title: Increased transactivation associated with SOX3 polyalanine tract deletion in a patient with hypopituitarism.
abstract: OBJECTIVE
  Correct gene dosage of SOX3 is critical for the development of the hypothalamo-pituitary axis. Both overdosage of SOX3, as a result of gene duplication, and loss of function resulting from expansion of the first polyalanine (PA) tract are associated with variable degrees of hypopituitarism, with or without mental retardation. The aim of this study was to further investigate the contribution of SOX3 in the etiology of hypopituitarism and the mechanisms involved in the phenotypic variability.
  
  
  METHODS
  We screened 154 patients with congenital hypopituitarism and an undescended posterior pituitary for mutations in SOX3 and variability in the length of the first PA tract. In addition, 300 patients with variable septooptic dysplasia were screened for variability of the PA tract.
  
  
  RESULTS
  We report a novel 18-base pair deletion (p.A243_A248del6, del6PA) in a female patient with hypopituitarism resulting in a 2-fold increase in transcriptional activation in vitro, compared with wild-type SOX3. We also identified a previously reported seven-alanine expansion (p.A240_A241ins7, +7PA) in two male siblings with isolated GH deficiency and a distinct phenotype, in addition to the nonsynonymous variant p.R5Q in an unrelated individual; this appears to have no functional effect on the protein. In contrast to +7PA, del6PA maintained its ability to repress β-catenin mediated transcription in vitro.
  
  
  CONCLUSIONS
  This is the first study to report that PA tract deletions associated with hypopituitarism have functional consequences in vitro, possibly due to increased activation of SOX3 target genes. In addition, we have expanded the phenotypic spectrum associated with PA tract expansion (+7PA) mutations to include panhypopituitarism or isolated GH deficiency, with or without mental retardation.
authors.affiliation: Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, University College London Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom.
authors.forename: Kyriaki S
authors.initials: KS
authors.lastname: Alatzoglou
authors.forename: Daniel
authors.initials: D
authors.lastname: Kelberman
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Cowell
authors.forename: Rodger
authors.initials: R
authors.lastname: Palmer
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: Maria E
authors.initials: ME
authors.lastname: Melo
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnabel
authors.forename: Annette
authors.initials: A
authors.lastname: Grueters
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007018:Hypopituitarism / Q000000981:diagnostic imaging / Q000235:genetics*; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D010455:Peptides / Q000235:genetics*; D011859:Radiography; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D017384:Sequence Deletion / Q000502:physiology*; D015533:Transcriptional Activation; D018911:Trinucleotide Repeats / Q000235:genetics; D015854:Up-Regulation
chemical_list: D010455:Peptides; C527785:SOX3 protein, human; D055748:SOXB1 Transcription Factors; C019529:polyalanine