title: Nonclassic TSH resistance: TSHR mutation carriers with discrepantly high thyroidal iodine uptake.
abstract: BACKGROUND
  Inactivating mutations in the TSH receptor gene (TSHR) cause TSH resistance. Most patients with TSH resistance have low to normal thyroidal radioiodine uptake (RAIU), which is consistent with the physiological knowledge that TSH stimulates iodine uptake. To date, only one TSHR mutation-carrying family with discrepantly high RAIU has been reported.
  
  
  OBJECTIVE
  We aimed to test whether TSHR mutation carriers with high RAIU are observed in a cohort of Japanese patients with congenital hypothyroidism (CH).
  
  
  METHODS
  Twenty-four Japanese CH patients with high RAIU were screened for TSHR mutations. The capacities of mutant TSHR to activate Gs- and Gq-coupled signaling pathways were evaluated in vitro.
  
  
  RESULTS
  Two patients were found to have biallelic TSHR mutations: p.[T145I]+[R450H] in one and p.[R450H]+[I661fs] in the other. The two subjects had permanent CH with slightly high RAIU (41.8 and 43.0%, reference 8-40) but did not have goiter. One had a slightly high perchlorate discharge rate (10%, reference <10). Expression experiments revealed that T145I-TSHR retained partial ability to transduce both Gs- and Gq-coupled pathways, whereas I661fs-TSHR could transduce neither of them. R450H-TSHR had partial ability to transduce Gs-coupled signaling but had abrogated ability to transduce Gq-coupled signaling, indicating that coupling to Gq was dominantly affected.
  
  
  CONCLUSIONS
  We show that 8% of Japanese CH patients with high RAIU (two in 24) has inactivating TSHR mutations. Expression of this apparently discrepant phenotype, which we term nonclassic TSH resistance, is presumably associated with the characteristic signaling property of the mutant TSHR, namely the Gq-dominant coupling defect.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Narumi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagasaki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ishii
authors.forename: Koji
authors.initials: K
authors.lastname: Muroya
authors.forename: Yumi
authors.initials: Y
authors.lastname: Asakura
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D002648:Child; D015331:Cohort Studies; D003409:Congenital Hypothyroidism / Q000000981:diagnostic imaging / Q000208:ethnology / Q000235:genetics*; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D006801:Humans; D007455:Iodine / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011877:Radionuclide Imaging; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013961:Thyroid Gland / Q000502:physiology*
chemical_list: D007457:Iodine Radioisotopes; D011989:Receptors, Thyrotropin; D007455:Iodine; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs