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 anophthahnia/microphthahnia, 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.

Kelberman, D., Rizzoti, K., Avilion, A., Bitner Glindzicz, M., Cianfarani, S., Collins, J., et al. (2006). Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamopituitary-gonadal axis in mice and humans. THE JOURNAL OF CLINICAL INVESTIGATION, 116(9), 2442-2455 [10.1172/JCI28658].

Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamopituitary-gonadal axis in mice and humans

CIANFARANI, STEFANO;
2006-01-01

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 anophthahnia/microphthahnia, 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.
2006
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/13 - ENDOCRINOLOGIA
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
English
transcription factor Sox2; adult; amino acid sequence; animal experiment; animal tissue; article; child; controlled study; corpus callosum; DNA binding; embryo; embryo development; esophagus atresia; eye malformation; female; frameshift mutation; gene mutation; hamartoma; heterozygosity; human; hypogonadotropic hypogonadism; hypophysis disease; hypophysis gonad system; hypothalamus disease; hypothalamus hypophysis system; infant; major clinical study; male; mouse; nonhuman; nonsense mutation; perception deafness; phenotype; priority journal; protein expression; protein function; transactivation; Abnormalities, Multiple; Adult; Animals; Child; DNA-Binding Proteins; Eye Abnormalities; Female; HMGB Proteins; Humans; Hypothalamus; Infant; Male; Mice; Mutation; Pituitary Gland; Trans-Activators; Transcription Factors
Kelberman, D., Rizzoti, K., Avilion, A., Bitner Glindzicz, M., Cianfarani, S., Collins, J., et al. (2006). Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamopituitary-gonadal axis in mice and humans. THE JOURNAL OF CLINICAL INVESTIGATION, 116(9), 2442-2455 [10.1172/JCI28658].
Kelberman, D; Rizzoti, K; Avilion, A; Bitner Glindzicz, M; Cianfarani, S; Collins, J; Kling Chong, W; Kirk, J; Achermann, J; Ross, R; Carmignac, D; Lovell, B; R. Robinson I. C. A., F; Dattani, Mt
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/43576
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