Molecular advances in thyroglobulin disorders

Rivolta, Carina M.; Targovnik, Héctor M.

doi:10.1016/j.cca.2006.05.043

Cited by 58 publications

(83 citation statements)

References 229 publications

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“…20, 28, and 29 with others reviewed in Ref. 24). Both defective intramolecular chaperone function (14) and defective Tg dimerization (31) are expected consequences of such mutations.…”

Section: Discussionmentioning

confidence: 89%

“…In human congenital hypothyroidism with deficient Tg, the ChEL domain is a commonly affected site of mutation, including the recently described A2215D (20,21), R2223H (22), G2300D, R2317Q (23), G2355V, G2356R, and the skipping of exon 45 (which normally encodes 36 amino acids), as well as the Q2638stop mutant (24) (in addition to polymorphisms including P2213L, W2482R, and R2511Q that may be associated with thyroid overgrowth (25)). As best as is currently known, all of the congenital hypothyroidism-inducing Tg mutants are defective for intracellular transport (26).…”

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confidence: 99%

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The Cholinesterase-like Domain, Essential in Thyroglobulin Trafficking for Thyroid Hormone Synthesis, Is Required for Protein Dimerization

Lee

Wang

Jeso

et al. 2009

Journal of Biological Chemistry

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The carboxyl-terminal cholinesterase-like (ChEL) domain of thyroglobulin (Tg) has been identified as critically important in Tg export from the endoplasmic reticulum. In a number of human kindreds suffering from congenital hypothyroidism, and in the cog congenital goiter mouse and rdw rat dwarf models, thyroid hormone synthesis is inhibited because of mutations in the ChEL domain that block protein export from the endoplasmic reticulum. We hypothesize that Tg forms homodimers through noncovalent interactions involving two predicted ␣-helices in each ChEL domain that are homologous to the dimerization helices of acetylcholinesterase. This has been explored through selective epitope tagging of dimerization partners and by inserting an extra, unpaired Cys residue to create an opportunity for intermolecular disulfide pairing. We show that the ChEL domain is necessary and sufficient for Tg dimerization; specifically, the isolated ChEL domain can dimerize with full-length Tg or with itself. Insertion of an N-linked glycan into the putative upstream dimerization helix inhibits homodimerization of the isolated ChEL domain. However, interestingly, co-expression of upstream Tg domains, either in cis or in trans, overrides the dimerization defect of such a mutant. Thus, although the ChEL domain provides a nidus for Tg dimerization, interactions of upstream Tg regions with the ChEL domain actively stabilizes the Tg dimer complex for intracellular transport.

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“…20, 28, and 29 with others reviewed in Ref. 24). Both defective intramolecular chaperone function (14) and defective Tg dimerization (31) are expected consequences of such mutations.…”

Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

The Cholinesterase-like Domain, Essential in Thyroglobulin Trafficking for Thyroid Hormone Synthesis, Is Required for Protein Dimerization

Lee

Wang

Jeso

et al. 2009

Journal of Biological Chemistry

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“…Previous reports have mainly examined reproductive functions [2][3][4] and the abnormalities of the thyroglobulin gene [1,9,10]. There has been no study investigating the pituitary-adrenal functions in the rdw rat, although hypothyroidism is known to cause adrenal dysfunction.…”

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confidence: 99%

Pituitary-Adrenal Functions in a Hereditary Hypothyroid (rdw) Rat

et al. 2010

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Abstract:The rdw rat is a hereditary hypothyroid strain isolated from Wistar-Imamichi rats. In the present study, adrenocorticotropic hormone (ACTH) and corticosterone responses to restraint stress (120 min) were examined in rdw adult male rats. ACTH response to restraint stress was higher in rdw rats than in hetero control rats. The plasma concentrations of corticosterone were lower in rdw rats than in control rats during the first 30 min after the onset of stress. Both ACTH and corticosterone responses to restraint stress in rdw rats recovered to control levels after thyroxine (T4) replacement therapy. These results suggest that hereditary hypothyroidism causes adrenal dysfunction directly and that hypersecretion of ACTH is a result of reduced corticosterone in rdw rats. Key words: ACTH, corticosterone, hypothyroid A. Tohei, Laboratory Animal Research Center, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Japan Thyroid hormone has been reported to play an important role in adrenal function [16]. Hypothyroidism reduces the weight of the adrenals [5,12] and the plasma concentration of corticosterone, and also affects circadian adrenocortical rhythm [8]. We have reported that hypothyroidism causes adrenal dysfunction directly and results in hypersecretion of ACTH [12][13][14]16] mediated by corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) in the hypothalamus [13].The WIC-Tg rdw (rdw) rat is a hereditary hypothyroid strain which was isolated as a dwarf model from a closed colony of Wistar-Imamichi (WIC) rats [7,18,19]. Previous reports have mainly examined reproductive functions [2-4] and the abnormalities of the thyroglobulin gene [1,9,10]. There has been no study investigating the pituitary-adrenal functions in the rdw rat, although hypothyroidism is known to cause adrenal dysfunction.To investigate the effect of hereditary hypothyroidism on the pituitary-adrenal function, we examined the plasma concentrations of ACTH and corticosterone in response to restraint stress for 2 h in the present study. The rdw rats and normal littermates (Wistar-Imamichi) were produced by mating adult F 1 male and female rats, as previously reported [2][3][4]. Adult (12-15 weeks old) male rdw and age-matched hetero control (+/-) rats were used in the present study. The thyroid and adrenal func--Note-

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“…Elimination of this exon does not affect the reading frame of the mRNA and potentially codifi es a shortened polypeptide. The deletion is localized in the TG type III repeat domain, causing the loss of 1-putative N-linked glycosylation site (5,17). The loss of 46 aminoacids can modify the tertiary and quaternary structure of the protein.…”

Section: Discussionmentioning

confidence: 99%

“…Thyroglobulin (TG) is a large glycoprotein synthesized by the thyroid gland, and functions as a matrix for thyroid hormone synthesis (4). Thirty-eight inactivating mutations have been identifi ed, characterized in the human TG gene and associated to congenital goiter and hypothyroidism (5). We have previously identifi ed the intronic IVS30+1G>T mutation in two Brazilian families with a complex history of fetal goiter and congenital goiter, born to consanguineous parents (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

A molecular analysis and long-term follow-up of two siblings with severe congenital hypothyroidism carrying the IVS30+1G>T intronic thyroglobulin mutation

Rubio

Galrão

Pardo

et al. 2008

Arq Bras Endocrinol Metab

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Objective: To extend the molecular analysis of the IVS30+1G>T intronic thyroglobulin (TG) mutation, and to report the eleven year follow-up of the affected patients. Methods: Two siblings with severe congenital hypothyroidism with fetal and neonatal goiter, harboring the IVS30+1G>T mutation were included. Nodular and non-nodular thyroid tissue specimens were collected. Specifi c thyroid genes expression was evaluated by real-timePCR and by immunohistochemistry. Results: In non-nodular tissue specifi c thyroid genes mRNA were reduced when compared to normal thyroid sample. In the nodule, TPO and NIS expression was very low. Microscopic examinations showed very large follicular-lumina and swollen vesicles of endoplasmatic-reticulum. Strong cytoplasmatic and low follicular-lumen TG immunostaining were detected. Intracellular NIS, membrane TPO and TSHR immunostaining had higher positivity in nonnodular sample. Both patients had a long-term adequate developmental outcome, besides one patient have been lately-treated. Conclusions: IVS30+1G>T mutation not only lead to very enlarge endoplasmatic-reticulum, but also to alterations of specifi c thyroid genes expression. The clinical evolution of patients harboring these mutations strengthen the concept of the infl uence of environment, like iodine nutrition, to determine the fi nal phenotypic appearance. RESUMO Análise Molecular e Acompanhamento a Longo Prazo de Dois Irmãos com Hipotireoidismo Congênito Portadores da Mutação Intrônica IVS30+1G>T noGene da Tireoglobulina. Objetivo: Aprofundar a análise molecular da mutação intrônica IVS30+1G>T do gene tireoglobulina (TG) e relatar a clínica de pacientes portadores da mutação, acompanhados por 11 anos. Métodos: Foram estudados dois irmãos com hipotireoidismo congênito grave com bócio fetal e bócio neonatal, portadores da mutação IVS30+1G>T. Foram coletadas amostras de tecido nodular e não-nodular. Avaliou-se a expressão de genes específi cos da tireóide por PCR em tempo real e imunohistoquímica. Resultados: A expressão de genes específi -cos da tireóide foi menor no tecido não-nodular que no tecido normal controle. Expressões de TPO e NIS foram extremamente baixas no tecido nodular. Verifi cou-se lúmen folicular aumentado com grandes vesículas de retículo endoplasmático, e detectou-se forte marcação de TG no citoplasma e fraca no lúmen folicular. No tecido não-nodular observou-se forte positividade de NIS intracelular e, TPO e TSHR na membrana plasmática. O acompanhamento em longo prazo dos pacientes mostrou adequado desenvolvimento, apesar de um deles ter recebido tratamento tardio. Conclusões: A mutação IVS30+1G>T não só promove alterações no retículo endoplasmático, como alterações na expressão de genes específi cos da tireóide. A evolução clínica destes pacientes reforça o conceito da infl uência do meio ambiente, como o aporte nutricional de iodo, no fenótipo fi nal.

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Molecular advances in thyroglobulin disorders

Cited by 58 publications

References 229 publications

The Cholinesterase-like Domain, Essential in Thyroglobulin Trafficking for Thyroid Hormone Synthesis, Is Required for Protein Dimerization

The Cholinesterase-like Domain, Essential in Thyroglobulin Trafficking for Thyroid Hormone Synthesis, Is Required for Protein Dimerization

Pituitary-Adrenal Functions in a Hereditary Hypothyroid (rdw) Rat

A molecular analysis and long-term follow-up of two siblings with severe congenital hypothyroidism carrying the IVS30+1G>T intronic thyroglobulin mutation

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