title: Two rare TSH receptor amino acid substitutions in toxic thyroid adenomas.
abstract: Toxic adenoma and toxic multinodular goiter (TMNG) are common causes of hyperthyroidism in iodine-deficient regions, but they are relatively rare in iodine-sufficient regions, including Japan.  Constitutive activating mutations of the thyroid stimulating hormone receptor (TSHR) gene and adenylate cyclase-stimulating G α protein (GNAS) gene are frequent in these thyrotoxic disorders.  Here we report two cases of rare TSHR gene mutations in Japanese thyrotoxicosis patients.  In Case 1, we observed multiple toxic nodules with thyrotoxicosis, and in Case 2, we detected a solitary toxic nodule in an 8-year-old girl.  In both cases, ultrasonography showed thyroid nodules and scintigraphy revealed increased uptake.  Total thyroidectomy was performed for Case 1 and a hemi-thyroidectomy was performed for Case 2.  Genetic analysis of the resected tissues revealed an I568F mutation in Case 1 and a S281I mutation in the TSHR gene in Case 2.  The I568F mutation was located in the second extracellular loop, and the S281I mutation was located in the N-terminal extracellular domain of the TSH receptor.  In Case 1, the mutation was restricted to the largest nodule, and was not detected in other functioning nodules or non-nodule thyroid tissue.  Bi-allelic expression of the TSHR gene was confirmed by reverse transcription-polymerase chain reaction in both tumors.  Both the I568F and S281I mutations were studied previously in vitro, and were revealed to cause basal activation of the protein kinase A pathway.  Case 1 represents the second reported case of an I568F mutation and Case 2 represents the third reported case of an S281I mutation.
authors: Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
authors: Kazutaka
authors: K
authors: Nanba
authors: Takeshi
authors: T
authors: Usui
authors: Sachiko
authors: S
authors: Minamiguchi
authors: Yusuke
authors: Y
authors: Mori
authors: Yoshiki
authors: Y
authors: Watanabe
authors: Keigo
authors: K
authors: Honda
authors: Ryo
authors: R
authors: Asato
authors: Kanako
authors: K
authors: Nakao
authors: Sachiko-Tsukamoto
authors: ST
authors: Kawashima
authors: Akiko
authors: A
authors: Yuno
authors: Tamiko
authors: T
authors: Tamanaha
authors: Tetsuya
authors: T
authors: Tagami
authors: Mitsuhide
authors: M
authors: Naruse
authors: Yuichi
authors: Y
authors: Akiyama
authors: Akira
authors: A
authors: Shimatsu
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D019943:Amino Acid Substitution; D002648:Child; D005260:Female; D006801:Humans; D007564:Japan; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D016606:Thyroid Nodule / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D013965:Thyroidectomy; D013971:Thyrotoxicosis / Q000209:etiology*
chemical_list: D009363:Neoplasm Proteins; D011989:Receptors, Thyrotropin