The Role of Type 1 and Type 2 5′-Deiodinase in the Pathophysiology of the 3,5,3′-Triiodothyronine Toxicosis of McCune-Albright Syndrome

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Abstract

Context:

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.

Design:

This was a retrospective analysis.

Setting:

The study was conducted at the National Institutes of Health Clinical Center.

Patients:

The study included 100 consecutive MAS patients.

Interventions:

There were no interventions.

Main Outcome Measure:

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 T3 to T4 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).

Conclusion:

Thyroid pathology is a common occurrence in MAS. Consistent with the molecular etiology of the disease, the shift in T3 to T4 ratio is at least in part secondary to a cAMP-mediated intrathyroidal activation of D2 and to elevated D1 activity.

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