translocations at chromosome 17p13.3. Miller-Dieker syndrome (MDS) is associated with larger deletions of 17p13.3 and consists of classical lissencephaly with additional phenotypes including facial abnormalities. We have isolated the murine homologs of three genes located inside and outside the MDS region: Lis1, Mnt/Rox, and 14-3-3 epsilon. These genes are all located on mouse chromosome 11B2, as determined by metaphase FISH, and the relative order and approximate gene distance was determined by interphase FISH analysis. The transcriptional orientation and intergenic distance of Lis1 and Mnt/Rox were ascertained by fragmentation analysis of a mouse yeast artificial chromosome containing both genes. To determine the distance and orientation of 14-3-3 epsilon with respect to Lis1 and Mnt/Rox, we introduced a super-rare cutter 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 this gene was determined by pulsed field gel electrophoresis and Southern blot analysis. Our results demonstrate that the MDS region is conserved between human and mouse. This conservation of linkage suggests that the mouse can be used to model microdeletions that occur in ILS and MDS.
authors.forename: S
authors.initials: S
authors.lastname: Hirotsune
authors.forename: S D
authors.initials: SD
authors.lastname: Pack
authors.forename: S S
authors.initials: SS
authors.lastname: Chong
authors.forename: C M
authors.initials: CM
authors.lastname: Robbins
authors.forename: W J
authors.initials: WJ
authors.lastname: Pavan
authors.forename: D H
authors.initials: DH
authors.lastname: Ledbetter
authors.forename: A
authors.initials: A
authors.lastname: Wynshaw-Boris
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D048948:14-3-3 Proteins; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001921:Brain / Q000002:abnormalities*; D002874:Chromosome Mapping; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D003001:Cloning, Molecular; D017124:Conserved Sequence; D016521:Electrophoresis, Gel, Pulsed-Field; D004706:Endodeoxyribonucleases / Q000235:genetics; D005147:Facial Bones / Q000002:abnormalities; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008869:Microtubule-Associated Proteins; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D011506:Proteins / Q000235:genetics*; D006180:Proton-Translocating ATPases; D011995:Recombination, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D012689:Sequence Homology, Nucleic Acid; D014446:Tyrosine 3-Monooxygenase
chemical_list: D048948:14-3-3 Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C106465:MNT protein, human; D008869:Microtubule-Associated Proteins; C484561:Mnt protein, mouse; D011506:Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014446:Tyrosine 3-Monooxygenase; D004706:Endodeoxyribonucleases; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; C513190:Pafah1b1 protein, mouse; D006180:Proton-Translocating ATPases; C081687:VMA1 protein, S cerevisiae