title: SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development.
abstract: BACKGROUND
  Heterozygous, de novo mutations in the transcription factor SOX2 are associated with bilateral anophthalmia or severe microphthalmia and hypopituitarism. Variable additional abnormalities include defects of the corpus callosum and hippocampus.
  
  
  OBJECTIVE
  We have ascertained a further three patients with severe eye defects and pituitary abnormalities who were screened for mutations in SOX2. To provide further evidence of a direct role for SOX2 in hypothalamo-pituitary development, we have studied the expression of the gene in human embryonic tissues.
  
  
  RESULTS
  All three patients harbored heterozygous SOX2 mutations: a deletion encompassing the entire gene, an intragenic deletion (c.70_89del), and a novel nonsense mutation (p.Q61X) within the DNA binding domain that results in impaired transactivation. We also show that human SOX2 can inhibit beta-catenin-driven reporter gene expression in vitro, whereas mutant SOX2 proteins are unable to repress efficiently this activity. Furthermore, we show that SOX2 is expressed throughout the human brain, including the developing hypothalamus, as well as Rathke's pouch, the developing anterior pituitary, and the eye.
  
  
  CONCLUSIONS
  Patients with SOX2 mutations often manifest the unusual phenotype of hypogonadotropic hypogonadism, with sparing of other pituitary hormones despite anterior pituitary hypoplasia. SOX2 expression patterns in human embryonic development support a direct involvement of the protein during development of tissues affected in these individuals. Given the critical role of Wnt-signaling in the development of most of these tissues, our data suggest that a failure to repress the Wnt-beta-catenin pathway could be one of the underlying pathogenic mechanisms associated with loss-of-function mutations in SOX2.
authors.affiliation: Developmental Endocrinology Research Unit, Clinical and Molecular Genetics Unit, Institute of Child Health, 30 Guilford Street, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kelberman
authors.forename: Sandra C P
authors.initials: SC
authors.lastname: de Castro
authors.forename: Shuwen
authors.initials: S
authors.lastname: Huang
authors.forename: John A
authors.initials: JA
authors.lastname: Crolla
authors.forename: Rodger
authors.initials: R
authors.lastname: Palmer
authors.forename: John W
authors.initials: JW
authors.lastname: Gregory
authors.forename: David
authors.initials: D
authors.lastname: Taylor
authors.forename: Luciano
authors.initials: L
authors.lastname: Cavallo
authors.forename: Maria F
authors.initials: MF
authors.lastname: Faienza
authors.forename: Rita
authors.initials: R
authors.lastname: Fischetto
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Martinez-Barbera
authors.forename: Karine
authors.initials: K
authors.lastname: Rizzoti
authors.forename: Robin
authors.initials: R
authors.lastname: Lovell-Badge
authors.forename: Iain C A F
authors.initials: IC
authors.lastname: Robinson
authors.forename: Dianne
authors.initials: D
authors.lastname: Gerrelli
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005123:Eye / Q000196:embryology*; D005124:Eye Abnormalities / Q000209:etiology / Q000235:genetics; D005260:Female; D024002:HMGB Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007018:Hypopituitarism / Q000209:etiology / Q000235:genetics; D009154:Mutation; D010902:Pituitary Gland / Q000196:embryology*; D016548:Prosencephalon / Q000196:embryology*; D012333:RNA, Messenger / Q000032:analysis; D055748:SOXB1 Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D024002:HMGB Proteins; D012333:RNA, Messenger; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin