title: Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.
abstract: The transcription factor SOX2 is expressed most notably in the developing CNS and placodes, where it plays critical roles in embryogenesis. Heterozygous de novo mutations in SOX2 have previously been associated with bilateral anophthalmia/microphthalmia, developmental delay, short stature, and male genital tract abnormalities. Here we investigated the role of Sox2 in murine pituitary development. Mice heterozygous for a targeted disruption of Sox2 did not manifest eye defects, but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone. Consequently, we identified 8 individuals (from a cohort of 235 patients) with heterozygous sequence variations in SOX2. Six of these were de novo mutations, predicted to result in truncated protein products, that exhibited partial or complete loss of function (DNA binding, nuclear translocation, or transactivation). Clinical evaluation revealed that, in addition to bilateral eye defects, SOX2 mutations were associated with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, sensorineural hearing loss, and esophageal atresia. Our data show that SOX2 is necessary for the normal development and function of the hypothalamo-pituitary and reproductive axes in both humans and mice.
authors.affiliation: London Centre for Paediatric Endocrinology, Biochemistry, Endocrinology, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kelberman
authors.forename: Karine
authors.initials: K
authors.lastname: Rizzoti
authors.forename: Ariel
authors.initials: A
authors.lastname: Avilion
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.forename: Stefano
authors.initials: S
authors.lastname: Cianfarani
authors.forename: Julie
authors.initials: J
authors.lastname: Collins
authors.forename: W Kling
authors.initials: WK
authors.lastname: Chong
authors.forename: Jeremy M W
authors.initials: JM
authors.lastname: Kirk
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
authors.forename: Richard
authors.initials: R
authors.lastname: Ross
authors.forename: Danielle
authors.initials: D
authors.lastname: Carmignac
authors.forename: Robin
authors.initials: R
authors.lastname: Lovell-Badge
authors.forename: Iain C A F
authors.initials: IC
authors.lastname: Robinson
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000328:Adult; D000818:Animals; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D024002:HMGB Proteins / Q000235:genetics*; D006801:Humans; D007031:Hypothalamus / Q000002:abnormalities*; D007223:Infant; D008297:Male; D051379:Mice; D009154:Mutation; D010902:Pituitary Gland / Q000002:abnormalities*; D055748:SOXB1 Transcription Factors; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D024002:HMGB Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors