Endocrine Abstracts

Background: SOX3, a member of the SOXB1 subfamily of transcription factors, is a single-exon gene located on the X-chromosome and expressed in neuroepithelial and progenitor cells from the earliest stages. In mice, its expression in the infundibulum is important for the correct induction of Rathke’s pouch morphogenesis, with loss of function resulting in defects of CNS midline structures, teeth misalignment and variable hypopituitarism. We have previously demonstrated that both loss-of-function polyalanine tract mutations and over-dosage of SOX3 as a result of gene duplication are associated with similar hypopituitary phenotypes.

Study design and results: The aim of this study was to screen a cohort of patients with congenital hypopituitarism and an undescended posterior pituitary for variability in the size of the polyalanine (PA) tract in SOX3. 154 patients (80% male), with either multiple pituitary hormone deficiencies (N=93) or isolated growth hormone deficiency (N=45) were analysed. In 21 cases (13.6%), the condition was reported as familial. We identified a 7-alanine expansion in SOX3 in a pedigree where two males presented with IGHD and learning difficulties. This mutation has previously been reported by us in association with panhypopituitarism, and shown to result in loss of function due to cytoplasmic aggregation of the mutant protein. Additionally we identified a deletion of 18 bp within the same PA tract. Transient transfection assays revealed a 2-fold activation by the deleted mutant PA tract protein as compared with WT SOX3. To date, no confirmed pathogenic point mutations have been reported in SOX3. We have identified a G>A transition in codon 5 (c.14G>A) leading to substitution of arginine by glycine (p.R5G) in a boy with hypopituitarism and a solitary median maxillary central incisor. Transfection assays revealed that this is probably a benign change.

Conclusions: Although mutations in SOX3 are rare in patients with hypopituitarism, expansion of the PA tract can be associated with variable phenotypes ranging from IGHD to panhypopituitarism. We have now shown that PA deletions are associated with hypopituitarism, possibly due to increased transcriptional activation of SOX3 target genes, a mechanism that might be similar to overdosage of SOX3 due to gene duplication.