Endocrine Abstracts

Background: SOX2 is a member of the SOX (SRY-related HMG box) family of transcription factors, and shares homology with SOX1 and SOX3 which are members of the SOXB1 subfamily. Heterozygous, de novo, loss-of-function mutations in SOX2 were initially reported in patients with bilateral anophthalmia/microphthalmia, developmental delay and male genital tract abnormalities, with variable manifestations including defects of the corpus callosum, oesophageal atresia and sensorineural hearing loss. We have recently reported a number of SOX2 mutations in patients with anterior pituitary hypoplasia and hypogonadotrophic hypogonadism, which highlight the role of SOX2 in hypothalamo-pituitary development. Five regions that may be implicated in SOX2 regulation have been identified, four upstream (4.9–1 kb) and one downstream of SOX2, based on sequence conservation and previously published data on sox2 regulation.

Aim and methods: The aim of the study was to screen a cohort of 200 patients, who did not have changes within the SOX2 coding sequence, for variations within these regions. This cohort included patients with a) eye phenotype of varying severity and b) patients with an ectopic posterior pituitary, without eye phenotype, who had been initially screened for SOX3.

Results: Direct sequencing showed that these regions were highly conserved in our cohort. However, in one patient with anterior pituitary hypoplasia, undescended posterior pituitary and GH, ACTH and TSH deficiency, we have identified a single base change (C>T) in a region ~4.5 kb upstream of SOX2. We did not find this change in 100 matched controls. Transient transfection of NT2/D1 cells that constitutively express SOX2 has shown no difference compared with the wild type (wt) construct. However, the lack of an effect may be explained by the cell- and tissue-specific regulation of SOX2 expression. Search for transcription factor binding sites using Genomatix Mat-Inspector, showed that this change is predicted to affect binding of transcription factors including Foxo3 and SF-1.

Conclusion: This variation in a highly conserved region may provide further insight into the phenotypic consequences of mutations affecting regulation of SOX2 expression.