Prevalence of TSH Receptor and Gs.ALPHA. Mutations in 45 Autonomously Functioning Thyroid Nodules in Japan

Nishihara, Eijun; Amino, Nobuyuki; Maekawa, Keisuke; Yoshida, Hiroshi; M, Ito; Kubota, Sumihisa; Fukata, Shuji; Miyauchi, Akira

doi:10.1507/endocrj.k09e-073

Cited by 29 publications

(27 citation statements)

References 45 publications

(48 reference statements)

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“…However, a later detailed study of 134 nodules from 50 hyperthyroid cats found ten missense mutations, of which five have previously been associated with human hyperthyroidism (Watson et al 2005). The most common TSHR mutation detected in cats is Met452-Thr (a substitution of methionine by threonine), which is analogous to the human mutation Met453-Thr observed in sporadic human nodular goiter , Nishihara et al 2009). In addition, GNAS mutations have also been documented in four of ten hyperthyroid cats examined (Peeters et al 2002).…”

Section: Figurementioning

confidence: 98%

ANIMAL MODELS OF DISEASE: Feline hyperthyroidism: an animal model for toxic nodular goiter

Peterson¹

2014

Journal of Endocrinology

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Section: Figurementioning

confidence: 98%

ANIMAL MODELS OF DISEASE: Feline hyperthyroidism: an animal model for toxic nodular goiter

Peterson¹

2014

Journal of Endocrinology

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“…Although the prevalence of autonomous thyroid nodules causing hyperthyroidism is very low in Japan, where iodine intake is sufficient, the frequency of constitutively active somatic TSHR mutations in patients with this condition is similar to that in iodine-insufficient areas (32,33). In another family with hereditary nonautoimmune hyperthyroidism in Japan, the hyperthyroidism in the affected members was well controlled with inorganic iodine (17).…”

Section: Discussionmentioning

confidence: 97%

Subclinical Nonautoimmune Hyperthyroidism in a Family Segregates with a Thyrotropin Receptor Mutation with Weakly Increased Constitutive Activity

Nishihara

Chen

Higashiyama

et al. 2010

Thyroid

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Background: Subclinical hyperthyroidism is usually associated with Graves' disease or toxic nodular goiter. Here we report a family with hereditary subclinical hyperthyroidism caused by a constitutively activating germline mutation of the thyrotropin receptor (TSHR) gene. Methods: The proband was a 64-year-old Japanese woman who presented with a thyroid nodule and was found to be euthyroid with a suppressed serum TSH. The nodule was not hot. Although antibodies to thyroid peroxidase and thyroglobulin antibodies were present, TSHR antibodies were not detected by TSH-binding inhibition or by bioassay. Two of her middle-aged sons, but not her daughter, also had subclinical hyperthyroidism without TSHR antibodies. Without therapy, the clinical condition of the affected individuals remained unchanged over 3 years without development of overt hyperthyroidism. Results: A novel heterozygous TSHR point mutation causing a glutamic acid to lysine substitution at codon 575 (E575K) in the second extracellular loop was detected in the three family members with subclinical hyperthyroidism, but was absent in her one daughter with normal thyroid function. In vitro functional studies of the E575K TSHR mutation demonstrated a weak, but significant, increase in constitutive activation of the cAMP pathway. Conclusion: Although hereditary nonautoimmune overt hyperthyroidism is very rare, TSHR activating mutations as a cause of subclinical hyperthyroidism may be more common and should be considered in the differential diagnosis, especially if familial.

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“…Iodine deficiency is a wellknown risk factor for nodular thyroid disease [14,15]. Although the frequencies of TSHR and GNAS mutations in Japan had been believed to be much lower than those observed in iodine-deficient areas [7,8], a recent report suggests that the frequencies as well as the hot spots of TSHR and GNAS mutations are similar to those in iodine-deficient regions [9]. In our series, TSHR mutations were detected in 5 cases out of 8 cases (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…In iodine-deficient region, either codon 281 or 568 mutations are found in 6 out of 52 TSHR mutations (11.5%), including S281N in 1 case, S281T in 1 case and I568T in 4 cases [10]. A report from Japan, iodine sufficient region, these mutations are found in 2 out of 22 TSHR mutations (9.1%), including S281N in 1 case and I568T in 1 case [9].…”

Section: Casementioning

confidence: 90%

“…In iodinesufficient regions, toxic nodules in the thyroid gland are relatively rare [6], and the frequencies of TSHR and GNAS mutations in Japan are believed to be much lower than those observed in iodine-deficient regions [7,8]. A recent report, however, suggests that the frequencies of TSHR and GNAS mutations in Japan are similar to those in iodine-deficient regions [9].…”

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confidence: 99%

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Two rare TSH receptor amino acid substitutions in toxic thyroid adenomas

et al. 2012

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Seven transmembrane (7TM) receptors play important roles in various biologic signal transduction systems, including endocrine and neural regulation. Mutations in these receptors cause various health disorders. Gain-of-function mutations in the thyroid stimulating hormone receptor (TSHR) gene result in hyperthyroidism [1]. In addition to germ-line mutations, somatic mutations of the TSHR gene and the adenylate cyclase-stimulating G α protein (GNAS) gene are responsible for toxic adenoma and toxic multinodular Abstract. Toxic adenoma and toxic multinodular goiter (TMNG) are common causes of hyperthyroidism in iodinedeficient 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.

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Prevalence of TSH Receptor and Gs.ALPHA. Mutations in 45 Autonomously Functioning Thyroid Nodules in Japan

Cited by 29 publications

References 45 publications

ANIMAL MODELS OF DISEASE: Feline hyperthyroidism: an animal model for toxic nodular goiter

ANIMAL MODELS OF DISEASE: Feline hyperthyroidism: an animal model for toxic nodular goiter

Subclinical Nonautoimmune Hyperthyroidism in a Family Segregates with a Thyrotropin Receptor Mutation with Weakly Increased Constitutive Activity

Two rare TSH receptor amino acid substitutions in toxic thyroid adenomas

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