Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening

Baquedano, María Sonia; Ciaccio, Marta; Dujovne, Noelia; Herzovich, Viviana; Longueira, Yésica; Warman, Diana M.; Rivarola, Marco A.; Belgorosky, Alicia

doi:10.1210/jc.2010-0223

Cited by 38 publications

(38 citation statements)

References 26 publications

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“…The transcriptional and posttranscriptional mechanisms involved in TSH glycosylation result in folding of these subunits, leading to their heterodimerization. These mechanisms also qualitatively regulate TSH secretion, prevent intracellular degradation, and influence TSH clearance rate from the circulation (14,15). A three-dimensional TSH structure has been proposed in the 1990s based on crystallographic studies and comparisons with other glycoprotein hormones (16), but the schemes have not been fully confirmed by more recent studies, including structures of the follicle stimulating hormone extracellular domain and the TSH extracellular domain (17)(18)(19).…”

Section: Glycosylation Patterns and Tsh Bioactivitymentioning

confidence: 99%

“…In such patients, serum FT4 is low-normal or reduced, and serum free triiodothyronine (FT3) concentrations usually remain normal until thyroid function level has markedly declined (52). In an iodine-sufficient patient, a transient elevation in TSH occurs during the recovery phase after a severe illness (15), when the hypothalamic-pituitarythyroid axis is temporarily overactive. In general, such patients do not have an underlying thyroid dysfunction.…”

Section: Tsh Measurementsmentioning

confidence: 99%

“…Immunometric assays based on monoclonal antibodies of murine origin are more prone to HAMA interference than competitive immunoassays because HAMA are able to form a bridge between the capture and signal antibody reagents and create a signal that is reported as a falsely high value (15,103). Of concern are the instances when such HAMA interferences produce inappropriately normal values in patients who eventually prove to have clinical disease (104).…”

Section: Human Antimouse Antibodiesmentioning

confidence: 99%

“…Extremely rare conditions associated with elevated TSH include inherited autosomal recessive forms of partial (euthyroid hyperthyrotropinemia) or complete (congenital hypothyroidism) TSH resistance that are associated with biallelic inactivating point mutations of the TSHR gene (15). Inherited dominant forms of partial TSH resistance have also been described in the absence of TSHR gene mutations (15).…”

mentioning

confidence: 99%

“…Inherited dominant forms of partial TSH resistance have also been described in the absence of TSHR gene mutations (15). More frequently, in patients who have elevated serum FT4, normal or elevated TSH requires further investigation for resistance to thyroid hormone or a thyrotroph tumor (123,124).…”

mentioning

confidence: 99%

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Thyrotropin Isoforms: Implications for Thyrotropin Analysis and Clinical Practice

Estrada

Soldin

Buckey

et al. 2014

Thyroid

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Serum thyrotropin (TSH) is considered the single most sensitive and specific measure of thyroid function in the general population owing to its negative logarithmic association with free triiodothyronine and free thyroxine concentrations. It is therefore often the test of choice for screening, diagnosis, and monitoring of primary hypothyroidism. Serum TSH concentrations can be analyzed quantitatively using third-generation immunoassays, whereas its bioactivity can be measured by TSH activity assays in cell culture. Theoretically, if serum TSH concentrations are directly related to TSH activity, the two tests should yield comparable results. However, on occasion, the results are discordant, with serum concentrations being higher than TSH biological activity. This review focuses on the dissociation between the clinical state and serum TSH concentrations and addresses clinically important aspects of TSH analysis. Thyrotropin SynthesisT hyrotropin (TSH) is a heterodimeric 28-kDa-glycoprotein hormone released from the anteromedial pituitary and is a regulator of thyroid function. Its synthesis is controlled by the hypothalamic neuropeptide TSH-releasing hormone (TRH). The two peptide subunits of TSH are noncovalently linked and cotranslationally glycosylated with mannose-rich oligosaccharides (1). Posttranslationally, the two subunits are combined and the attached oligosaccharides are further processed. Synthesis of a mature TSH molecule requires the excision of signal peptides from both TSH a-and b-subunits, followed by trimming of mannose and further addition of fucose, galactose, and sialic acids (2). Thus, mature TSH molecules are asparagine-(N)-linked [Asp(N)-linked] complex carbohydrate structures capped with sulfate and/or sialic acid molecules (3,4) (Fig. 1). TSH oligosaccharide structures vary according to the source of TSH: human pituitaryderived TSH comprises fucosylated biantennary glycans with terminal N-acetylgalactosamine sulfate and low sialic acid content (5-7), while recombinant human TSH (rhTSH), synthesized in Chinese hamster ovary cells, specifically terminates in a2,3-linked sialic acid (8-11) and rhTSH formed in yeast lacks sialic acid residues altogether (12). Glycosylation Patterns and TSH BioactivityAppropriate glycosylation is necessary to maintain normal TSH bioactivity (13). Indeed, both a-and b-subunits of TSH have functionally important domains associated with TSH receptor (TSHR) binding and activation. The a-subunit has two Asp(N)-linked oligosaccharide chains with a typical biantennary structure, while TSH b-subunit has only one chain (Fig. 2). The transcriptional and posttranscriptional mechanisms involved in TSH glycosylation result in folding of these subunits, leading to their heterodimerization. These mechanisms also qualitatively regulate TSH secretion, prevent intracellular degradation, and influence TSH clearance rate from the circulation (14,15). A three-dimensional TSH structure has been proposed in the 1990s based on crystallographic studies and comparisons with other glyco...

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Section: Glycosylation Patterns and Tsh Bioactivitymentioning

confidence: 99%

Section: Tsh Measurementsmentioning

confidence: 99%

Section: Human Antimouse Antibodiesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Thyrotropin Isoforms: Implications for Thyrotropin Analysis and Clinical Practice

Estrada

Soldin

Buckey

et al. 2014

Thyroid

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Analysis on DNA sequence of TSHB gene and its association with reproductive seasonality in goats

et al. 2012

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Thyroid stimulating hormone beta chain (TSHB) is mainly expressed in pituitary and its expression is closely related to photoperiodic control of seasonal reproduction in animals. In the present study, ten primer pairs have been used to clone the DNA sequence and to detect genetic mutations of goat TSHB gene. Two DNA fragments of goat TSHB gene were obtained, which were 2,614 and 1,031 bp in length, respectively. They comprised about 2.5 kb 5' regulatory region, all of the three exons and two introns. Goat TSHB gene has a coding region of 417 bp, encoding 138 amino acids which was predicted to be a secretory protein with a signal peptide of 16 amino acids. The sequence of TSHB gene is highly conserved among mammals. In addition, five mutations (C53A, 3 bp Indel at the 287-289 locus, 34 bp Indel at the 584-617 locus, A1819C and E2_72TA) were found in goat TSHB gene and they were shown to be in strong linkage disequilibrium. Interestingly, the genotype distributions for both single locus and haplotype have shown to be significant different between seasonal and nonseasonal goat breeds. And haplotype H2 and diplotype H2/H4 may be related to year-round estrus. We preliminarily presumed that the five closely linked mutations of goat TSHB gene may be part of the causal sources for the diversities of reproductive seasonality in goats. Our study may provide a possible efficient genetic way to decrease seasonality in goats.

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Endogenous and Synthetic Regulators of the Peripheral Components of the Hypothalamo-Hypophyseal-Gonadal and -Thyroid Axes

Шпаков

2021

Neurosci Behav Physi

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Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening

Cited by 38 publications

References 26 publications

Thyrotropin Isoforms: Implications for Thyrotropin Analysis and Clinical Practice

Thyrotropin Isoforms: Implications for Thyrotropin Analysis and Clinical Practice

Analysis on DNA sequence of TSHB gene and its association with reproductive seasonality in goats

Endogenous and Synthetic Regulators of the Peripheral Components of the Hypothalamo-Hypophyseal-Gonadal and -Thyroid Axes

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