Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations (original) (raw)

Nature Genetics volume 26, pages 93–96 (2000)Cite this article

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 (Reln rl), 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), 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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Reiner, O. et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein β-subunit-like repeats. Nature 364, 717–721 (1993).
    Article CAS Google Scholar
  2. Gleeson, J.G. et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein . Cell 92, 63–72 (1998).
    Article CAS Google Scholar
  3. des Portes, V. et al. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 92, 51–61 ( 1998).
    Article CAS Google Scholar
  4. Pilz, D.T. et al. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum. Mol. Genet. 7, 2029–2037 (1998).
    Article CAS Google Scholar
  5. Walsh, C.A. Genetic malformations of the human cerebral cortex. Neuron 23, 19–29 (1999).
    Article CAS Google Scholar
  6. Caviness, V.S. & Rakic, P. Mechanisms of cortical development: a view from mutations in mice. Annu. Rev. Neurosci. 1, 297–326 (1978).
    Article Google Scholar
  7. Lambert de Rouvroit, C. & Goffinet, A.M. The reeler mouse as a model of brain development. Adv. Anat. Embryol. Cell Biol. 150, 1–106 ( 1998).
    Article CAS Google Scholar
  8. D'Arcangelo, G. et al. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374, 719–723 (1995).
    Article CAS Google Scholar
  9. D'Arcangelo, G. et al. Reelin is a ligand for lipoprotein receptors. Neuron 24, 471–479 ( 1999).
    Article CAS Google Scholar
  10. Hiesberger, T. et al. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation . Neuron 24, 481–489 (1999).
    CAS Google Scholar
  11. Trommsdorff, M. et al. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97, 689–701 (1999).
    CAS Google Scholar
  12. Dulabon, L. et al. Reelin binds α3β1 integrin and inhibits neuronal migration. Neuron 27, 33– 44 (2000).
    Article CAS Google Scholar
  13. Senzaki, K., Ogawa, M. & Yagi, T. Proteins of the CNR family are multiple receptors for Reelin. Cell 99, 635–647 ( 1999).
    Article CAS Google Scholar
  14. Hourihane, J.O., Bennett, C.P., Chaudhuri, R., Robb, S.A. & Martin, N.D.T. A sibship with a neuronal migration defect, cerebellar hypoplasia and congenital lymphedema. Neuropediatrics 24, 43–46 ( 1993).
    Article CAS Google Scholar
  15. DeSilva, U. et al. The human reelin gene: isolation, sequencing, and mapping on chromosome 7. Genome Res. 7, 157– 164 (1997).
    Article CAS Google Scholar
  16. Lambert de Rouvroit, C. & Goffinet, A.M. Cloning of human DAB1 and mapping to chromosome 1p31–p32. Genomics 53, 246–247 (1998).
    Article CAS Google Scholar
  17. Gonzalez, J.L. et al. Birthdate and cell marker analysis of scrambler: a novel mutation affecting cortical development with a reeler-like phenotype. J. Neurosci. 17, 9204–9211 (1997).
    Article CAS Google Scholar
  18. Royaux, I., Lambert de Rouvroit, C., D'Arcangelo, G., Demirov, D. & Goffinet, A.M. Genomic organization of the mouse reelin gene. Genomics 46, 240 –250 (1997).
    Article CAS Google Scholar
  19. Lambert de Rouvroit, C., Bernier, B., Royaux, I., de Bergeyck, V. & Goffinet, A.M. Evolutionarily conserved, alternative splicing of reelin during brain development. Exp. Neurol. 156, 229–238 (1999).
    Article CAS Google Scholar
  20. Shapiro, M.B. & Senapathy, P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 15, 7155–7174 (1987).
    Article CAS Google Scholar
  21. Smalheiser, N.R. et al. Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells. Proc. Natl Acad. Sci. USA 97, 1281–1286 ( 2000).
    Article CAS Google Scholar
  22. D'Arcangelo, G. et al. Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. J. Neurosci. 17, 23 –31 (1997).
    Article CAS Google Scholar
  23. de Bergeyck, V. et al. A truncated Reelin protein is produced but not secreted in the ‘Orleans’ reeler mutation (Reln[rl-Orl]). Brain Res. Mol. Brain Res. 50, 85–90 (1997).
    Article CAS Google Scholar
  24. Royaux, I., Bernier, B., Montgomery, J.C., Flaherty, L. & Goffinet, A.M. Reln(rl-Alb2), an allele of reeler isolated from a chlorambucil screen, is due to an IAP insertion with exon skipping. Genomics 42, 479– 482 (1997).
    Article CAS Google Scholar
  25. Takahara, T. et al. Dysfunction of the orleans reeler gene arising from exon skipping due to transposition of a full-length copy of an active L1 sequence into the skipped exon. Hum. Mol. Genet. 5, 989– 993 (1996).
    Article CAS Google Scholar
  26. Hirotsune, S. et al. The reeler gene encodes a protein with an EGF-like motif expressed by pioneer neurons. Nature Genet. 10, 77 –83 (1995).
    Article CAS Google Scholar
  27. Impagnatiello, F. et al. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc. Natl Acad. Sci. USA 95, 15718–15723 (1998).
    Article CAS Google Scholar
  28. NIH/CEPH Collaborative Mapping Group A comprehensive genetic linkage map of the human genome. Science 258 , 67–86 (1992).

Download references

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.

Author information

Authors and Affiliations

  1. Division of Neurogenetics, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts, USA
    Susan E. Hong, David T. Huang & Christopher A. Walsh
  2. Center for Inherited Disease Research, Johns Hopkins University, Bayview Campus, Baltimore, Maryland, USA
    Yin Yao Shugart
  3. Departments of Pediatrics and Neuroscience, Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia
    Saad Al Shahwan
  4. Department of Radiology, Neuroradiology Service, Massachusetts General Hospital, Boston, Massachusetts, USA
    P. Ellen Grant
  5. Department of Pediatrics, Kent and Canterbury Hospital, Canterbury, Kent, UK
    Jonathan O'B. Hourihane & Neil D.T. Martin

Authors

  1. Susan E. Hong
    You can also search for this author inPubMed Google Scholar
  2. Yin Yao Shugart
    You can also search for this author inPubMed Google Scholar
  3. David T. Huang
    You can also search for this author inPubMed Google Scholar
  4. Saad Al Shahwan
    You can also search for this author inPubMed Google Scholar
  5. P. Ellen Grant
    You can also search for this author inPubMed Google Scholar
  6. Jonathan O'B. Hourihane
    You can also search for this author inPubMed Google Scholar
  7. Neil D.T. Martin
    You can also search for this author inPubMed Google Scholar
  8. Christopher A. Walsh
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toChristopher A. Walsh.

Rights and permissions

About this article

Cite this article

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

Download citation