title: A novel thyrotropin receptor germline mutation (Asp617Tyr) causing hereditary hyperthyroidism.
abstract: Constitutively activating germline mutations of the thyrotropin receptor (TSHR) gene have been identified as a molecular cause of hereditary nonautoimmune hyperthyroidism. We describe here a Japanese kindred with two affected individuals who showed overt hyperthyroidism and mild goiter in the absence of TSHR antibodies. A novel heterozygous germline point mutation, identified in both individuals, resulted in an amino acid substitution of aspartic acid for tyrosine at codon 617 (Asp617Tyr) in the third intracellular loop of the TSHR. Screening of 7 additional family members led to the identification of the same mutation in 4 relatives: 1 had undergone thyroidectomy due to hyperthyroidism but 3 were asymptomatic with subclinical hyperthyroidism. In vitro functional studies of the Asp617Tyr TSHR demonstrated a constitutive activation of the cyclic adenosine monophosphate pathway, but not of the inositol phosphate cascade, with data similar to those of Asp619Gly, the first constitutively activating mutant TSHR identified. Treatment with inorganic iodine for 7 months successfully relieved all symptoms of hyperthyroidism in both patients.
authors.affiliation: Kuma Hospital, Kobe, Japan.
authors.forename: Eijun
authors.initials: E
authors.lastname: Nishihara
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagayama
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amino
authors.forename: Akira
authors.initials: A
authors.lastname: Hishinuma
authors.forename: Toru
authors.initials: T
authors.lastname: Takano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Sumihisa
authors.initials: S
authors.lastname: Kubota
authors.forename: Shuji
authors.initials: S
authors.lastname: Fukata
authors.forename: Kanji
authors.initials: K
authors.lastname: Kuma
authors.forename: Akira
authors.initials: A
authors.lastname: Miyauchi
mesh_terms: D000328:Adult; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D006980:Hyperthyroidism / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics*; D018828:Immunoglobulins, Thyroid-Stimulating / Q000097:blood; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011193:Potassium Iodide / Q000627:therapeutic use; D011989:Receptors, Thyrotropin / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood; D014463:Ultrasonography
chemical_list: D018828:Immunoglobulins, Thyroid-Stimulating; D011989:Receptors, Thyrotropin; D014284:Triiodothyronine; D011193:Potassium Iodide; D015544:Inositol 1,4,5-Trisphosphate; D013972:Thyrotropin; D004247:DNA; D000242:Cyclic AMP; D013974:Thyroxine