Normal Level of Thyroglobulin Messenger Ribonucleic Acid ina Human Congenital Goiter with Thyroglobulin Deficiency*

Cabrer, Bartolomé; Brocas, Huguette; Pérez-Castillo, Ana; Pohl, Viviane; Navas, José J.; Targovnik, Héctor M.; Centenera, J. A. García; Vassart, Gilbert

doi:10.1210/jcem-63-4-931

Cited by 15 publications

(5 citation statements)

References 28 publications

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“…6 B ). Similar ER distention was found upon thyroid electron microscopy of kindred N (not shown), as well as other similar kindreds (25)(26)(27)(28)(29). Taken together, the data in Figs.…”

Section: Resultssupporting

confidence: 87%

“…In human congenital hypothyroid goiter with deficient Tg, postulated defects have included abnormal mRNA splicing, translation, protein transport, posttranslational modifications, or exocytosis, although the most frequently described morphological phenotype involves an enlarged thyroid gland with minimal Tg in the follicle lumen, and intracellular Tg immunopositivity within a distended, vesiculated ER (25)(26)(27)(28)(29). This has led us to ask whether a thyroid ERSD similar to that of cog / cog mice might occur in humans.…”

Section: Introductionmentioning

confidence: 99%

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Congenital hypothyroid goiter with deficient thyroglobulin. Identification of an endoplasmic reticulum storage disease with induction of molecular chaperones.

Medeiros‐Neto

Kim²,

Yoo³

et al. 1996

J. Clin. Invest.

123

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Recent advances in understanding the molecular pathogenesis of congenital hypothyroid goiter in cog / cog mice, have raised important questions concerning the maturation of thyroglobulin (the thyroid prohormone) in certain human kindreds with congenital goiter. We have now examined affected siblings from two unrelated families that synthesize an apparently normally glycosylated, Ͼ 300 kD immunoreactive thyroglobulin, yet have a reduced quantity of intraglandular thyroglobulin and that secreted into the circulation. From thyroid tissues of the four patients, light microscopic approaches demonstrated presence of intracellular thyroglobulin despite its absence in thyroid follicle lumina, while electron microscopy indicated abnormal distention of the endoplasmic reticulum (ER). We have confirmed biochemically that most intrathyroidal thyroglobulin fails to reach the (Golgi) compartment where complex carbohydrate modification takes place. Moreover, the disease in the affected patients is associated with massive induction of specific ER molecular chaperones including the hsp90 homolog, GRP94, and the hsp70 homolog, BiP. The data suggest that these patients synthesize a mutant thyroglobulin which is defective for folding/assembly, leading to a markedly reduced ability to export the protein from the ER. Thus, these kindreds suffer from a thyroid ER storage disease, a cell biological defect phenotypically indistinguishable from that found in cog / cog mice.

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“…6 B ). Similar ER distention was found upon thyroid electron microscopy of kindred N (not shown), as well as other similar kindreds (25)(26)(27)(28)(29). Taken together, the data in Figs.…”

Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Congenital hypothyroid goiter with deficient thyroglobulin. Identification of an endoplasmic reticulum storage disease with induction of molecular chaperones.

Medeiros‐Neto

Kim²,

Yoo³

et al. 1996

J. Clin. Invest.

123

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“…Abnormalities of Tg are associated with genetically determined congenital goiters and hypothyroidism in humans and some animal species (3)(4)(5)(6)(7)(8)(9). The best studied Tg abnormality, demonstrated in goitrous Afri¬ kander cattle, is caused by a nonsense point mutation and alternative splicing of the Tg mRNA (10,11).…”

Section: Introductionmentioning

confidence: 99%

Low-Molecular-Weight Iodoproteins in the Congenital Goiters of cog/cog Mice*

Fogelfeld

Harel²,

Beamer³

et al. 1992

Thyroid

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Previously we described sedimentation and immunologic abnormalities of thyroglobulin (Tg) in a strain of mice with inherited congenital goiter and hypothyroidism (cog/cog). The goals of the present study were to determine the extent to which thyroid gland stimulation by TSH accounts for the abnormal properties of cog/cog Tg and to characterize further the abnormally small iodoproteins found in cog/cog mice. Cog/cog and control +/cog and BALB/c mice were fed with either normal or thyroid-hormone-containing diets and were injected with Na125I. Sucrose density gradient centrifugation of labeled thyroid extracts from cog/cog mice on normal diet showed that 82% of the iodine was in iodoproteins smaller than Tg, with sedimentation rates of 3-8S. No 12S and 19S peaks, characteristic of normal Tg, were present, but distinct and stable 12S and 19S peaks emerged after recentrifugation of the 12S and 19S areas. In contrast, in cog/cog mice treated with T4, a smaller (55%) amount of 3-8S iodoproteins and distinct 12S and 19S peaks were present. In both groups of mice, the labeled 3-8S iodoproteins were composed of three fractions: 15% precipitated by antirat Tg serum, 38% precipitated by antimouse albumin serum, and 47% not precipitated by either serum. The 3-8S iodoproteins contained labeled MIT and DIT and no T4. On sodium dodecyl sulfate polyacrylamide gel electrophoresis the 3-8S iodoprotein fraction that reacted with anti-Tg serum contained a distinct electrophoretic band at 49K. The 3-8S nonreactive iodoproteins resolved into several bands of lower molecular weight. We conclude that the 3-8S iodoproteins in cog/cog mice are heterogeneous and that TSH stimulation contributes to the production of these low-molecular-weight iodoproteins.

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“…Lefranc et al 1981;Targovnik, Pohl, Christophe et al 1984;Cabrer, Brocas, Perez-Castillo et al 1986;Monticelli, Avvedimento, Mariano et al 1987). In…”

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Interleukin-1 inhibits thyrotrophin-induced human thyroglobulin gene expression

Yamashita

Kimura²,

Ashizawa³

et al. 1989

Journal of Endocrinology

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The regulation of thyroglobulin (Tg) and its specific mRNA by interleukin-1 (IL-1) in cultured human thyrocytes was investigated. Specific binding of 125I-labelled IL-1 on thyrocytes was confirmed by solid-phase binding assay. Thyrocytes dispersed from Graves' thyroid tissues were incubated with TSH with or without recombinant human IL-1. TSH stimulated Tg release from cultured human thyrocytes in a dose- and time-dependent manner. Both IL-1 alpha and beta inhibited TSH-induced Tg release at concentrations ranging from 0.01 to 10 U/ml. The suppressive activities of IL-1 alpha and beta were similar. They did not alter the basal level of Tg release. Unstimulated human thyrocytes did not contain any detectable Tg mRNA, but TSH-stimulated thyrocytes expressed a single species of Tg mRNA (8.5 kb). Both IL-1 alpha and beta inhibited TSH-induced Tg mRNA in a dose-responsive manner. IL-1 (10 U/ml) caused maximal suppression of TSH-induced Tg mRNA to nearly basal levels. In contrast, the gamma-actin mRNA hybridization signal was not altered in control or treated cells. Furthermore, IL-1 stimulated [3H]thymidine uptake into thyrocyte DNA. These results demonstrate that IL-1 directly inhibits TSH-induced Tg gene expression and provide further support for a functional role of IL-1 as a local modulator of thyroid hormone synthesis.

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Normal Level of Thyroglobulin Messenger Ribonucleic Acid ina Human Congenital Goiter with Thyroglobulin Deficiency*

Cited by 15 publications

References 28 publications

Congenital hypothyroid goiter with deficient thyroglobulin. Identification of an endoplasmic reticulum storage disease with induction of molecular chaperones.

Congenital hypothyroid goiter with deficient thyroglobulin. Identification of an endoplasmic reticulum storage disease with induction of molecular chaperones.

Low-Molecular-Weight Iodoproteins in the Congenital Goiters of cog/cog Mice*

Interleukin-1 inhibits thyrotrophin-induced human thyroglobulin gene expression

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