Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a novel somatic mutation (serine281--&gt;isoleucine) in the extracellular domain of the thyrotropin receptor.

Kopp, Peter; Muirhead, Sarah; Jourdain, N; Gu, Wen; Jameson, J. Larry; Rodd, Celia

doi:10.1172/jci119687

Cited by 126 publications

(61 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although most of the gain-of-function mutations were found in the TM region of different GPCRs (12)(13)(14), studies using thyrotropin and gonadotropin receptors indicate that point mutations in the ectodomain could also confer conformational changes in their TM regions. These point mutations were found in the hinge region of TSH and gonadotropin receptors (15)(16)(17)(18) and suggest the importance of the ectodomains of these receptors in constraining their TM region. In addition, deletion of the ectodomain of the TSH receptor also led to the constitutive activity of the TM region (19), whereas recent photoaffinity labeling and cross-linking experiments suggest a direct interaction between the hinge region and exoloop 2 of the LH receptor (20).…”

mentioning

confidence: 95%

The Ectodomain of the Luteinizing Hormone Receptor Interacts with Exoloop 2 to Constrain the Transmembrane Region

Nishi

Nakabayashi

Kobilka

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Lutropin (LH) and follitropin (FSH) receptors belong to a group of leucine-rich repeat-containing, G proteincoupled receptors (LGRs) found in vertebrates and flies.We fused the ectodomain of human LH or FSH receptors to the transmembrane region of fly LGR2. The chimeric human/fly receptors, unlike their wild type counterparts, exhibited ligand-independent constitutive activity. Because ectodomains likely interact with exoloops to constrain the receptors, individual exoloops of the chimeric receptor containing the ectodomain of the LH receptor and transmembrane region of fly LGR2 was replaced with LH receptor sequences. Chimeric receptors with the ectodomain and exoloop 2, but not exoloop 1 or 3, from LH receptors showed decreases in constitutive activity, but ligand treatment stimulated cAMP production. Furthermore, substitution of key resides in the hinge region of fly LGR2 with LH receptor sequences led to constitutive receptor activation; however, concomitant substitution of the homologous exoloop 2 of the LH receptor decreased G s coupling. These results suggest that the hinge region of the LH receptor interacts with exoloop 2 to constrain the receptor in an inactive conformation whereas ligand binding relieves this constraint, leading to G s activation.The receptors for lutropin (LH), 1 follitropin (FSH), and thyrotropin (TSH) belong to the large G protein-coupled receptor (GPCR) family with seven-transmembrane (TM) helices, but are unique in having a large N-terminal extracellular (ecto-) domain containing leucine-rich repeats important for interaction with the glycoprotein ligands (1, 2). Recent studies indicate the evolution of a large family of the leucine-rich repeat-containing, G protein-coupled receptors (LGRs) with at least seven members in mammals, including the well studied glycoprotein hormone receptors (3, 4) and LGR4 -7 (5, 6). In addition, homologous LGRs were found in fly (LGR1 and LGR2) (7, 8), nematode (nLGR) (9), sea anemone (10), and snail (11). These genes can be divided into three subgroups, each with unique structural characteristics (6). Understanding of the evolutionary relationship of these receptors and the availability of recombinant proteins provided the opportunity to elucidate their ligand-signaling mechanisms.The allosteric ternary complex model proposes the isomerization of GPCRs from an inactive to an active state capable of coupling to G proteins (12). This isomerization involves conformational changes that may be induced or can occur spontaneously, thus allowing the constrained receptor to relax into an active conformation. The active conformation could be achieved following ligand activation of GPCRs or by gain-of-function mutations discovered in constitutively activated GPCRs. Although most of the gain-of-function mutations were found in the TM region of different , studies using thyrotropin and gonadotropin receptors indicate that point mutations in the ectodomain could also confer conformational changes in their TM regions. These point mutations were found in the hinge...

show abstract

mentioning

confidence: 95%

The Ectodomain of the Luteinizing Hormone Receptor Interacts with Exoloop 2 to Constrain the Transmembrane Region

Nishi

Nakabayashi

Kobilka

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In addition, 22 cats had no detected mis-sense mutations in any nodules, and an additional four cats harboured only the S6 polymorphism thought not to be associated with the disease (Nguyen et al 2002). Activating mutations may occur in exons 1-9 in these cats; however, there have been very few mutations detected in the extracellular region of the human TSHR gene (Duprez et al 1997b, Kopp et al 1997b, Parma et al 1997, Gruters et al 1998, Biebermann et al 2000. Mutations may also occur in other genes involved in the signalling transduction pathway of the TSHR, and mutations have previously been found in a Gs subunit (a protein coupled to the TSHR) gene, in both human and feline hyperthyroidism (Lyons et al 1990, O'Sullivan et al 1991, Russo et al 1995, Parma et al 1997, Murakami et al 1999, Tonacchera et al 1999, Trulzsch et al 2001, Peeters et al 2002, Vanvooren et al 2002, Georgopoulos et al 2003.…”

Section: Tablementioning

confidence: 97%

Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism

Watson¹,

Radford²,

Kipar³

et al. 2005

Journal of Endocrinology

View full text Add to dashboard Cite

Hyperthyroidism is the most common endocrinopathy in cats, and is both clinically and histopathologically very similar to human toxic nodular goitre (TNG). Molecular studies on human TNG have revealed the presence of mis-sense mutations in the thyroid-stimulating hormone receptor (TSHR) gene, most frequently in exon 10. Our hypothesis was that similar mutations exist in hyperthyroid cats. Genomic DNA was extracted from 134 hyperplastic/ adenomatous nodules (from 50 hyperthyroid cats), and analysed for the presence of mutations in exon 10 of the TSHR gene. 11 different mutations were detected, one silent and 10 mis-sense, of which nine were somatic mutations. 28 of the 50 cats (67/134 nodules) had at least one mis-sense mutation. The mis-sense mutations were Met-452

show abstract

“…Toxic thyroid hyperplasia occuring at various ages in at least two generations, absence of thyroid antibodies, lack of ophthalmopathy-dermopathy and autosomal dominant inheritance suggest this condition (42). In addition, it may be related with sporadic germline mutations.…”

Section: Autosomal Dominant Non-autoimmune Hyperthyroidismmentioning

confidence: 99%

“…In addition, it may be related with sporadic germline mutations. Late-onset and mild hyperthyroidism is generally observed in hereditary TSHR-activated mutations, whereas severe neonatal thyrotoxicosis is observed in sporadic cases, though this is not a definite rule (42). Different clinical pictures in individuals with the same mutation suggest that environmental factors and genetic-epigenetic mechanisms are also involved.…”

Section: Autosomal Dominant Non-autoimmune Hyperthyroidismmentioning

confidence: 99%

Fetal neonatal hyperthyroidism: diagnostic and therapeutic approachment

Kurtoğlu¹,

Özdemır²

2017

Turk Pediatri Ars

View full text Add to dashboard Cite

Fetal and neonatal hyperthyroidism may occur in mothers with Graves' disease. Fetal thyrotoxicosis manifestation is observed with the transition of TSH receptor stimulating antibodies to the fetus from the 17th-20th weeks of pregnancy and with the fetal TSH receptors becoming responsive after 20 weeks. The diagnosis is confirmed by fetal tachycardia, goiter and bone age advancement in pregnancy and maternal treatment is conducted in accordance. The probability of neonatal hyperthyroidism is high in the babies of mothers that have ongoing antithyroid requirement and higher antibody levels in the last months of pregnancy. Clinical manifestation may be delayed by 7-17 days because of the antithyroid drugs taken by the mother. Neonatal hyperthyroidism symptoms can be confused with sepsis and congenital viral infections. Herein, the diagnosis and therapeutic approach are reviewed in cases of fetal neonatal hyperthyroidism. (Turk Pediatri Ars 2017; 52: 1-9)

show abstract

Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a novel somatic mutation (serine281-->isoleucine) in the extracellular domain of the thyrotropin receptor.

Cited by 126 publications

References 38 publications

The Ectodomain of the Luteinizing Hormone Receptor Interacts with Exoloop 2 to Constrain the Transmembrane Region

The Ectodomain of the Luteinizing Hormone Receptor Interacts with Exoloop 2 to Constrain the Transmembrane Region

Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism

Fetal neonatal hyperthyroidism: diagnostic and therapeutic approachment

Contact Info

Product

Resources

About