SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development.
BACKGROUND
Heterozygous, de novo mutations in the transcription factor SOX2 are associated with bilateral anophthalmia or severe microphthalmia and hypopituitarism. Variable additional abnormalities include defects of the corpus callosum and hippocampus.


OBJECTIVE
We have ascertained a further three patients with severe eye defects and pituitary abnormalities who were screened for mutations in SOX2. To provide further evidence of a direct role for SOX2 in hypothalamo-pituitary development, we have studied the expression of the gene in human embryonic tissues.


RESULTS
All three patients harbored heterozygous SOX2 mutations: a deletion encompassing the entire gene, an intragenic deletion (c.70_89del), and a novel nonsense mutation (p.Q61X) within the DNA binding domain that results in impaired transactivation. We also show that human SOX2 can inhibit beta-catenin-driven reporter gene expression in vitro, whereas mutant SOX2 proteins are unable to repress efficiently this activity. Furthermore, we show that SOX2 is expressed throughout the human brain, including the developing hypothalamus, as well as Rathke's pouch, the developing anterior pituitary, and the eye.


CONCLUSIONS
Patients with SOX2 mutations often manifest the unusual phenotype of hypogonadotropic hypogonadism, with sparing of other pituitary hormones despite anterior pituitary hypoplasia. SOX2 expression patterns in human embryonic development support a direct involvement of the protein during development of tissues affected in these individuals. Given the critical role of Wnt-signaling in the development of most of these tissues, our data suggest that a failure to repress the Wnt-beta-catenin pathway could be one of the underlying pathogenic mechanisms associated with loss-of-function mutations in SOX2.
Kelberman
Daniel
D
Developmental Endocrinology Research Unit, Clinical and Molecular Genetics Unit, Institute of Child Health, 30 Guilford Street, London, United Kingdom.
de Castro
Sandra C P
SC
Huang
Shuwen
S
Crolla
John A
JA
Palmer
Rodger
R
Gregory
John W
JW
Taylor
David
D
Cavallo
Luciano
L
Faienza
Maria F
MF
Fischetto
Rita
R
Achermann
John C
JC
Martinez-Barbera
Juan Pedro
JP
Rizzoti
Karine
K
Lovell-Badge
Robin
R
Robinson
Iain C A F
IC
Gerrelli
Dianne
D
Dattani
Mehul T
MT
D000293:Adolescent; D000328:Adult; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005123:Eye / Q000196:embryology*; D005124:Eye Abnormalities / Q000209:etiology / Q000235:genetics; D005260:Female; D024002:HMGB Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007018:Hypopituitarism / Q000209:etiology / Q000235:genetics; D009154:Mutation; D010902:Pituitary Gland / Q000196:embryology*; D016548:Prosencephalon / Q000196:embryology*; D012333:RNA, Messenger / Q000032:analysis; D055748:SOXB1 Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
D004268:DNA-Binding Proteins; D024002:HMGB Proteins; D012333:RNA, Messenger; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin