title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.
abstract: Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. Two identified lissencephaly genes do not account for all known cases, and additional lissencephaly syndromes have been described. An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin (RELN). The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein. LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration and abnormal axonal connectivity. RELN encodes a large (388 kD) secreted protein that acts on migrating cortical neurons by binding to the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor 2 (ApoER2; refs 9-11 ), alpha3beta1 integrin and protocadherins. Although reelin was previously thought to function exclusively in brain, some humans with RELN mutations show abnormal neuromuscular connectivity and congenital lymphoedema, suggesting previously unsuspected functions for reelin in and outside of the brain.
authors.affiliation: Division of Neurogenetics, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Hong
authors.forename: Y Y
authors.initials: YY
authors.lastname: Shugart
authors.forename: D T
authors.initials: DT
authors.lastname: Huang
authors.forename: S A
authors.initials: SA
authors.lastname: Shahwan
authors.forename: P E
authors.initials: PE
authors.lastname: Grant
authors.forename: J O
authors.initials: JO
authors.lastname: Hourihane
authors.forename: N D
authors.initials: ND
authors.lastname: Martin
authors.forename: C A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001933:Brain Stem / Q000002:abnormalities* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D002531:Cerebellum / Q000002:abnormalities* / Q000473:pathology; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D018076:DNA, Complementary / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive / Q000235:genetics*; D008040:Genetic Linkage; D006624:Hippocampus / Q000002:abnormalities* / Q000473:pathology; D006801:Humans; D008126:Lod Score; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018895:Microsatellite Repeats; D008957:Models, Genetic; D009154:Mutation; D009419:Nerve Tissue Proteins; D010375:Pedigree; D010641:Phenotype; D012326:RNA Splicing; D000091042:Reelin Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D018076:DNA, Complementary; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases