Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations

Susan E. Hong, Yin Yao Shugart, David T. Huang, Saad Al Shahwan, P. Ellen Grant, Jonathan O B Hourihane, Neil D T Martin, Christopher A. Walsh

Research output: Contribution to journalArticlepeer-review

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), α3β1 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.

Original languageEnglish (US)
Pages (from-to)93-96
Number of pages4
JournalNature Genetics
Volume26
Issue number1
DOIs
StatePublished - Sep 2000

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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