PUBLICATION
Mutations in SOX2 Cause Anophthalmia-Esophageal-Genital (AEG) Syndrome
- Authors
- Williamson, K.A., Hever, A.M., Rainger, J., Rogers, R.C., Magee, A., Fiedler, Z., Keng, W.T., Sharkey, F.H., McGill, N., Hill, C.J., Schneider, A., Messina, M., Turnpenny, P.D., Fantes, J.A., van Heyningen, V., and Fitzpatrick, D.R.
- ID
- ZDB-PUB-060323-34
- Date
- 2006
- Source
- Human molecular genetics 15(9): 1413-1422 (Journal)
- Registered Authors
- van Heyningen, Veronica
- Keywords
- none
- MeSH Terms
-
- Animals
- Anophthalmos/embryology
- Anophthalmos/enzymology
- Anophthalmos/genetics*
- Chickens
- DNA Mutational Analysis
- DNA-Binding Proteins/genetics
- Esophagus/abnormalities*
- Esophagus/embryology
- Esophagus/enzymology
- Female
- Gene Expression Regulation, Developmental/physiology
- Genitalia, Male/abnormalities*
- Genitalia, Male/embryology
- Genitalia, Male/enzymology
- HMGB Proteins/genetics*
- Humans
- Male
- Mice
- Point Mutation*
- SOXB1 Transcription Factors
- Syndrome
- Transcription Factors/genetics*
- Zebrafish
- PubMed
- 16543359 Full text @ Hum. Mol. Genet.
Citation
Williamson, K.A., Hever, A.M., Rainger, J., Rogers, R.C., Magee, A., Fiedler, Z., Keng, W.T., Sharkey, F.H., McGill, N., Hill, C.J., Schneider, A., Messina, M., Turnpenny, P.D., Fantes, J.A., van Heyningen, V., and Fitzpatrick, D.R. (2006) Mutations in SOX2 Cause Anophthalmia-Esophageal-Genital (AEG) Syndrome. Human molecular genetics. 15(9):1413-1422.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping