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SOX2 Plays a Critical Role in the Pituitary, Forebrain, and Eye during Human Embryonic Development

Developmental Endocrinology Research Group (D.K., J.C.A., M.T.D.), Clinical and Molecular Genetics Unit, and Medical Research Council-Wellcome Trust Human Developmental Biology Resource (S.C.P.d.C., D.G.), Neural Development Unit (J.P.M.-B.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; National Genetics Reference Laboratory (Wessex) (S.H., J.A.C.), Salisbury District Hospital, Salisbury SP2 8BJ, United Kingdom; Departments of Cytogenetics (R.P.) and Ophthalmology (D.T.), Great Ormond Street Hospital for Children National Health Service Trust, London WC1N 3JH, United Kingdom; Department of Child Health (J.W.G.), Wales College of Medicine, Cardiff University, Cardiff, Wales CF10 3XQ, United Kingdom; Department of Biomedicine of Evolutive Age (L.C., M.F.F., R.F.), University of Bari, Bari 70121, Italy; and Divisions of Developmental Genetics (K.R., R.L.-B.) and Molecular Neuroendocrinology (I.C.A.F.R.), Medical Research Council National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom

Address all correspondence and requests for reprints to: Professor Mehul T. Dattani, Clinical and Molecular Genetics Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom. E-mail: mdattani{at}ich.ucl.ac.uk.

Context: 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 β-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-β-catenin pathway could be one of the underlying pathogenic mechanisms associated with loss-of-function mutations in SOX2.