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Human Molecular Genetics Advance Access published online on March 16, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl064
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 23, 2005
Revised March 10, 2006
Accepted March 10, 2006

Article

Mutations in SOX2 Cause Anophthalmia-Esophageal-Genital (AEG) Syndrome

Kathleen A. Williamson 1, Ann M. Hever 1, Joe Rainger 1, R. Curtis Rogers 2, Alex Magee 3, Zdenek Fiedler 4, Wee Teik Keng 1, Freddie H. Sharkey 1, Niolette McGill 1, Clare J. Hill 5, Adele Schneider 6, Mario Messina 7, Peter D. Turnpenny 8, Judy A. Fantes 1, Veronica van Heyningen 1, and David R. FitzPatrick 1 *

1 Medical Genetics Section, MRC Human Genetics Unit, Western General Hospital, Edinburgh, EH4 2XU, UK
2 Greenwood Genetic Center, 1 Gregor Mendel Circle, Greenwood, South Carolina 29646, USA
3 Regional Genetics Service A Floor, Belfast City Hospital, Lisburn Road, Belfast. BT9 7AB UK
4 Department of Biological and Biochemical Sciences, University Pardubice, Czech Republic
5 Institute of Medical Genetics, University Hospital of Wales, Cardiff, CF14 4XW, UK
6 Department of Clinical Genetics, Albert Einstein Medical Center, Philadelphia USA
7 Section of Pediatric Surgery, Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Italy
8 Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK

* To whom correspondence should be addressed.
David R. FitzPatrick, E-mail: david.fitzpatrick{at}hgu.mrc.ac.uk


  Abstract
We report heterozygous, loss-of-function SOX2 mutations in three unrelated individuals with Anophthalmia-Esophageal-Genital (AEG) syndrome. One previously reported case (Rogers, 1988) has a 2.7 Mb deletion encompassing SOX2 and associated with a cryptic translocation t(3;7)(q28;p21.3). The deletion and translocation breakpoints on chromosome 3q are > 8.6 Mb apart and both chromosome rearrangements have occurred de novo. Another published case (Petrackova et al. 2004) has a de novo nonsense mutation, Q55X. A previously unreported case with severe bilateral microphthalmia and oesophageal atresia has a de novo missense mutation, R74P, that alters a highly evolutionarily conserved residue within the HMG domain, which is critical for DNA binding of SOX2. In a yeast one-hybrid assay this mutation abolishes Sox2-induced activation of the chick delta-crystallin DC5 enhancer. Four other reported AEG syndrome cases were extensively screened and do not have detectable SOX2 mutations. Two of these cases have unilateral eye malformations. SOX2 mutations are known to cause severe bilateral eye malformations but this is the first report implicating loss of function mutations in this transcription factor in oesophageal malformations. Sox2 is expressed in the developing foregut in mouse and zebrafish embryos and an apparently normal pattern of expression is maintained in Shh-/- mouse embryos, suggesting either that Sox2 acts upstream of Shh or functions in a different pathway. Three dimensional reconstructions of the major morphological events in the developing foregut and eye from Carnegie Stages 12 and 13 human embryos are presented and compared to data from model organisms. SOX2, with NMYC and CHD7, is now the third transcriptional regulator known to be critical for normal oesophageal development in humans.
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