Congenital Hyperthyroidism Caused by a Mutation in the Thyrotropin-Receptor Gene

Kopp, Peter; Sande, Jacqueline Van; Parma, Jasmine; Duprez, Laurence; Gerber, H; Joss, E; Jameson, J. Larry; Dumont, Jacques Emile; Vassart, Gilbert

doi:10.1056/nejm199501193320304

Cited by 304 publications

(204 citation statements)

References 25 publications

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“…Under these conditions the potency of the receptors was measured as activation of endogenous adenylyl cyclase. Since cAMP stimulates the growth and the di erentiation of thyroid cells, it was concluded that TSH-independent growth of thyroid autonomous adenomas was caused by these somatic activating mutations, which increased the basal cAMP levels (Parma et al, 1993Porcellini et al, 1994Porcellini et al, , 1995Kopp et al, 1995;Paschke et al, 1994). This is the ®rst demonstration that these mutations of the receptor confer TSH independent growth when expressed in thyroid cells.…”

Section: Discussionmentioning

confidence: 99%

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Mutations of thyrotropin receptor isolated from thyroid autonomous functioning adenomas confer TSH-independent growth to thyroid cells

et al. 1997

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TSH receptor mutants in the VI transmembrane segment, found in thyroid autonomously functioning adeonomas, have been expressed in di erentiated thyroid cells. All mutant receptors constitutively stimulated adenylyl cyclase. The biological activity, measured as cAMP production relative to the wild type receptor, was speci®c for each mutant in transient and stable transfection assays. Cells expressing these mutants proliferated in the absence of TSH. The rate of growth in the absence of TSH paralleled basal cAMP production for each mutant receptor. Low TSH concentrations stimulated the growth of mutant receptor-expressing cells, and not of the cells expressing the wild type receptor. Also, the entry in the cell cycle and the plating e ciency were markedly stimulated by the expression of the mutant receptors. These data provide a molecular link between the occurrence of TSH receptor mutations and thyroid autonomously functioning adenomas.

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Section: Discussionmentioning

confidence: 99%

“…A germ-line mutation located in the same domain of the receptor has also been reported in a case of congenital hyperthyroidism (Kopp et al, 1995).…”

Section: Introductionmentioning

confidence: 85%

Mutations of thyrotropin receptor isolated from thyroid autonomous functioning adenomas confer TSH-independent growth to thyroid cells

et al. 1997

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“…The current theory is that enhancement of the cAMP cascade relates to stimulation and control of functional characteristics in human and FRTL-5 (rat) thyrocytes, including iodide uptake and expression of thyroid-specific proteins thyroglobulin and thyroid peroxidase (Maenhaut et al, 1990). In agreement with this theory is the recent demonstration that gain-of-function mutations in the TSH-R cause hyperfunctioning thyroid adenomas (Parma et al, 1993) and congenital hyperthyroidism (Kopp et al, 1995), which are characterised by higher basal intracellular cAMP concentrations in agreement with the original report by Kasagi et al (1980) in a collection of human adenoma tissues. Dedifferentiating tumours may then be caused by activation of growth factor and phorbol ester cascades (Maenhaut et al, 1990;Mockel et al, 1994), and not through activation of cAMP cascade.…”

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confidence: 76%

Dissociation of thyrotropin receptor function and thyrotropin dependency in rat thyroid tumour cell lines derived from FRTL-5

Kallen

Coes²,

Grafhorst³

et al. 1996

Br J Cancer

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Summary Spontaneously transformed somatic thyrocyte mutants, FRTL-5/TA and FRTL-5/TP, are thyrotropin (TSH) independent for growth and show loss of the thyroid-specific phenotype, with absent thyroglobulin and thyroid peroxidase gene expression. To investigate the role of TSH-receptor (TSH-R) activation in rat thyroid growth and function, binding of TSH and TSH-induced cAMP production were measured in intact cells under identical assay conditions. TSH binding did not differ in terms of affinity and receptor number and presence of 5.6 kb and 3.3 kb mRNA rat TSH-R transcripts was determined in all variants. By contrast, basal cAMP was I1-fold lower in FRTL-5/TA and 6-fold lower in FRTL-5/TP than in wild-type FRTL-5 (1.1+0.4; P<0.01). Maximal cAMP production was similar between wild-type and cell variants and stimulation by bovine, rat and recombinant human TSH revealed normal activation patterns. Therefore, a dissociation was present between the loss of TSH control on growth and function, and the presence of a normally functioning TSH-R. Subsequent to TSH incubation FRTL-5/TP and FRTL-5/TA cells showed a different expression pattern of TSH-R and the proto oncogenes c-myc and fos than FRTL-5 wildtype. The data indicated that the cause of the TSH-independency is located down-stream of the cAMP cascade, influencing genes that control the expression of cell cycle-related proto-oncogenes and thyroid-specific genes.

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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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Congenital Hyperthyroidism Caused by a Mutation in the Thyrotropin-Receptor Gene

Cited by 304 publications

References 25 publications

Mutations of thyrotropin receptor isolated from thyroid autonomous functioning adenomas confer TSH-independent growth to thyroid cells

Mutations of thyrotropin receptor isolated from thyroid autonomous functioning adenomas confer TSH-independent growth to thyroid cells

Dissociation of thyrotropin receptor function and thyrotropin dependency in rat thyroid tumour cell lines derived from FRTL-5

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

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