Germline mutations in the thyrotropin receptor gene cause non–autoimmune autosomal dominant hyperthyroidism

Duprez, Laurence; Parma, Jasmine; Sande, Jacqueline Van; Allgeier, Anouk; Leclère, J; Schvartz, Claire; Delisle, M. J.; Decoulx, M; Orgiazzi, Jacques; Dumont, Jacques Emile; Vassart, Gilbert

doi:10.1038/ng0794-396

Cited by 367 publications

(235 citation statements)

References 25 publications

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“…In previous studies, germ line and somatic mutations of the TSH-R, which might cause hyperthyroidism have been reported [9][10][11][12][13]. The common clinical characteristics of these patients with congenital hyperthyroidism include autosomal dominant mode of inheritance [10], no signs or symptoms of autoimmnune thyroid disease, and no detection of anti-TSH-R antibodies and anti-thyroid antibodies [10][11][12][13].…”

Section: Discussionmentioning

confidence: 99%

“…The common clinical characteristics of these patients with congenital hyperthyroidism include autosomal dominant mode of inheritance [10], no signs or symptoms of autoimmnune thyroid disease, and no detection of anti-TSH-R antibodies and anti-thyroid antibodies [10][11][12][13].…”

Section: Discussionmentioning

confidence: 99%

“…The structure of the C-terminal half of the TSH-R is characteristic of members of the G protein-coupled receptor family and plays an important role in signal transduction [3]. Recently, some cases of hyperthyroidism caused by germ line and somatic mutations of the TSH-R gene have been reported [9][10][11][12][13].…”

Section: The Main Causes Of Hyperthyroidismmentioning

confidence: 99%

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Genomic DNA Analysis of Thyrotropin Receptor in a Family with Hereditary Hyperthyroidism.

et al. 2000

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Abstract.Mutations of the thyrotropin receptor (TSH-R) gene have been reported in some cases of hyperthyroidism.We report a case of a family that had a high incidence of hyperthyroidism (6/13) which strongly suggested hereditary factors. We then analyzed whether the family had mutations of the TSH-R gene. No significant mutations in exon 10 of the TSH-R gene were found in the patient by restriction fragment length polymorphism analysis and polymerase chain reaction direct sequencing, when compared with those with 4 normal subjects and 2 patients with Graves' disease. Unknown mutations in the extracellular region of the receptor or other genes in this family remain to be studied.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Genomic DNA Analysis of Thyrotropin Receptor in a Family with Hereditary Hyperthyroidism.

et al. 2000

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“…For Tg, a signi®cant increase was also induced by over-expression of wtTSHR, re¯ecting its limited constitutive activity Parma et al, 1993;Duprez et al, 1994) but interestingly this was not associated with any increase in cAMP. We also investigated expression of another recently cloned thyroid-speci®c gene ± the Na + /I 7 symporter (Dai et al, 1996) ± although the non-availability of antibodies restricted this to assessment of transcript abundance.…”

Section: Activated Gsp and Tshr Both Confer Tsh-independent Growth Anmentioning

confidence: 97%

Contrasting effects of activating mutations of GαS and the thyrotropin receptor on proliferation and differentiation of thyroid follicular cells

et al. 1999

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The cyclic AMP pathway is a major regulator of thyrocyte function and proliferation and, predictably, its inappropriate activation is associated with a sub-set of human thyroid tumours. Activating mutations are, however, more common in the thyrotropin receptor (TSHR) than in its downstream transducer, Gas. To investigate whether this re¯ects an inherent di erence in their oncogenic potency, we compared the e ects of retrovirally-transduced mutant (A623I) TSHR or (Q227L) Gas (GSP), using the rat thyroid cell line FRTL5 and primary human thyrocytes. In FRTL5, expression of GSP or mutant (m) TSHR induced a 2 ± 3-fold increase in basal levels of cAMP. This was associated with TSH-independent proliferation (assessed by both cell number and DNA synthesis) and function (as shown by increased expression of thyroglobulin (Tg) and the sodium/iodide symporter). In primary cultures, expression of mTSHR, but not GSP, consistently induced formation of colonies with epithelial morphology and thyroglobulin expression, capable of 10 ± 15 population doublings (PD) compared to less than three in controls. Thus, while mTSHR and GSP exert similar e ects in FRTL5, use of primary cultures reveals a major di erence in their ability to induce sustained proliferation in normal human thyrocytes, and provides the ®rst direct evidence that mTSHR is su cient to initiate thyroid tumorigenesis.

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“…Mutations in genes of this pathway are often observed in thyroid tumors independent of TSH in their secretory function and growth. Mutations in the TSHR gene have been observed in human adenomas (Russo et al, 1995a;Paschke et al, 1994;Parma et al, 1993) and in congenital hyperthyroidism (Duprez et al, 1994;Kopp et al, 1995;De Roux et al, 1996;Tonacchera et al, 1996). These mutated TSHR permanently activate adenylyl cyclase; some of them also activate the phosphatidylinositide pathway .…”

Section: Introductionmentioning

confidence: 99%

Oncogenic potential of a mutant human thyrotropin receptor expressed in FRTL-5 cells

et al. 1998

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An abnormal stimulation of the cAMP pathway has been recognized as the primary event in various pathological situations that lead to goitrogenesis or thyroid tumors. Thyroid adenomas are monoclonal neoplasms that become independent of thyroid stimulating hormone (TSH) in their secretory function and growth. Mutated forms of the TSH receptor (TSHR) and the adenylyl cyclase-activating Gsa protein, which confer a constitutive activity on these proteins, have been observed in human adenomas. The FRTL-5 rat thyroid cell line is a permanent but untransformed line; the growth of which depends on the presence of TSH, and at least in part, on the stimulation of the cAMP pathway. In order to compare the oncogenic potential of the activated mutant Gsa protein and the constitutively activated TSHR, we have transfected FRTL-5 cells with an expression vector bearing either the cDNA of the Gsa gene carrying the A201S mutation or the cDNA of the TSH receptor carrying the M453T mutation recently identi®ed in a case of congenital hyperthyroidism. The expression of these two cDNAs was driven by the bovine thyroglobulin gene promoter. We show that, although the expression of both the Gsa or TSHR mutant proteins leads to TSHindependent proliferation and to constitutive cAMP accumulation in FRTL-5 cells, only the mutant TSHR is able to induce neoplastic transformation, as demonstrated by growth in semi-solid medium and tumorigenesis in nude mice.

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Germline mutations in the thyrotropin receptor gene cause non–autoimmune autosomal dominant hyperthyroidism

Cited by 367 publications

References 25 publications

Genomic DNA Analysis of Thyrotropin Receptor in a Family with Hereditary Hyperthyroidism.

Genomic DNA Analysis of Thyrotropin Receptor in a Family with Hereditary Hyperthyroidism.

Contrasting effects of activating mutations of GαS and the thyrotropin receptor on proliferation and differentiation of thyroid follicular cells

Oncogenic potential of a mutant human thyrotropin receptor expressed in FRTL-5 cells

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