Nature Genetics
26, 93 - 96 (2000)
doi:10.1038/79246
Autosomal recessive lissencephaly with cerebellar hypoplasia is associated
with human RELN mutationsSusan E. Hong1, Yin Yao Shugart2, David T. Huang1, Saad Al Shahwan3, P. Ellen Grant4, Jonathan O'B. Hourihane5, Neil D.T. Martin5
& Christopher A. Walsh11
Division of Neurogenetics, Department of Neurology,
Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine,
Boston, Massachusetts, USA. 2
Center for Inherited Disease Research, Johns Hopkins
University, Bayview Campus, Baltimore,
Maryland, USA. 3
Departments of Pediatrics and Neuroscience, Riyadh
Armed Forces Hospital, Riyadh, Saudi Arabia. 4
Neuroradiology Service, Department of Radiology, Massachusetts
General Hospital, Boston, Massachusetts, USA
. 5
Department of Pediatrics, Kent and Canterbury Hospital
, Canterbury, Kent, UK.
Correspondence should be addressed to Christopher A. Walsh cwalsh@caregroup.harvard.eduNormal 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 9−11
),  3 1 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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