SOX2 is a transcription factor involved in early embryonic development. It plays a critical role in eye, forebrain, and hypothalamo-pituitary development. Individuals with SOX2 mutations have major eye abnormalities including anophthalmia, microphthalmia, and coloboma. Hypogonadotropic hypogonadism is a complex developmental disorder characterized by gonadotropin deficiency. Recently, a number of patients with SOX2 mutations have been shown to have hypogonadotropic hypogonadism, making SOX2 an interesting addition to the list of genes implicated in the etiology of the condition. Most of the patients demonstrate anterior pituitary hypoplasia. Surprisingly, although most patients with anterior pituitary hypoplasia manifest GH (growth hormone) deficiency, gonadotropin deficiency appeared to be the most consistent endocrinopathy in patients with SOX2 mutations. SOX2 may be involved at multiple levels during the development of the hypothalamo-pituitary-gonadal axis, and is likely to play an essential role in GnRH (gonadotropin-releasing hormone) neuronal differentiation and migration. Animal data also suggest an additional role for the gene in gonadal development. Given the critical role of Sox2 in normal hypothalamo-pituitary development in the mouse and the anterior pituitary hypoplasia observed in most human patients with SOX2 mutations, it remains to be established whether further pituitary hormone deficiencies might evolve with time.

Keywords:
Hypogonadotropic hypogonadism, Hypothalamo-pituitary development, SOX2
1.
Asteria C, Oliveira JH, Abucham J, Beck-Peccoz P: Central hypocortisolism as part of combined pituitary hormone deficiency due to mutations of PROP-1 gene. Eur J Endocrinol 143:347–352 (2000).
2.
Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R: Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17:126–140 (2003).
3.
Brunelli S, Silva Casey E, Bell D, Harland R, Lovell-Badge R: Expression of Sox3 throughout the developing central nervous system is dependent on the combined action of discrete, evolutionarily conserved regulatory elements. Genesis 36:12–24 (2003).
4.
Carvalho LR, Woods KS, Mendonca BB, Marcal N, Zamparini AL, et al: A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. J Clin Invest 112:1192–1201 (2003).
5.
Cavallaro M, Mariani J, Lancini C, Latorre E, Caccia R, et al: Impaired generation of mature neurons by neural stem cells from hypomorphic Sox2 mutants. Development 135:541–557 (2008).
6.
Chassaing N, Gilbert-Dussardier B, Nicot F, Fermeaux V, Encha-Razavi F, et al: Germinal mosaicism and familial recurrence of a SOX2 mutation with highly variable phenotypic expression extending from AEG syndrome to absence of ocular involvement. Am J Med Genet A 143:289–291 (2007).
7.
Collignon J, Sockanathan S, Hacker A, Cohen-Tannoudji M, Norris D, et al: A comparison of the properties of Sox-3 with Sry and two related genes, Sox-1 and Sox-2. Development 122:509–520 (1996).
8.
Faivre L, Williamson KA, Faber V, Laurent N, Grimaldi M, et al: Recurrence of SOX2 anophthalmia syndrome with gonosomal mosaicism in a phenotypically normal mother. Am J Med Genet A 140:636–639 (2006).
9.
Fantes J, Ragge NK, Lynch SA, McGill NI, Collin JR, et al: Mutations in SOX2 cause anophthalmia. Nat Genet 33:461–463 (2003).
10.
Fauquier T, Rizzoti K, Dattani M, Lovell-Badge R, Robinson IC: SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. Proc Natl Acad Sci USA 105:2907–2912 (2008).
11.
Gubbay J, Collignon J, Koopman P, Capel B, Economou A, et al: A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 346:245–250 (1990).
12.
Hagstrom SA, Pauer GJ, Reid J, Simpson E, Crowe S, et al: SOX2 mutation causes anophthalmia, hearing loss, and brain anomalies. Am J Med Genet A 138:95–98 (2005).
13.
Kan L, Israsena N, Zhang Z, Hu M, Zhao LR, et al: Sox1 acts through multiple independent pathways to promote neurogenesis. Dev Biol 269:580–594 (2004).
14.
Kelberman D, Rizzoti K, Avilion A, Bitner-Glindzicz M, Cianfarani S, et al: Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest 116:2442–2455 (2006).
15.
Kelberman D, de Castro SC, Huang S, Crolla JA, Palmer R, et al: SOX2 plays a critical role in the pituitary, forebrain and eye during human embryonic development. J Clin Endocrinol Metab 93:1865–1873 (2008).
16.
Kiefer JC: Back to basics: Sox genes. Dev Dyn 236:2356–2366 (2007).
17.
Kondoh H, Uchikawa M, Kamachi Y: Interplay of Pax6 and SOX2 in lens development as a paradigm of genetic switch mechanisms for cell differentiation. Int J Dev Biol 48:819–827 (2004).
18.
Lefebvre V, Dumitriu B, Penzo-Mendez A, Han Y, Pallavi B: Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. Int J Biochem Cell Biol 39:2195–2214 (2007).
19.
Mansukhani A, Ambrosetti D, Holmes G, Cornivelli L, Basilico C: Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation. J Cell Biol 168:1065–1076 (2005).
20.
Mendonca BB, Osorio MG, Latronico AC, Estefan V, Lo LS, Arnhold IJ: Longitudinal hormonal and pituitary imaging changes in two females with combined pituitary hormone deficiency due to deletion of A301,G302 in the PROP1 gene. J Clin Endocrinol Metab 84:942–945 (1999).
21.
Pernasetti F, Toledo SP, Vasilyev VV, Hayashida CY, Cogan JD, et al: Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone deficiency caused by a two-base pair deletion (301–302delAG) in the prophet of Pit-1 gene. J Clin Endocrinol Metab 85:390–397 (2000).
22.
Ragge NK, Lorenz B, Schneider A, Bushby K, de Sanctis L, et al: SOX2 anophthalmia syndrome. Am J Med Genet A 135:1–7; discussion 8 (2005).
23.
Sato N, Kamachi Y, Kondoh H, Shima Y, Morohashi K, et al: Hypogonadotropic hypogonadism in an adult female with a heterozygous hypomorphic mutation of SOX2. Eur J Endocrinol 156:167–171 (2007).
24.
Tobet SA, Bless EP, Schwarting GA: Developmental aspect of the gonadotropin-releasing hormone system. Mol Cell Endocrinol 185:173–184 (2001).
25.
Williamson KA, Hever AM, Rainger J, Rogers RC, Magee A, et al: Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum Mol Genet 15:1413–1422 (2006).
26.
Wood HB, Episkopou V: Comparative expression of the mouse Sox1, Sox2 and Sox3 genes from pre-gastrulation to early somite stages. Mech Dev 86:197–201 (1999).
27.
Woods KS, Cundall M, Turton J, Rizotti K, Mehta A, et al: Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet 76:833–849 (2005).
28.
Zenteno JC, Gascon-Guzman G, Tovilla-Canales JL: Bilateral anophthalmia and brain malformations caused by a 20-bp deletion in the SOX2 gene. Clin Genet 68:564–566 (2005).
29.
Zorn AM, Barish GD, Williams BO, Lavender P, Klymkowsky MW, Varmus HE: Regulation of Wnt signaling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin. Mol Cell 4:487–498 (1999).
© 2008 S. Karger AG, Basel
2008
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