title: The role of type 1 and type 2 5'-deiodinase in the pathophysiology of the 3,5,3'-triiodothyronine toxicosis of McCune-Albright syndrome.
abstract: BACKGROUND
  McCune-Albright syndrome (MAS) is caused by mutations in GNAS (most often R201C or R201H) leading to constitutive cAMP signaling and multiple endocrine dysfunctions, including morphological and functional thyroid involvement.
  
  
  OBJECTIVE
  The objective of the study was to characterize the clinical and molecular features of the MAS-associated thyroid disease in a large cohort of patients.
  
  
  METHODS
  This was a retrospective analysis.
  
  
  METHODS
  The study was conducted at the National Institutes of Health Clinical Center.
  
  
  METHODS
  The study included 100 consecutive MAS patients.
  
  
  METHODS
  There were no interventions.
  
  
  METHODS
  Functional and morphological evaluation of the thyroid was measured. Ex vivo experiments were performed on MAS thyroid samples to study the effects of the GNAS mutations on the 5'-deiodinases. Reconstitution experiments in HEK-293 cells were performed to study the effects of GNAS mutations on the type-2 5'-deiodinase.
  
  
  RESULTS
  Fifty-four patients had abnormal thyroid ultrasound findings. This group, compared with patients without abnormal findings, had higher T(3) to T(4) ratio, indicating an elevated 5'-deiodinase activity. Thyroid samples from MAS subjects, compared with normal tissue, showed a significant increase in both type 1 (D1) and type 2 (D2) 5'-deiodinase activity (D1 control 5.9 +/- 4.5 vs. MAS 41.7 +/- 26.8 fmol/min.mg, P < 0.001; D2 control 28.3 +/- 13.8 vs. MAS 153.1 +/- 43.7 fmol/min.mg, P < 0.001). Compared with cells transfected with the wild-type R201 allele, the basal transcriptional activity of the D2 promoter was significantly increased in both mutants (C and H) (R 10733 +/- 2855, vs. C 18548 +/- 4514, vs. H 19032 +/- 4410 RLU +/- SD, P < 0.001).
  
  
  CONCLUSIONS
  Thyroid pathology is a common occurrence in MAS. Consistent with the molecular etiology of the disease, the shift in T(3) to T(4) ratio is at least in part secondary to a cAMP-mediated intrathyroidal activation of D2 and to elevated D1 activity.
authors: Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Clinical Research Center, room 6-3940, 10 Center Drive MSC 1613, Bethesda, MD 20892-1613, USA. fc93a@nih.gov
authors: Francesco S
authors: FS
authors: Celi
authors: Giuseppe
authors: G
authors: Coppotelli
authors: Aaron
authors: A
authors: Chidakel
authors: Marilyn
authors: M
authors: Kelly
authors: Beth A
authors: BA
authors: Brillante
authors: Thomas
authors: T
authors: Shawker
authors: Natasha
authors: N
authors: Cherman
authors: Penelope P
authors: PP
authors: Feuillan
authors: Michael T
authors: MT
authors: Collins
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D004252:DNA Mutational Analysis; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic / Q000150:complications* / Q000201:enzymology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D006801:Humans; D007223:Infant; D007453:Iodide Peroxidase / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D013971:Thyrotoxicosis / Q000201:enzymology / Q000209:etiology*; D014162:Transfection; D014284:Triiodothyronine / Q000009:adverse effects; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D002864:Chromogranins; D019205:GTP-Binding Protein alpha Subunits, Gs; D007453:Iodide Peroxidase; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II; C406732:GNAS protein, human