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

A Correction to this article was published on 01 February 2001

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 genes1,2,3 do not account for all known cases4, and additional lissencephaly syndromes have been described5. 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 (Relnrl), in which Reln mutations cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration and abnormal axonal connectivity6,7. RELN encodes a large (388 kD) secreted protein8 that acts on migrating cortical neurons by binding to the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor 2 (ApoER2; refs 911), α3β1 integrin12 and protocadherins13. 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.

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Figure 1: Pedigree, microsatellite and multipoint linkage analysis of LCH.
Figure 2: MRI analysis of chromosome 7q22-linked lissencephaly with cerebellar hypoplasia (LCH).
Figure 3: Mutational analysis of RELN in LCH.
Figure 4: Western-blot analysis shows loss of reelin from the serum of LCH patients.
Figure 5: Effects of human and naturally occurring mouse RELN mutations on the predicted protein.

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Acknowledgements

We thank the families for participation; other clinicians, especially W.B. Dobyns, for samples of other lissencephaly patients not analysed here; W.B. Dobyns and A.J. Barkovich for discussions about the phenotype and nomenclature for LCH; A. Raina for technical assistance; other members of the Walsh lab for support; A. Goffinet for anti-reelin antibodies; E.D. Green for human RELN cDNA probes; and E. Engle for DNA from normal Saudi Arabian subjects. This work was supported by NIH grants RO1 NS38097, RO1 NS35129 and PO1 NS39404 to C.A.W., and by the National Alliance for Autism Research and the National Alliance for Research in Schizophrenia and Depression.

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Correspondence to Christopher A. Walsh.

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Hong, S., Shugart, Y., Huang, D. et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 26, 93–96 (2000). https://doi.org/10.1038/79246

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