title: Two different corticosteroid-binding globulin variants that lack cortisol-binding activity in a greek woman.
abstract: BACKGROUND
  Corticosteroid-binding globulin (CBG), encoded by SERPINA6, is the principal plasma binding protein for cortisol. Most nonsynonymous single-nucleotide polymorphisms that alter the production or function of CBG occur rarely, and their clinical significance remains obscure.
  
  
  METHODS
  Serum and DNA were obtained from a Greek woman with low morning cortisol levels and from family members. SERPINA6 exons were sequenced, and serum CBG was measured by ELISA and cortisol-binding capacity assay. Recombinant CBG variants were produced for detailed functional studies.
  
  
  RESULTS
  A novel heterozygous c.1282G>C transversion in exon 5 of SERPINA6, resulting in a p.Trp393Ser (W371S) substitution, was identified in the proband, who was also heterozygous for single-nucleotide polymorphisms encoding the CBG Lyon (D367N) and CBG A224S variants. The proband had no measurable plasma cortisol-binding activity despite a CBG level of 273 nm by ELISA. She inherited CBG W371S from her mother whose plasma cortisol-binding capacity was approximately 50% lower than the CBG measurements by ELISA (314 nm). The proband's father and four children were heterozygous for CBG D367N; their CBG levels by ELISA were normal, but corresponding cortisol-binding capacity measurements were 50% lower. Pedigree analysis revealed that W371S segregates with A224 and that D367N and W371S segregate separately. Recombinant CBG D367N and CBG W371S had no measureable cortisol-binding activity.
  
  
  CONCLUSIONS
  A new CBG Athens (W371S) variant that lacks cortisol-binding activity has been identified in a carrier of the cortisol-binding deficient CBG Lyon (D367N) variant. Analyses of CBG levels in this pedigree illustrate how immunoassays fail to accurately reflect cortisol-binding activity.
authors.affiliation: Endocrine Unit, Attikon University Hospital, Athens University Medical School, Second Department of Internal Medicine-Research Institute and Diabetes Center, 1 Rimini Street, Haidari, Athens 12462, Greece. dimitra.vas@googlemail.com
authors.forename: L A
authors.initials: LA
authors.lastname: Hill
authors.forename: D A
authors.initials: DA
authors.lastname: Vassiliadi
authors.forename: M
authors.initials: M
authors.lastname: Simard
authors.forename: A
authors.initials: A
authors.lastname: Pavlaki
authors.forename: I
authors.initials: I
authors.lastname: Perogamvros
authors.forename: D
authors.initials: D
authors.lastname: Hadjidakis
authors.forename: G L
authors.initials: GL
authors.lastname: Hammond
mesh_terms: D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding / Q000235:genetics; D014156:Transcortin / Q000235:genetics* / Q000378:metabolism
chemical_list: D014156:Transcortin; D006854:Hydrocortisone