Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations

Hebrant, Aline; Staveren, Wilma C.G. van; Maenhaut, Carine; Dumont, Jacques Emile; Leclère, J

doi:10.1530/eje-10-0775

Cited by 76 publications

(70 citation statements)

References 66 publications

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“…Somatic mutations are implicated in the pathogenesis of a number of endocrine adenomas, including GNAS1 mutations in growth hormone-secreting pituitary adenomas 18 and activating mutations in the thyrotropin receptor gene associated with thyroid adenomas. 19 It is also interesting that these somatic mutations often cluster around a few key amino acid residues. For example, in 40% of growth hormone-secreting adenomas somatic mutations substitute just 2 residues in GNAS1, encoding arginine 201 (R201) or glutamine 227 (Q227).…”

Section: Discussionmentioning

confidence: 99%

Somatic Mutations Affecting the Selectivity Filter of KCNJ5 Are Frequent in 2 Large Unselected Collections of Adrenal Aldosteronomas

et al. 2012

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Abstract-Primary hyperaldosteronism, one cause of which is aldosterone-producing adenomas (APAs), may account for Յ5% to 10% of cases of essential hypertension. Germline mutations have been identified in 2 rare familial forms of primary hyperaldosteronism, but it has been reported recently that somatic mutations of the KCNJ5 gene, which encodes a potassium channel, are present in some sporadic nonsyndromic APAs. To address this further we screened 2 large collections of sporadic APAs from the United Kingdom and Australia (totalling 73) and found somatic mutations in the selectivity filter of KCNJ5 in 41% (95% CI: 31% to 53%) of the APAs (30 of 73). These included the previously noted nonsynonymous mutations, G151R and L158R, and an unreported 3-base deletion, delI157, in the region of the selectivity filter. APAs containing a somatic KCNJ5 mutation were significantly larger than those without ( Key Words: hyperaldosteronism Ⅲ hypertension Ⅲ potassium channels Ⅲ KCNJ5 Ⅲ aldosterone-producing adenoma Ⅲ posture response P rimary hyperaldosteronism (PA) is now recognized as a common, treatable, and potentially curable form of hypertension, which may account for Յ10% of cases of socalled essential hypertension. [1][2][3] Most cases of PA are sporadic and result from 2 major types of adrenal pathology, an aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. In recently published series, the frequency of APA varied between 28% and 50% of patients with PA. 4 Choi et al 5 recently reported somatic mutations in a potassium channel, KCNJ5 (also called GIRK4 or Kir3.4), in 8 of 20 APAs studied and a germline mutation in the same gene in all 3 affected members of a family with florid, early onset, nondexamethasone-suppressible PA associated with marked hyperplasia of zona fasciculata (ZF), suggesting a novel pathway that might activate growth of aldosteronesecreting cells. These mutations within the selectivity filter of the potassium channel reduce the normal K ϩ /Na ϩ selectivity of the channel, and the resulting depolarization of the adrenocortical cell could lead to calcium loading and growth. However, the APAs carrying KCNJ5 mutations were large (mean of 2.8 cm and all Ͼ2 cm in diameter) and might represent a subgroup with a phenotype more relevant to the giant hyperplastic adrenals seen in the family with the germline KCNJ5 mutation. 5 To address this issue we have screened a large collection of APAs (totalling 73) from geographically distinct centers (United Kingdom and Australia) to determine whether somatic mutations of KCNJ5 are present in unselected APAs regardless of size. We also

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Section: Discussionmentioning

confidence: 99%

Somatic Mutations Affecting the Selectivity Filter of KCNJ5 Are Frequent in 2 Large Unselected Collections of Adrenal Aldosteronomas

et al. 2012

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“…Mutations in the TSHR gene result in either gain or loss of the receptor function. Gain-of-function mutations are the cause of the following three syndromes: Familial nonautoimmune hyperthyroidism (FNAH), sporadic congenital nonautoimmune hyperthyroidism (SCNAH) and autonomous adenomas (AA) (17). FNAH is also termed hereditary toxic thyroid hyperplasia or autosomal dominant autoimmune hyperthyroidism.…”

Section: Discussionmentioning

confidence: 99%

Identification and functional characterization of a novel thyrotropin receptor mutation (V87L) in a Chinese woman with subclinical hypothyroidism

Zhang

Zhou

Dong

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The thyrotropin receptor (TSHR) gene has been defined as a highly mutable gene. Mutations in the TSHR gene result in either gain or loss of the receptor function. Subclinical hypothyroidism (SH) is a clinical condition defined as an elevated serum TSH level associated with normal free thyroxine and free triiodothyronine. Chronic autoimmune thyroiditis is the most frequent cause of subclinical hypothyroidism in adults. In rare cases, a loss-of-function mutation of TSHR is the cause of SH. In the present study, a novel TSHR mutation (V87L; confirmed to be a loss-of-function mutation) was identified in a 59-year-old Chinese woman, as the potential cause of the patient's subclinical hypothyroidism. The case may provide valuable insight into the etiology of SH.

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“…To date, at least 20 different mutations have been identified as the cause of HNAH in 27 families with more than a hundred affected indivi duals, while only 15 subjects with 10 different mutations leading to SNAH have been described (10,11).…”

Section: Sumáriomentioning

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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Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations

Cited by 76 publications

References 66 publications

Somatic Mutations Affecting the Selectivity Filter of KCNJ5 Are Frequent in 2 Large Unselected Collections of Adrenal Aldosteronomas

Somatic Mutations Affecting the Selectivity Filter of KCNJ5 Are Frequent in 2 Large Unselected Collections of Adrenal Aldosteronomas

Identification and functional characterization of a novel thyrotropin receptor mutation (V87L) in a Chinese woman with subclinical hypothyroidism

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

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