Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism

Gözü, Hülya Ilıksu; Lüblinghoff, Julia; Bircan, Rıfat; Paschke, Ralf

doi:10.1016/j.mce.2010.02.001

Cited by 66 publications

(44 citation statements)

References 57 publications

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“…Up to this date more than 40 kinds of loss of function mutations in the TSHR gene have been reported as the causative defect in congenital hypothyroidism (64). By contrast, gain of function mutations in the TSHR gene were identified in familial non-autoimmune hyperthyroidism or sporadic non-autoimmune hyperthyroidism (65).…”

Section: Clinical Manifestation Of Th Signaling Related Mutations In mentioning

confidence: 99%

Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development

Kim

Mohan

2013

Bone Res.

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The importance of the thyroid hormone axis in the regulation of skeletal growth and maintenance has been well established from clinical studies involving patients with mutations in proteins that regulate synthesis and/or actions of thyroid hormone. Data from genetic mouse models involving disruption and overexpression of components of the thyroid hormone axis also provide direct support for a key role for thyroid hormone in the regulation of bone metabolism. Thyroid hormone regulates proliferation and/or differentiated actions of multiple cell types in bone including chondrocytes, osteoblasts and osteoclasts. Thyroid hormone effects on the target cells are mediated via ligand-inducible nuclear receptors/transcription factors, thyroid hormone receptor (TR) α and β, of which TRα seems to be critically important in regulating bone cell functions. In terms of mechanisms for thyroid hormone action, studies suggest that thyroid hormone regulates a number of key growth factor signaling pathways including insulin-like growth factor-I, parathyroid hormone related protein, fibroblast growth factor, Indian hedgehog and Wnt to influence skeletal growth. In this review we describe findings from various genetic mouse models and clinical mutations of thyroid hormone signaling related mutations in humans that pertain to the role and mechanism of action of thyroid hormone in the regulation of skeletal growth and maintenance. Keywords: thyroid hormone; bone; cartilage; growth factors; bone cells Bone Research (2013) 2: 146-161. doi: 10.4248/BR201302004 IntroductionThyroid hormone (TH) plays an important role in normal endochondral ossification and is essential for skeletal development, linear growth, maintenance of bone mass, and efficient fracture healing ( 1). Juvenile hypothyroidism causes growth arrest with delayed bone formation and mineralization, and T4 replacement induces rapid catch-up growth (2). By contrast, childhood thyrotoxicosis accelerates bone formation with premature closure of the growth plates and skull sutures, leading to short stature and craniosynostosis (3). Although there is considerable evidence regarding the importance of TH in skeletal development, the molecular mechanisms of TH action in bone are poorly understood. In this chapter, we discuss regulation and mechanisms of action of TH during skeletal development with particular emphasis on areas in which recent advances have been made. Physiology of TH: Regulation, metabolism and TH receptorRegulation Systemic TH levels are maintained by the classical negative feedback loop involving the hypothalamus-pituitary--thyroid (HPT) axis ( Figure 1). Thyrotropin releasing hormone (TRH) is synthesized in the paraventricular nucleus (PVN) of the hypothalamus and stimulates synthesis and secretion of thyroid stimulating hormone (TSH) fromHa-Young Kim et al. www.boneresearch.org | Bone Research 147thyrotroph cells in the anterior pituitary gland. TSH subsequently acts via the TSH receptor (TSHR) on thyroid follicular cells to stimulate synthesis and release of 3,5...

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Section: Clinical Manifestation Of Th Signaling Related Mutations In mentioning

confidence: 99%

Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development

Kim

Mohan

2013

Bone Res.

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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%

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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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“…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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Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism

Cited by 66 publications

References 57 publications

Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development

Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development

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

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