Mutations in SOX2 cause anophthalmia anophthalmiaesophageal-esophageal-genital (AEG) syndrome

摘要

We report heterozygous, loss-of-function SOX2 mutations in three unrelated individuals withnAnophthalmia-Esophageal-Genital (AEG) syndrome. One previously reported case [Rogers, R.C. (1988)nUnknown cases. Proceedings of the Greenwood Genetic Center. 7, 57.] has a 2.7 Mb deletion encompassingnSOX2 and associated with a cryptic translocation t(3;7)(q28;p21.3). The deletion and translocation breakpointsnon chromosome 3q are >8.6 Mb apart and both chromosome rearrangements have occurrednde novo. Another published case [Petrackova et al. (2004) Association of oesophageal atresia, anophthalmianand renal duplex. Eur. J. Pediatr., 163, 333–334.] has a de novo nonsense mutation, Q55X. A previously unreportedncase with severe bilateral microphthalmia and oesophageal atresia has a de novo missense mutation,nR74P, that alters a highly evolutionarily conserved residue within the high mobility group domain, which isncritical for DNA-binding of SOX2. In a yeast one-hybrid assay, this mutation abolishes Sox2-induced activationnof the chick delta-crystallin DC5 enhancer. Four other reported AEG syndrome cases were extensivelynscreened and do not have detectable SOX2 mutations. Two of these cases have unilateral eye malformations.nSOX2 mutations are known to cause severe bilateral eye malformations but this is the first report implicatingnloss of function mutations in this transcription factor in oesophageal malformations. SOX2 is expressed innthe developing foregut in mouse and zebrafish embryos and an apparently normal pattern of expression isnmaintained in Shh2/2 mouse embryos, suggesting either that Sox2 acts upstream of Shh or functionsnin a different pathway. Three-dimensional reconstructions of the major morphological events in the developingnforegut and eye from Carnegie Stages 12 and 13 human embryos are presented and compared with thendata from model organisms. SOX2, with NMYC and CHD7, is now the third transcriptional regulator known tonbe critical for normal oesophageal development in humans.