Endocrine Abstracts

Background: SOX2 is an early developmental transcription factor implicated in pituitary development. It consists of a N-terminal domain, a high mobility group (HMG)-DNA binding domain and a carboxyl-terminal domain. Heterozygous SOX2 mutations have been described in patients with a severe ocular phenotype and hypogonadotrophic hypogonadism (HH) with/without associated abnormalities. In vitro SOX2 interacts with β-catenin, a member of the Wnt signalling pathway, and represses β-catenin mediated target activation via the carboxyl-terminus. We now report a novel SOX2 mutation in the HMG domain revealing a distinct mechanism of action.

Case presentation: A female patient first presented at the age of 21 years with primary amenorrhoea (breast stage 2). She had bilateral congenital anophthalmia, developmental delay and HH (FSH 1.0 IU/l, LH 0.6 IU/l, oestradiol <15 pg/ml) with thinning of the corpus callosum on MRI.

Results: Genetic analysis revealed heterozygosity for a novel SOX2 mutation (c.G261T, p.K87N) in the HMG domain. The mutant protein had comparable transactivation to the wild type (WT) SOX2 (P>0.5) and, unlike previous HMG domain mutations, retained its ability to bind to a consensus DNA probe on electrophoretic mobility shift assay (EMSA). Immunostaining confirmed nuclear localisation. However, co-transfection of p.K87N SOX2 with a constitutively active form of human β-catenin (S33Y) in the TOPFLASH reporter assay failed to repress β-catenin mediated activation (P<0.001), in contrast to WT SOX2. This may result from altered direct interaction with β-catenin rather than binding to TCF/LEF sites, as we demonstrate that neither WT nor p.K87N SOX2 bind to a TCF/LEF consensus probe on EMSA.

Conclusion: We report a novel SOX2 mutation in the HMG domain that, unexpectedly, fails to repress β-catenin mediated activation suggesting that the HMG domain is critical for the interaction with β-catenin. We report, for the first time to our knowledge, that clinical phenotypes may result from altered interaction between SOX2 and β-catenin.