title: Increased LIS1 expression affects human and mouse brain development.
abstract: Deletions of the PAFAH1B1 gene (encoding LIS1) in 17p13.3 result in isolated lissencephaly sequence, and extended deletions including the YWHAE gene (encoding 14-3-3epsilon) cause Miller-Dieker syndrome. We identified seven unrelated individuals with submicroscopic duplication in 17p13.3 involving the PAFAH1B1 and/or YWHAE genes, and using a 'reverse genomics' approach, characterized the clinical consequences of these duplications. Increased PAFAH1B1 dosage causes mild brain structural abnormalities, moderate to severe developmental delay and failure to thrive. Duplication of YWHAE and surrounding genes increases the risk for macrosomia, mild developmental delay and pervasive developmental disorder, and results in shared facial dysmorphologies. Transgenic mice conditionally overexpressing LIS1 in the developing brain showed a decrease in brain size, an increase in apoptotic cells and a distorted cellular organization in the ventricular zone, including reduced cellular polarity but preserved cortical cell layer identity. Collectively, our results show that an increase in LIS1 expression in the developing brain results in brain abnormalities in mice and humans.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.forename: Tamar
authors.initials: T
authors.lastname: Sapir
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Shchelochkov
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Marjorie A
authors.initials: MA
authors.lastname: Withers
authors.forename: Jill V
authors.initials: JV
authors.lastname: Hunter
authors.forename: Talia
authors.initials: T
authors.lastname: Levy
authors.forename: Vera
authors.initials: V
authors.lastname: Shinder
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Peiffer
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Gunderson
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Nezarati
authors.forename: Vern Ann
authors.initials: VA
authors.lastname: Shotts
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Amato
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Savage
authors.forename: David J
authors.initials: DJ
authors.lastname: Harris
authors.forename: Debra-Lynn
authors.initials: DL
authors.lastname: Day-Salvatore
authors.forename: Michele
authors.initials: M
authors.lastname: Horner
authors.forename: Xin-Yan
authors.initials: XY
authors.lastname: Lu
authors.forename: Trilochan
authors.initials: T
authors.lastname: Sahoo
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.forename: Salvador
authors.initials: S
authors.lastname: Martinez
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Orly
authors.initials: O
authors.lastname: Reiner
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000196:embryology* / Q000254:growth & development; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002886:Chromosomes, Human, Pair 17; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics; D004622:Embryo, Mammalian; D005260:Female; D020440:Gene Duplication; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D010375:Pedigree; D015854:Up-Regulation / Q000502:physiology
chemical_list: D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human