title: Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism.
abstract: Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.
authors.affiliation: London Centre for Paediatric Endocrinology, Biochemistry, Endocrinology, and Metabolism Unit, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Woods
authors.forename: Maria
authors.initials: M
authors.lastname: Cundall
authors.forename: James
authors.initials: J
authors.lastname: Turton
authors.forename: Karine
authors.initials: K
authors.lastname: Rizotti
authors.forename: Ameeta
authors.initials: A
authors.lastname: Mehta
authors.forename: Rodger
authors.initials: R
authors.lastname: Palmer
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Wong
authors.forename: W K
authors.initials: WK
authors.lastname: Chong
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Al-Zyoud
authors.forename: Maryam
authors.initials: M
authors.lastname: El-Ali
authors.forename: Timo
authors.initials: T
authors.lastname: Otonkoski
authors.forename: Juan-Pedro
authors.initials: JP
authors.lastname: Martinez-Barbera
authors.forename: Paul Q
authors.initials: PQ
authors.lastname: Thomas
authors.forename: Iain C
authors.initials: IC
authors.lastname: Robinson
authors.forename: Robin
authors.initials: R
authors.lastname: Lovell-Badge
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Woodward
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002828:Choristoma / Q000235:genetics; D041321:Chromosomes, Human, X; D004268:DNA-Binding Proteins / Q000235:genetics*; D020440:Gene Duplication; D006609:High Mobility Group Proteins / Q000235:genetics*; D019382:Human Growth Hormone / Q000172:deficiency; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics*; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D010903:Pituitary Gland, Anterior; D010904:Pituitary Gland, Posterior / Q000002:abnormalities*; D011110:Polymorphism, Genetic; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C527785:SOX3 protein, human; D055748:SOXB1 Transcription Factors; C527786:Sox3 protein, mouse; D014157:Transcription Factors; D019382:Human Growth Hormone