The role of type 1 and type 2 5'-deiodinase in the pathophysiology of the 3,5,3'-triiodothyronine toxicosis of McCune-Albright syndrome.
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.
Celi
Francesco S
FS
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
Coppotelli
Giuseppe
G
Chidakel
Aaron
A
Kelly
Marilyn
M
Brillante
Beth A
BA
Shawker
Thomas
T
Cherman
Natasha
N
Feuillan
Penelope P
PP
Collins
Michael T
MT
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
D002864:Chromogranins; D019205:GTP-Binding Protein alpha Subunits, Gs; D007453:Iodide Peroxidase; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II; C406732:GNAS protein, human