title: A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3.
abstract: Miller-Dieker syndrome (MDS) is a multiple malformation syndrome characterized by classical lissencephaly and a characteristic facies. It is associated with visible or submicroscopic deletions within chromosome band 17p13.3. Lissencephaly without facial dysmorphism has also been observed and is referred to as isolated lissencephaly sequence (ILS). Apparently partial and non-overlapping deletions of the 5' or 3' end of a candidate gene LIS1 in one ILS and one MDS patient had suggested that MDS was a single gene disorder, and that LIS1 spans in excess of 400 kb. However, the originally presumed 5' end of LIS1 was found to belong to the 14-33 epsilon gene residing more distally on 17p13.3. We have now isolated the correct 5' end of LIS1, constructed a approximately 500 kb genomic contig encompassing LIS1, and estimated its gene to be approximately 80 kg. Fluorescence in situ hybridization analysis of an ILS patient with a de novo balanced translocation, as well as analysis of several other key MDS and ILS deletion patients, localizes the lissencephaly critical region within the LIS1 gene. Therefore, LIS1 remains the strongest candidate gene for the lissencephaly phenotype in ILS and MDS. Our analyses also suggest that additional genes distal to LIS1 may be responsible for the facial dysmorphology and other abnormalities seen in MDS but not in ILS patients, supporting our original concept MDS as a contiguous gene deletion syndrome.
authors.affiliation: National Center for Human Genome Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Chong
authors.forename: S D
authors.initials: SD
authors.lastname: Pack
authors.forename: A V
authors.initials: AV
authors.lastname: Roschke
authors.forename: A
authors.initials: A
authors.lastname: Tanigami
authors.forename: R
authors.initials: R
authors.lastname: Carrozzo
authors.forename: A C
authors.initials: AC
authors.lastname: Smith
authors.forename: W B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: D H
authors.initials: DH
authors.lastname: Ledbetter
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000015:Abnormalities, Multiple / Q000235:genetics*; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities*; D002886:Chromosomes, Human, Pair 17; D003360:Cosmids; D018076:DNA, Complementary; D005145:Face / Q000002:abnormalities; D017353:Gene Deletion; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008869:Microtubule-Associated Proteins; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D013577:Syndrome
chemical_list: D018076:DNA, Complementary; D008869:Microtubule-Associated Proteins; D011506:Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human