Increased transactivation and impaired repression of β-catenin-mediated transcription associated with a novel SOX3 missense mutation in an X-linked hypopituitarism pedigree with modest growth failure.

SOX3, a transcription factor of the SRY-related high mobility group box family, has been implicated in the etiology of X-linked hypopituitarism. Here, we report a Chinese pedigree of X-linked hypopituitarism with variable phenotypes. Despite the complete growth hormone deficiency, the growth failure of the patients was relatively modest. A rare point variant of SOX3 (c.424C > A; p. P142T) was identified in the pedigree via target panel sequencing. An in vitro study showed that both the expression and nuclear targeting of SOX3 remained unaffected by the variant. However, increased transcriptional activation and impaired repression of β-catenin-mediated transcription were noticed as a result of the SOX3 variant. This is the first study to report that the rare SOX3 missense variant associated with hypopituitarism possibly due to increased activation of SOX3 target genes and disregulation of β-catenin target genes. In addition, we have expanded the phenotypic spectrum associated with SOX3 mutations.