title: Identification and functional analysis of novel inactivating thyrotropin receptor mutations in patients with thyrotropin resistance.
abstract: OBJECTIVE
  We identified and analyzed novel thyrotropin (TSH) receptor mutations in three Japanese families with resistance to TSH.
  
  
  METHODS
  The TSH receptor gene was sequenced and the mutations were determined. The mutant TSH receptors were transfected into COS-7 cells, and their functions were analyzed.
  
  
  METHODS
  The patients were compound-heterozygotes for the R450H mutation and novel mutations in the TSH receptor gene. The first patient was a compound-heterozygote for R450H and V473I. The second sibling possessed R450H and R519C. The third sibling had R450H and R519G.
  
  
  RESULTS
  The R450H mutant exhibited moderately impaired receptor functions and a moderately decreased cell surface expression in agreement with previous results. The V473I mutant exhibited an almost normal TSH binding, a slightly decreased cyclic adenosine monophosphate (cAMP) response, a moderately decreased inositolphosphate (IP) response, and an almost normal cell surface expression. TSH binding and TSH stimulation of cAMP and IPs were markedly decreased in the R519C and R519G mutants. Cell surface expression was decreased in the R519C mutant and negligible in the R519G mutant. All of these mutants showed normal intracellular synthesis of TSH receptors.
  
  
  CONCLUSIONS
  These novel inactivating mutations contribute to understanding of the structure-function relationship of the TSH receptor. To date, all of the patients with TSH resistance resulting from TSH receptor mutations identified in Japan possessed the R450H mutation at least in one allele. These observations suggest that the R450H mutation is a commonly observed TSH receptor mutation in patients with TSH resistance in Japan.
authors.affiliation: Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tsunekawa
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Onigata
authors.forename: Tadashi
authors.initials: T
authors.lastname: Morimura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kasahara
authors.forename: Soroku
authors.initials: S
authors.lastname: Nishiyama
authors.forename: Tomohito
authors.initials: T
authors.lastname: Kamoda
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
authors.forename: Akihiro
authors.initials: A
authors.lastname: Morikawa
authors.forename: Masami
authors.initials: M
authors.lastname: Murakami
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011989:Receptors, Thyrotropin / Q000235:genetics*; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics*; D013972:Thyrotropin / Q000235:genetics*
chemical_list: D011989:Receptors, Thyrotropin; D013972:Thyrotropin