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Sox2/SOX2 Mutation and Abnormalities in Hypothalamo-pituitary-gonadal Axis« Back to Volume 23, Issue 1, March 2007 - Table of Contents Many transcription factors are required for normal development of the adenohypophysis, including LHX3, LHX4, HESX1, PROP1, POU1F1, SF1, SOX3, and others. To this growing list may now be added SOX2 (OMIM 184429, chromosome 3q26.3-q27), another member of the family of transcription factors that contain an SRY-related, 79 amino acid, high-mobility group box (HMG) DNA-binding domain. The 20 members of the SOX gene family encode proteins that are necessary for neuroepithelial cell differentiation. Humans with heterozygous mutations of SOX2 have bilateral anophthalmia/microphthalmia, sensorineural hearing loss, anomalies of the male genital tract, short stature, and developmental delay. To this clinical picture, the present authors have added hypogonadotropic hypogonadism. The investigators examined the SOX2 genotype in 235 patients (143 male) with congenital hypothalamic-pituitary disorders (97 subjects with congenital hypopituitarism and no midline cranial or eye defects; 126 patients with septo-optic dysplasia [SOD], 12 patients with anophthalmia/microphthalmia). They identified heterozygous loss-of-function mutations in SOX2 in 8 patients, 6 of whom had bilateral or unilateral anophthalmia/microphthalmia and 2 of whom had SOD (Table). The 6 patients with congenital defects of eye formation had isolated hypogonadotropic hypogonadism, one subject with SOD had deficiencies of growth hormone (GH), TSH, and ACTH, while the second patient with SOD was short but pituitary function had not been evaluated. Depending on the site of the SOX2 mutation, there was defective nuclear localization of the SOX2 protein, impairment of its binding to DNA, or decrease in its ability to transactivate target genes. The investigators then evaluated mice in which Sox2 had been partially inactivated. Homozygous loss of Sox2 was lethal, while partial heterozygous loss of Sox2 led to impaired growth and subfertility in males, which was associated with decreased pituitary content of GH and LH (but no ocular abnormalities). The adenohypophyses of these animals were small, the morphology of the somatotrophs and gonadotrophs abnormal, and the number of these cells low compared to wild-type animals. The pituitary contents of TSH and prolactin were variably low in the heterozygous mice, but that of ACTH was normal. In addition, Sox2 heterozygous male mice were subfertile; many had small testes with abnormal spermatogenesis. The Sox2 heterozygous female mice had normal fertility. The data indicate that Sox2 is an important transcription factor for development of the anterior pituitary (and testes/spermatogenesis). The pituitary expression of Sox2 normally declines as the adenohypophysis develops, but its expression is maintained in the hypothalamus, suggesting that an abnormality of hypothalamic function may also be present in mice with heterozygous mutations in Sox2. (With more stringent Sox2 deficiency, ocular anomalies can be produced experimentally.1) Editor’s CommentLoss of SOX3 (OMIM 313430, chromosome Xq26.3) activity in man is associated with X-linked GH deficiency and mental retardation.2 Reynaud and co-workers3 reported the distribution of mutations in PROP1, POU1F1, LHX3, LHX4, and HESX1 in a population of 165 unrelated families (195 patients) with deficiencies of multiple anterior pituitary hormones (combined pituitary hormone deficiency [CPHD]) with or without SOD or pituitary stalk interruption syndrome (PSIS). Overall mutations in one of the 5 transcription factor genes examined were found in 22 of 165 index patients (13.3%). CPHD was familial in 21 families, with mutations identified in 10 of these 21 families (52.4%).Homozygous or double heterozygous mutations in PROP1 were identified in 20 patients, in 8 of whom CPHD was familial. A mutation in POU1F1 or LHX4 was identified in only one patient each, and no mutations in LHX4 or HESX1 were found in this CPHD population. Although mutations of HESX1 have been found in patients with SOD, none were identified in the report of Reynaud and co-workers. It would be of interest to analyze SOX2 in these subjects. Reynaud et al also correlated phenotype with genotype and outlined a schematic algorithm through which gene analysis of patients with CPHD and associated anomalies might be pursued (Figure). Allen W. Root, MD References - (linked to
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Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
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