title: A familial thyrotropin (TSH) receptor mutation provides in vivo evidence that the inositol phosphates/Ca2+ cascade mediates TSH action on thyroid hormone synthesis.
abstract: BACKGROUND
  In the human thyroid gland, TSH activates both the cAMP and inositol phosphates (IP) signaling cascades via binding to the TSH receptor (TSHR). Biallelic TSHR loss-of-function mutations cause resistance to TSH, clinically characterized by hyperthyrotropinemia, and normal or reduced thyroid gland volume, thyroid hormone output, and iodine uptake.
  
  
  OBJECTIVE
  We report and study a novel familial TSHR mutation (L653V).
  
  
  RESULTS
  Homozygous individuals expressing L653V had euthyroid hyperthyrotropinemia. Paradoxically, patients had significantly higher 2-h radioiodide uptake and 2- to 24-h radioiodide uptake ratios compared with heterozygous, unaffected family members, suggesting an imbalance between 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 EC50 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.
  
  
  CONCLUSIONS
  We identified and characterized a TSHR defect, preferentially affecting the IP pathway, with a phenotype distinct from previously reported loss-of-function mutations. Results provide the first in vivo evidence for the physiological role of the TSHR/IP/Ca2+ cascade in regulating iodination. According to systematic in vitro mutagenesis studies, other TSHR mutations can result in even complete loss of IP signaling with retained cAMP induction. We hypothesize that such TSHR mutations could be the cause in unexplained partial organification defects.
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois 60637, USA. hgrasber@uchicago.edu
authors: Helmut
authors: H
authors: Grasberger
authors: Jacqueline
authors: J
authors: Van Sande
authors: Ahmad
authors: A
authors: Hag-Dahood Mahameed
authors: Yardena
authors: Y
authors: Tenenbaum-Rakover
authors: Samuel
authors: S
authors: Refetoff
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002648:Child; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D010375:Pedigree; D010641:Phenotype; D011989:Receptors, Thyrotropin / Q000097:blood* / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D013959:Thyroid Diseases / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism*; D013963:Thyroid Hormones / Q000096:biosynthesis*
chemical_list: D007295:Inositol Phosphates; D011989:Receptors, Thyrotropin; D013963:Thyroid Hormones; D000242:Cyclic AMP; D002118:Calcium