A TSHR mutation causing an imbalance between iodide trapping and organification

TOPIC: A new type of mutation in the TSH receptor

Title: A familial thyrotropin (TSH) receptor mutation provides in vivo evidence that the inositol phosphates/Ca 2+ cascade mediates TSH action on thyroid hormone synthesis.

Authors: Grasberger H , Van Sande J , Hag-Dahood MA , Tenenbaum-Rakover Y , & Refetoff S.

Reference: Journal of Clinical Endocrinology & Metabolism 92: 2816-2820, 2007



TSH activates both the cAMP and inositol phosphates (IP) signaling cascades via binding to the TSH receptor (TSHR). Bi-allelic TSHR loss-of-function mutations cause resistance to TSH, and are clinically characterized by hyperthyrotropinemia, and normal or reduced thyroid gland volume, thyroid hormone output, and iodine uptake.


To study and report a novel familial TSHR mutation (L653V).

Methods & Results: Homozygous individuals expressing L653V had euthyroid hyperthyrotropinemia. Paradoxically, patients had significantly higher 2-hr radioiodide uptake and 2- to 24-hr radioiodide uptake ratios compared with heterozygous, and unaffected family members, suggesting an imbalance between the iodide trapping and organification. In transfected COS-7 cells, the mutant TSHR had normal surface expression, basal activity, and TSH-binding affinity, equally (2.2-fold) increased EC 50 values for TSH-induced cAMP and IP accumulation, and normal maximum cAMP generation. In contrast, the efficacy of TSH for generating IP was more than 7-fold lower with the mutant compared with wild-type TSHR.


A novel TSHR defect, preferentially affecting the IP pathway, with a phenotype distinct from previously reported loss-of-function mutations. This is the first in vivo evidence for the physiological role of the TSHR/IP/Ca 2+ cascade in regulating iodination. Such TSHR mutations could be the cause of partial organification defects.


In the human thyroid gland, the G s /cAMP pathway controls positively iodide uptake, proliferation and thyroid hormone secretion, whereas the G q /IP pathway stimulates iodination and thyroid hormone synthesis. IP-triggered Ca 2+ signal is known to stimulate the generation of H 2 O 2 crucial for all thyroid peroxidase-catalyzed reactions. In the patients with the novel TSHR mutation described herein, whose iodination and thyroid hormone synthesis are limited by a defect in the IP pathway, the elevated TSH levels caused increased iodide trapping. This new type of TSHR mutation could cause iodide organification defects.

Summary and commentary prepared by Takashi Akamizu (related to Chapter 16a of TDM)

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