title: A new phenotype of nongoitrous and nonautoimmune hyperthyroidism caused by a heterozygous thyrotropin receptor mutation in transmembrane helix 6.
abstract: BACKGROUND
  Activating mutations in the TSHR gene were found in patients suffering from nonautoimmune hyperthyroidism. In the past, it was assumed that thyroid hyperplasia is due to constitutive activation of the Gs/adenylyl cyclase signaling pathway; however, the physiological role of the Gq/11 pathway in this context remains unclear.
  
  
  OBJECTIVE
  In this study, we investigated molecular details of the TSHR in a patient with nonautoimmune and nongoitrous hyperthyroidism.
  
  
  RESULTS
  We detected a heterozygous mutation in exon 10 of the TSHR gene leading to an exchange of a cysteine residue for tryptophan at amino acid position 636 in transmembrane helix 6. Functional characterization of the mutant receptor revealed a slight reduction of the cell surface expression and TSH induced cAMP accumulation compared to the wild type. Additional observations included a constitutive activation of the Gs-mediated signaling pathway and a simultaneous nearly complete loss-of-function for the Gq/11 pathway after bovine TSH stimulation. Studies on TSHR models suggest significant changes of important amino acid interactions and the overall helix arrangement caused by mutation C636W.
  
  
  CONCLUSIONS
  We report a patient in whom a TSHR mutation leads to nonautoimmune hyperthyroidism due to a mutation that constitutively activates the Gs signaling pathway but additionally completely inhibits the Gq/11 pathway. The absence of goiter in the patient suggests that the Gq/11 pathway is related to thyroid growth and that different signaling pathways are mediated and regulated by TSH. These functional data could be confirmed by reproducible findings of two siblings with a constitutive activation for both pathways.
authors.affiliation: Institute of Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Winkler
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
authors.forename: Patrick
authors.initials: P
authors.lastname: Tarnow
authors.forename: Anne
authors.initials: A
authors.lastname: Rediger
authors.forename: Lisa
authors.initials: L
authors.lastname: Grohmann
authors.forename: Imke
authors.initials: I
authors.lastname: Gaetjens
authors.forename: Gerd
authors.initials: G
authors.lastname: Krause
authors.forename: Dagmar
authors.initials: D
authors.lastname: L'Allemand
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
mesh_terms: D000293:Adolescent; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D006980:Hyperthyroidism / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011989:Receptors, Thyrotropin / Q000235:genetics*
chemical_list: D011989:Receptors, Thyrotropin