title: SOX2 haploinsufficiency is associated with slow progressing hypothalamo-pituitary tumours.
abstract: SOX2 is an early developmental transcription factor and marker of stem cells that has recently been implicated in the development of the pituitary gland. Heterozygous SOX2 mutations have been described in patients with hypopituitarism and severe ocular abnormalities. In the majority of published cases, the pituitary gland is either small or normal in size. Here, we report two unrelated patients with SOX2 haploinsufficiency (a heterozygous gene deletion and a novel c.143TC>AA/p.F48X mutation) who developed nonprogressive pituitary tumors of early onset, suggesting a congenital etiology. The truncating mutation resulted in significant loss of function and impaired nuclear localization of the mutant protein, in addition to a failure to repress β-catenin transcriptional activity in vitro. This is the first indication that SOX2 haploinsufficiency is implicated in the generation of pituitary tumors with distinct clinical characteristics, possibly mediated via its effects on the Wnt signaling pathway.
authors.affiliation: Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK.
authors.forename: Kyriaki S
authors.initials: KS
authors.lastname: Alatzoglou
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Andoniadou
authors.forename: Daniel
authors.initials: D
authors.lastname: Kelberman
authors.forename: Charles R
authors.initials: CR
authors.lastname: Buchanan
authors.forename: John
authors.initials: J
authors.lastname: Crolla
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Arriazu
authors.forename: Martin
authors.initials: M
authors.lastname: Roubicek
authors.forename: Daniel
authors.initials: D
authors.lastname: Moncet
authors.forename: Juan P
authors.initials: JP
authors.lastname: Martinez-Barbera
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
mesh_terms: D000293:Adolescent; D005260:Female; D017353:Gene Deletion; D057809:HEK293 Cells; D057895:Haploinsufficiency / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007018:Hypopituitarism / Q000151:congenital / Q000209:etiology / Q000235:genetics; D007029:Hypothalamic Neoplasms / Q000235:genetics*; D007223:Infant; D008297:Male; D009154:Mutation; D010902:Pituitary Gland / Q000473:pathology; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051176:beta Catenin