Autosomal recessive lissencephaly with cerebellar hypoplasia is associatedwith human RELN mutations

Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephal y ("smooth brain." from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is i mpaired, leading to a thickened cerebral cortex whose normally folded conto ur is simplified and smooth. Two identified lissencephaly genes(1-3) do not account for all known cases(4), and additional lissencephaly syndromes hav e been described(5). An autosomal recessive form of lissencephaly (LCH) ass ociated with severe abnormalities of the cerebellum, hippocampus and brains tem maps to chromosome 7q22, and is associated with two independent mutatio ns 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 Rein mutations c ause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration a nd abnormal axonal connectivity(6,7). RELN encodes a large (388 kD) secrete d proteins that acts on migrating cortical neurons by binding to the very l ow density lipoprotein receptor (VLDLR), the apolipoprotein E receptor 2 (A poER2; refs 9-11), alpha 3 beta 1 integrin(12) and protocadherins(13). Alth ough reelin was previously thought to function exclusively in brain, some h umans with RELN mutations show abnormal neuromuscular connectivity and cong enital lymphoedema, suggesting previously unsuspected functions for reelin in and outside of the brain.