title: Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency.
abstract: BACKGROUND
  Mutations within the gene encoding the pituitary-specific transcription factor POU1F1 are associated with combined pituitary hormone deficiency (CPHD). Most of the affected individuals manifest GH, prolactin, and TSH deficiency.
  
  
  OBJECTIVE
  We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1.
  
  
  RESULTS
  Causative mutations were identified in 10 of 129 individuals (7.8%). Of these, five patients harbored the dominant negative R271W mutation, which is a well-recognized mutational hot spot. We have also identified a second frequently occurring mutation, E230K, which appears to be common in Maltese patients. Additionally, we describe two novel mutations within POU1F1, an insertion of a single base pair (ins778A) and a missense mutation (R172Q). Functional studies have revealed that POU1F1 (E230K) is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wild-type protein. On the other hand, POU1F1 (R172Q) is associated with a reduction in DNA binding and transactivation, whereas POU1F1 (ins778A) is associated with loss of DNA binding and a reduction in transactivation.
  
  
  CONCLUSIONS
  Our data suggest that the phenotype associated with POU1F1 mutations may be more variable, with the occasional preservation of TSH secretion. Additionally, our data revealed POU1F1 mutations in three patients who were diagnosed as having ACTH deficiency but who, on further evaluation, were found to have normal cortisol secretion. Hence, elucidation of the genotype led to further evaluation of the phenotype, with the cessation of cortisol replacement that had been commenced unnecessarily. These data reflect the importance of mutational analysis in patients with CPHD.
authors.affiliation: Biochemistry, Endocrinology, and Metabolism Unit and London Centre for Paediatric Endocrinology, Institute of Child Health, London, United Kingdom.
authors.forename: James P G
authors.initials: JP
authors.lastname: Turton
authors.forename: Rachel
authors.initials: R
authors.lastname: Reynaud
authors.forename: Ameeta
authors.initials: A
authors.lastname: Mehta
authors.forename: John
authors.initials: J
authors.lastname: Torpiano
authors.forename: Alexandru
authors.initials: A
authors.lastname: Saveanu
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Woods
authors.forename: Anatoly
authors.initials: A
authors.lastname: Tiulpakov
authors.forename: Vera
authors.initials: V
authors.lastname: Zdravkovic
authors.forename: Jill
authors.initials: J
authors.lastname: Hamilton
authors.forename: Simon
authors.initials: S
authors.lastname: Attard-Montalto
authors.forename: Ray
authors.initials: R
authors.lastname: Parascandalo
authors.forename: Cecil
authors.initials: C
authors.lastname: Vella
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clayton
authors.forename: Stephen
authors.initials: S
authors.lastname: Shalet
authors.forename: John
authors.initials: J
authors.lastname: Barton
authors.forename: Thierry
authors.initials: T
authors.lastname: Brue
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
mesh_terms: D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D023281:Genomics; D019382:Human Growth Hormone / Q000172:deficiency; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010903:Pituitary Gland, Anterior / Q000473:pathology / Q000503:physiopathology; D010904:Pituitary Gland, Posterior / Q000473:pathology / Q000503:physiopathology; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C494187:POU1F1 protein, human; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D019382:Human Growth Hormone