BRIEF REPORT SOX2 Haploinsufﬁciency is Associated with Slow Progressing Hypothalamo-Pituitary Tumours OFFICIAL JOURNAL www.hgvs.org Kyriaki S. Alatzoglou,1† Cynthia L. Andoniadou,2† Daniel Kelberman,3 Charles R. Buchanan,4 John Crolla,5 Maria Cristina Arriazu,6 Martin Roubicek,6 Daniel Moncet,6 Juan P. Martinez-Barbera,2 and Mehul T. Dattani1∗ 1Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, United Kingdom; 2Neural Development Unit, Institute of Child Health, University College London, London, United Kingdom; 3Ulverscroft Vision Research Group, Developmental Biology Unit, Institute of Child Health, University College London, London, United Kingdom; 4Department of Child Health, Kings College Hospital NHS Foundation Trust, London, United Kingdom; 5Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, United Kingdom; 6Department of Pediatric Endocrinology, Hospital Privado de Comunidad, Buenos Aires, Argentina Communicated by Richard Wooster Received 14 March 2011; accepted revised manuscript 21 August 2011. Published online 12 September 2011 in Wiley Online Library (www.wiley.com/humanmutation).DOI: 10.1002/humu.21606 ABSTRACT: SOX2 is an early developmental transcrip- tion factor and marker of stem cells that has recently been implicated in the development of the pituitary gland. Het- erozygous SOX2 mutations have been described in patients with hypopituitarism and severe ocular abnormalities. In the majority of published cases, the pituitary gland is ei- ther small or normal in size. Here, we report two unrelated patients with SOX2 haploinsufﬁciency (a heterozygous gene deletion and a novel c.143TC>AA/p.F48X muta- tion) who developed nonprogressive pituitary tumors of early onset, suggesting a congenital etiology. The truncat- ing mutation resulted in signiﬁcant loss of function and impaired nuclear localization of the mutant protein, in addition to a failure to repress β-catenin transcriptional activity in vitro. This is the ﬁrst indication that SOX2 haploinsufﬁciency is implicated in the generation of pitu- itary tumors with distinct clinical characteristics, possibly mediated via its effects on the Wnt signaling pathway. Hum Mutat 32:1376–1380, 2011. C 2011 Wiley Periodicals, Inc. KEY WORDS: SOX2; pituitary; tumors; ß-catenin SOX2 (MIM# 184429), a member of the SOXB1 family of tran- scription factors, is a widely expressed marker of progenitor and stem cells. The single exon gene encodes a 317 amino acid protein that contains an N-terminal domain, a DNA-binding high-mobility group (HMG) domain and a C-terminal transcriptional activa- tion domain [Collignon et al., 1996]. SOX2 haploinsufﬁciency in both mouse and human has been associated with variable hypopi- tuitarism associated with anterior pituitary hypoplasia, suggesting Additional Supporting Information may be found in the online version of this article. †These two authors contributed equally to this work. ∗Correspondence to: Mehul T. Dattani, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London WC1N, 1EH, United Kingdom. E-mail: m.dattani@ich.ucl.ac.uk Contract grant sponsors: Wellcome Trust (084361, 078432, 086545); ESPE Research Fellowship (K.S.A.); The Ulverscroft Foundation (D.K.); Great Ormond Street Children’s Charity (M.T.D.). that it has a critical role in the development of the anterior pituitary [Kelberman et al., 2006]. Heterozygous de novo mutations in hu- mans are associated with severe ocular phenotypes (bilateral anoph- thalmia or severe microphthalmia) and hypogonadotropic hypog- onadism (HH) with or without associated abnormalities such as esophageal atresia, male genital anomalies, developmental delay, sensorineural deafness, hippocampal malformation, hypoplasia of the corpus callosum, and hypothalamic hamartoma [Kelberman et al., 2006, 2008]. In humans, SOX2 expression is detected within Rathke’s pouch and maintained throughout the development of the anterior pituitary, as well as in the presumptive hypothalamus and neural ectoderm [Kelberman et al., 2008]. In neural progenitors, SOX2 downregulation is associated with progression from a prolif- erating undifferentiated state to a committed phenotype [Graham et al., 2003]. In the murine adult pituitary, SOX2 expression is main- tained in a small population of cells lining the pituitary cleft, which show many of the properties of progenitor cells and have the abil- ity to differentiate into all hormone-producing cell types [Fauquier et al., 2008]. The speciﬁcity of the action of SOX proteins depends largely on their interaction with partner proteins. Recent data have suggested an interaction with components of another early developmental pathway, the Wnt/β-catenin signaling pathway. Members of the Wnt/β-catenin pathway are expressed in the developing pituitary and are implicated in the maintenance of normal morphology of the gland and the determination of hormone-secreting cell types [Olson et al., 2006; Potok et al., 2008]. Xenopus XSox3 and XSox17 as well as murine SOX2 interact with β-catenin and repress its ac- tivity in vitro [Mansukhani et al., 2005; Zorn et al., 1999]. We have shown that human SOX2 is also capable of inhibiting β-catenin- mediated transcriptional activation [Kelberman et al., 2008]. Recent studies have suggested that aberrant activation of the Wnt pathway, resulting from sustained β-catenin activation or downregulation of Wnt-inhibitors is associated with the development of pituitary tu- mors [Buslei et al., 2005; Elston et al., 2008; Gaston-Massuet et al., 2011]. Here we report, for the ﬁrst time to our knowledge, the iden- tiﬁcation of heterozygous SOX2 mutations in two unrelated patients in association with pituitary tumors of likely congenital origin and we provide in vitro evidence that disruption of the SOX2/β-catenin interaction may be the molecular mechanism underlying some hu- man pituitary tumors. Case 1 is a female patient with bilateral anophthalmia who pre- sented for the ﬁrst time at the age of 18 years for assessment of C 2011 WILEY PERIODICALS, INC.