Lack of consistent association of thyrotropin receptor mutations in vitro activity with the clinical course of patients with sporadic non-autoimmune hyperthyroidism

Lueblinghoff, Julia; Mueller, Sandra; Sontheimer, J.; Paschke, Ralf

doi:10.1007/bf03345784

Cited by 18 publications

(17 citation statements)

References 34 publications

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“…Therefore, our in vitro data show that the genotype alone could not explain the phenotypic severity of our familial cases with the M453T mutation. As suggested previously, other genetic and/or environmental factors are likely to influence the phenotype of nonautoimmune hyperthyroidism (10,11,18,19).…”

Section: Discussionmentioning

confidence: 74%

“…To date, ~30 constitutively activating TSHR mutations have been reported in nonautoimmune hyperthyroidism (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(15)(16)(17)(18)(19). Most of the activating mutations are present in TMD 1, 2, 3, and 5.…”

Section: Discussionmentioning

confidence: 99%

“…First, regarding goiter, its onset is variable even in cases and families harboring the same mutations of TSHR (10,11,16,18,19). In some patients, a goiter develops before the onset of clinical findings of hyperthyroidism (15); however, in other patients, the manifestation of hyperthyroidism precedes the onset of goiter (7,8,11,12,16).…”

Section: Discussionmentioning

confidence: 99%

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A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation

et al. 2014

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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. conclusion: We demonstrate that the M453R mutation is the cause of nonautoimmune hyperthyroidism.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

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A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation

et al. 2014

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“…(27) analyzed a possible genotype-phenotype correlation in a systematic review of the SNAH cases reported to date. They could not find any consistent association between the degree of in vitro activity of each TSHR mutant and the clinical course of patients with SNAH, and concluded that this may be due, at least in part, to the restricted number of case reports and limited follow-up.…”

Section: Discussionmentioning

confidence: 99%

Severe congenital non-autoimmune hyperthyroidism associated to a mutation in the extracellular domain of thyrotropin receptor gene

Scaglia

Chiesa

Bastida³

et al. 2012

Arq Bras Endocrinol Metab

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Activating mutations in the TSH Receptor (TSHR) gene have been identified as the molecular basis for congenital non-autoimmune hyperthyroidism. We describe the clinical findings and molecular characterization in a girl who presented severe non-autoimmune hyperthyroidism since birth, born to a mother with autoimmune thyroid disease. She was treated with methylmercaptoimidazol and β-blockers, but remained hyperthyroid and required total thyroidectomy. To characterize the presence of an activating mutation, the whole coding sequence and intron-exon boundaries of TSHR gene were analyzed. The patient was heterozygous for p.Ser281Asn mutation and p.Asp727Glu polymorphism. This recurrent mutation, p.Ser281Asn, characterized in vitro by increased basal production of cAMP, is the unique germline activating gene variant described so far in the extracellular domain of TSH receptor. Interestingly, the patient's mother presented hyperthyroidism but without any TSHR gene activating mutation. Although congenital non-autoimmune hyperthyroidism is a rare condition, it should be investigated when severe disease persists, even in a newborn from an autoimmune hyperthyroid mother, in order to differentiate it from the more common congenital autoimmune disease. Arq Bras Endocrinol Metab. 2012;56(8):513-8

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“…Analysis of genotype-phenotype correlations in nonautoimmune hyperthyroidism have shown no consistent relationship between in vitro activity of the mutant TSHR and the clinical course of the disease (31), suggesting that other genetic, epigenetic, and environmental modifiers, including iodine intake, might also affect clinical features. 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).…”

Section: Discussionmentioning

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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Lack of consistent association of thyrotropin receptor mutations in vitro activity with the clinical course of patients with sporadic non-autoimmune hyperthyroidism

Cited by 18 publications

References 34 publications

A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation

A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation

Severe congenital non-autoimmune hyperthyroidism associated to a mutation in the extracellular domain of thyrotropin receptor gene

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

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