Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly

Schizencephaly 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 regions. 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.