Sporadic Congenital Hyperthyroidism due to a Germline Mutation in the Thyrotropin Receptor Gene (Leu 512 Gln) in a Japanese Patient

Nishihara, Eijun; Fukata, Shuji; Hishinuma, Akira; Kudo, Takumi; Ohye, Hidemi; M, Ito; Kubota, Sumihisa; Amino, Nobuyuki; Kuma, Kanji; Miyauchi, Akira

doi:10.1507/endocrj.k06-090

Cited by 40 publications

(42 citation statements)

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“…For amplification of Gαs exons 7-10, primers were: forward primer, 5'-ttc ttt ttc tcc caG ctt cct-3'; and reverse primer, 5'-GGt tGG tct GGt tGt cct cc-3'. Direct sequencing of PCR products was performed using the Bigdye terminator v1.1 cycle sequencing kit (Applied Biosystems, Foster city, ca) and an automatic ABI 3130 sequencer (Applied Biosystems), using each of the above primers or internal primers for exon 10 of the TSHR, as previously described [19,20]. results in a series of 45 aFtn, we found 29 somatic mutations: 22 in the TSHR gene and 7 in the Gsα gene (Table 1).…”

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

et al. 2009

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Abstract. Somatic mutations of the thyrotropin receptor (TSHR) gene and the gene encoding the α subunit of the stimulatory GTP-binding protein (Gsα) are the main cause for autonomously functioning thyroid nodules (AFTN) in iodine-deficient regions of the world. In iodine-sufficient regions, including Japan, the genetic relevance of AFTN is unclear. In a series of 45 Japanese subjects with AFTN, exons 9 and 10 of the TSHR and exons 7-10 of Gsα, where the activating mutations have been found, were analyzed using direct sequencing. We found 29 somatic mutations: 22 in the TSHR gene and 7 in the Gsα gene. The most frequent mutation in TSHR was Met453Thr (10 cases), followed by clustered residues from codons 630 through 633 on TSHR (7 cases). Mutations of Gsα were detected at codon 201 in 5 cases and at codon 227 in 2 cases. No patients had coexistent TSHR and Gsα mutations in the same nodule. All mutated residues but one, which was deleted at codon 403 on the TSHR gene, are constitutively active. The prevalences of a germline polymorphism of Asp727Glu on the TSHR gene and incidental papillary thyroid carcinoma in thyroid surgical specimens were similar to those reported in other studies. In the present study, more than half of the cases with AFTN had a somatic activating mutation either of the TSHR or Gsα gene, despite their high iodine intake.

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

et al. 2009

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“…On the other hand, iodine deficiency is the most common cause of hypothyroidism worldwide. Recently, it has been reported that mutation of the TSH receptor, as well as TR β, causes a broad spectrum of thyroid dysfunction, including hypothyroidism and hyperthyroidism [14][15][16]. Therefore it is necessary to bear these conditions in mind, as well as genetic disorder of the thyroid.…”

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confidence: 99%

Evaluation of Thyroid Hormone Action in a Case of Generalized Resistance to Thyroid Hormone with Chronic Thyroiditis: Discovery of a Novel Heterozygous Missense Mutation (G347A)

et al. 2007

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Abstract. Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of variable tissue hyporesponsiveness to thyroid hormone (TH). Its characteristics are a high level of TH and inappropriate lack of TSH suppression. RTH is mainly categorized as generalized RTH (GRTH), pituitary RTH (PRTH), and peripheral tissue RTH (PTRTH). Untreated subjects with GRTH usually achieve a normal metabolic state. We describe a 21-year-old Japanese woman with GRTH and coincidental chronic thyroiditis. Physical examination revealed palpable goiter, congenital alopecia on top of the head, and short stature. She showed elevated levels of free triiodothyronine (FT3) and free thyroxine (FT4), and an inappropriately normal level of TSH. Anti-thyroglobulin and anti-thyroid peroxidase antibodies were positive. A TRH stimulation test showed a normal TSH response. The patient received the standardized diagnostic protocol, administration of incremental doses of liothyronine (L-T3). The peak TSH level after the TRH stimulation test gradually decreased. The patient showed low sensitivity to TH in terms of bone metabolism, protein catabolism, lipid metabolism, and urine magnesium metabolism. Sequence analysis of the TR β gene was performed with informed consent, and this revealed a novel heterozygous mutation at codon 347 resulting in a GGG (glycine) to GCG (alanine) substitution (G347A). The patient was diagnosed as having GRTH with chronic thyroiditis, and carrying a novel mutation, G347A, of the TR β gene.

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“…Exon 10 of the TSHR encoding the entire intracellular and transmembrane regions and part of the proximal extracellular domain of the TSHR was amplified by the polymerase chain reaction (PCR) using High Fidelity PCR Master (Roche Diagnostics) as described previously (23). Direct sequencing of PCR products was performed using the Bigdye terminator v1.1 cycle sequencing kit (Applied Biosystems, Foster City, CA) and an automatic ABI 3130 sequencer (Applied Biosystems).…”

Section: Dna Sequencingmentioning

confidence: 99%

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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Sporadic Congenital Hyperthyroidism due to a Germline Mutation in the Thyrotropin Receptor Gene (Leu 512 Gln) in a Japanese Patient

Cited by 40 publications

References 26 publications

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

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

Evaluation of Thyroid Hormone Action in a Case of Generalized Resistance to Thyroid Hormone with Chronic Thyroiditis: Discovery of a Novel Heterozygous Missense Mutation (G347A)

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

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