Abstract
Schizencephaly1 is an extremely rare human congenital disorder characterized by a full-thickness cleft within the cerebral hemispheres. These clefts are lined with grey matter and most commonly involve the parasylvian regions2. Large portions of the cerebral hemispheres may be absent and replaced by cerebro-spinal fluid. We examined eight severely affected patients, and found three who are heterozygous for different mutations in the EMX2 homeobox gene, the human cognate of murine Emx2 (refs 3,4) that is expressed in proliferating neuroblasts of the developing cerebral cortex. One of these mutations is a frameshift in the homeodomain resulting in the alteration of its carboxy terminus, including the entire recognition helix. The other two are 3′ splice site mutations in the first intron, upstream from the homeodomain, and prevent the appropriate splicing of EMX2 transcripts in vitro. All of these are de novo mutations, as they are not present in the patients' parents. The presence of different mutations in cases of severe schizencephaly suggests a requirement of the EMX2 protein for the correct formation of the human cerebral cortex.
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
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Wolpert,, S.M., Barnes, R.D. MRI in Pediatric Neuroradiology. (Mosby Year Book, St. Louis, 1992).
Barkovich, A.J., Chuang, S.H. & Norman, D. MR of neuronal migration anomalies. Am. J. Neuroradiol. 8, 1009–1017 (1987).
Simeone, A. et al. Two vertebrate homeobox genes related to the Drosophila empty spiracles gene are expressed in the embryonic cerebral cortex. EMBO J. 11, 2541–2550 (1992).
Simeone, A., Acampora, p., Gulisano, M., Stornaiuolo, A. & Boncinelli, E. Nested expression domains of four homoeobox genes in the developing rostral brain. Nature 358, 687–690 (1992).
Simeone, A. et al. A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo. EMBO J 12, 2735–2747 (1993).
Barkovich, A.J. & Norman, D. MR imaging of schizencephaly. Am. J. Radiol. 150, 1391–1396 (1988).
Barkovich, A.J. & Kjos, B.C. Schizencephaly: correlation of clinical findings with MR characteristics. AJNR. 13, 85–94 (1992).
McKusick, V. OMIM, Online Mendelian Inheritance in Man. The Johns Hopkins School of Medicine (1995).
Boncinelli, E., Gulisano, M., Spada, F. & Broccoli, V. Emx and Otx gene expression in the developing mouse brain. In: Development of the cerebral cortex. Wiley (ed.), Chichester (Ciba Foundation Symposium 193) 100–116 (1995).
Li, X. et al. Effect on splicing of a silent FGFR2 mutation in Crouzon syndrome. Nature Genet. 9, 232–233 (1995).
Richard, I. & Beckmann, J.S. How neutral are synonymous codon mutations? Nature Genet. 10, 259 (1995).
Tassabehji, M. et al. Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature 355, 635–636 (1992).
Baldwin, C.T., Hoth, C.F., Amos, J.A., da Silva, E.O. & Milunsky, A. An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome. Nature 355, 637–638 (1992).
Tassabehji, M. et al. Mutations in the PAX3 gene causing Waardenburg's syndrome type 1 and type 2. Nature Genet. 3, 26–30 (1993).
Tassabehji, M. et al. PAX3 gene structure and mutations: close analogies between Waardenburg's syndrome and the Splotch mouse. Hum. Molec. Genet. 3, 1069–1074 (1994).
Ton, C.T.T. et al. Positional cloning and characterization of a paired box-and homeobox-containing gene from the aniridia region. Cell 67, 1059–1074 (1991).
Jordan, T. et al. The human PAX6 gene is mutated in two patients with aniridia. Nature Genet. 1, 328–332 (1992).
Glaser, T. et al. PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophtalmia and central nervous system defects. Nature Genet. 9, 358–364 (1995).
Sanyanusin, P. et al. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nature Genet. 9, 358–364 (1995).
Zlotogora, J., Lerer, I., Bar-Dawid, S., Ergaz, Z. & Abeliovich, D. Homozygosity for Waardenburg Syndrome. Am. J. Hum. Genet. 56, 1173–1178 (1995).
Hodgson, S.V. & Saunders, K.E. A probable case of the homozygous condition of the aniridia gene. J. Med. Genet. 17, 478–480 (1980).
Nigro, V. et al. Detection of a nonsense mutation in the dystrophin gene by multiple SSCP. Hum. Molec. Genet. 1, 517–520 (1992).
Welsh, J. & McClelland, M. Fingerprinting genomes using PCR with arbitrary primers. Nucl. Acids Res. 18, 7213–7218 (1990).
Green, S., Issemann, I. & Sheer, E. A versatile in vivo and in vitro eukaryotic expression vector for protein engineering. Nucl. Acids Res. 16, 369 (1988).
Simeone, A. et al. Sequential activation of HOX2 homeobox genes by retinoic acid in human embryonal carcinoma cells. Nature 346, 763–766 (1990).
Erlich, H.A. PCR Technology. Principles and Application for DNA Amplification. (Stockton Press, New York, 1989).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brunelli, S., Faiella, A., Capra, V. et al. Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nat Genet 12, 94–96 (1996). https://doi.org/10.1038/ng0196-94
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0196-94
This article is cited by
-
Schizencephaly revisited
Neuroradiology (2018)
-
Pregnancy management and outcome in patients with four different tetrahydrobiopterin disorders
Journal of Inherited Metabolic Disease (2018)
-
EMX2 gene expression predicts liver metastasis and survival in colorectal cancer
BMC Cancer (2017)
-
Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly
Scientific Reports (2017)
-
Contactin-associated protein-like (CNTNAP) 2 gene mutation in a patient with bilateral schizencephaly
Acta Neurologica Belgica (2017)
