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SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development

Kelberman, D; de Castro, SCP; Huang, SW; Crolla, JA; Palmer, R; Gregory, JW; Taylor, D; ... Dattani, MT; + view all (2008) SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development. The Journal of Clinical Endocrinology & Metabolism , 93 (5) 1865 - 1873. 10.1210/jc.2007-2337. Green open access

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Abstract

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 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.

Type: Article
Title: SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development
Open access status: An open access version is available from UCL Discovery
DOI: 10.1210/jc.2007-2337
Publisher version: http://dx.doi.org/10.1210/jc.2007-2337
Language: English
Additional information: © 2008 by The Endocrine Society
Keywords: SEPTO-OPTIC DYSPLASIA, MESSENGER-RNA DECAY, BETA-CATENIN, ANOPHTHALMIA SYNDROME, LINEAGE DETERMINATION, MUTATIONS, GENE, MOUSE, TRANSCRIPTION, HESX1
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Targeted Intervention
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/140876
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