title: A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation.
abstract: BACKGROUND
  Hyperthyroidism caused by activating mutations of the thyrotropin receptor gene (TSHR) is rare in the pediatric population.
  
  
  METHODS
  We found a Japanese family with hyperthyroidism without autoantibody. DNA sequence analysis of TSHR was undertaken in this family. The functional consequences for the Gs-adenylyl cyclase and Gq/11-phospholipase C signaling pathways and cell surface expression of receptors were determined in vitro using transiently transfected human embryonic kidney 293 cells.
  
  
  RESULTS
  We identified a heterozygous mutation (M453R) in exon 10 of TSHR. In this family, this mutation was found in all individuals who exhibited hyperthyroidism. The results showed that this mutation resulted in constitutive activation of the Gs-adenylyl cyclase system. However, this mutation also caused a reduction in the activation capacity of the Gq/11-phospholipase C pathway, compared with the wild type.
  
  
  CONCLUSIONS
  We demonstrate that the M453R mutation is the cause of nonautoimmune hyperthyroidism.
authors.affiliation: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Akie
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Morikawa
authors.affiliation: Department of Pediatrics, Obihiro Kyokai Hospital, Obihiro, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Aoyagi
authors.affiliation: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Katsura
authors.initials: K
authors.lastname: Ishizu
authors.affiliation: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tajima
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D001483:Base Sequence; D015153:Blotting, Western; D005260:Female; D005434:Flow Cytometry; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D006980:Hyperthyroidism / Q000151:congenital* / Q000235:genetics; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D011989:Receptors, Thyrotropin / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D011989:Receptors, Thyrotropin; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases