Iodide handling disorders (NIS, TPO, TG, IYD)

Targovnik, Héctor M.; Citterio, Cintia E.; Rivolta, Carina M.

doi:10.1016/j.beem.2017.03.006

Cited by 86 publications

(44 citation statements)

References 92 publications

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“…p.Q570L in South Asians) suggesting that they may be an even more frequent contributor to CH than previously recognized (60). Mutations in SLC5A5, and IYD seem rare, with IYD mutations only identified in five families (55) and DUOXA2 mutations are also uncommon although probably occur most frequently in East Asian cases (59). Although Pendred syndrome occurs more frequently in the general population (estimated incidence 7.5-10 per 100 000), CH is a rare association such that Pendrin mutations account for less than 5% of CH (2,61,62).…”

Section: Netrin 1 (Ntn1)mentioning

confidence: 90%

“…The frequencies of dyshormonogenesis-associated mutations are heavily influenced by ethnicity, including the presence of founder mutations, and selection criteria for the study population. TG mutations are a common cause of dyshormonogenesis with an estimated frequency of at least 1:100 000 births (55). TPO defects represent the commonest cause of total iodide organification defect (TIOD, 56), and frequently underlie dyshormonogenesis in European and Pakistani cases (57) but may occur less frequently in East Asian individuals (58,59).…”

Section: Netrin 1 (Ntn1)mentioning

confidence: 99%

“…Thyroid dysfunction associated with NIS or TG mutations can range from severe CH to euthyroid goitre, especially if dietary iodine content is high. TPO mutations usually cause severe CH although milder cases with PIOD have been described, sometimes due to monoallelic defects (55) and both TG and TPO mutations are rarely associated with foetal goitre. Homozygous IYD mutation carriers generally exhibit goitrous congenital or childhood-onset hypothyroidism, and one heterozygote has also been described with hypothyroidism and goitre (55,76).…”

Section: Clinical Phenotypes In Dyshormonogenesismentioning

confidence: 99%

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DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

Peters

Trotsenburg

Schoenmakers

2018

European Journal of Endocrinology

112

103

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Congenital hypothyroidism (CH) may be primary, due to a defect affecting the thyroid gland itself, or central, due to impaired thyroid-stimulating hormone (TSH)-mediated stimulation of the thyroid gland as a result of hypothalamic or pituitary pathology. Primary CH is the most common neonatal endocrine disorder, traditionally subdivided into thyroid dysgenesis (TD), referring to a spectrum of thyroid developmental abnormalities, and dyshormonogenesis, where a defective molecular pathway for thyroid hormonogenesis results in failure of hormone production by a structurally intact gland. Delayed treatment of neonatal hypothyroidism may result in profound neurodevelopmental delay; therefore, CH is screened for in developed countries to facilitate prompt diagnosis. Central congenital hypothyroidism (CCH) is a rarer entity which may occur in isolation, or (more frequently) in association with additional pituitary hormone deficits. CCH is most commonly defined biochemically by failure of appropriate TSH elevation despite subnormal thyroid hormone levels and will therefore evade diagnosis in primary, TSH-based CH-screening programmes. This review will discuss recent genetic aetiological advances in CH and summarize epidemiological data and clinical diagnostic challenges, focussing on primary CH and isolated CCH.

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Section: Netrin 1 (Ntn1)mentioning

confidence: 90%

Section: Netrin 1 (Ntn1)mentioning

confidence: 99%

Section: Clinical Phenotypes In Dyshormonogenesismentioning

confidence: 99%

See 1 more Smart Citation

DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

Peters

Trotsenburg

Schoenmakers

2018

European Journal of Endocrinology

112

103

View full text Add to dashboard Cite

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“…From the viewpoint of enhancing thyroid hormone biosynthesis, Hsp90b1 (GRP94) and Pdia4 (ERp72) encourage prolongation of Tg folding and export as molecular chaperones in the maturation of Tg and promote thyroid hormone biosynthesis (Kuznetsov, Chen, & Nigam, ; Muresan & Arvan, ). Besides, Atp1a1, Atp1a2, Atp1b3 and Fxyd2 are Na + /K + ‐ATPase pumps, which generate the ion gradients required for the active uptake of iodide from the bloodstream into the thyroid gland (Targovnik, Citterio, & Rivolta, ). We do not know why all of these genes except for Atp1a2 were upregulated only in TPO inhibitor treatments.…”

Section: Discussionmentioning

confidence: 99%

Specific alteration of gene expression profile in rats by treatment with thyroid toxicants that inhibit thyroid hormone synthesis

Ôhara

Yamada

Fukuda

et al. 2018

J of Applied Toxicology

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Transcriptomics technologies have been used for risk assessment of chemicals, mainly to predict the modes of action (MOAs) of chemicals or identify biomarkers. Transcriptomics data may also be helpful to understand MOAs of chemicals at the molecular level in more detail. As an example of the known MOAs, there are two MOAs of thyroid toxicity: inhibition of thyroid hormone synthesis ("direct" effect) and hypermetabolism of thyroid hormone by enzyme induction in liver ("indirect" effect). In the present study, global profiles of gene expression were analyzed in rats treated with chemicals acting directly on the thyroid (thyroid peroxidase inhibitors such as propylthiouracil and methimazole) and chemicals acting indirectly on the thyroid (hepatic enzyme inducers such as phenobarbital and pregnenolone-16α-carbonitrile) using microarrays. Using a subtraction method between these two types of chemicals, we identified characteristic gene expression changes on the thyroid hormone synthesis pathway by direct-acting chemicals. Based on the functions of these genes, alterations of their expression seem to indicate the results of thyroid peroxidase inhibition, and might be helpful in more accurate evaluation of MOAs for thyroid toxicity.

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“…A C C E P T E D ACCEPTED MANUSCRIPT 6 2017), DUOX2 (Grasberger, 2010, Muzza andFugazzola, 2017), DUOX2 maturation factor (DUOXA2), thyroglobulin (TG) (Di Jeso and Arvan, 2016;Targovnik, 2012;, and iodotyrosine deiodinase (IYD, also known as iodotyrosine dehalogenase 1, DEHAL1) (Moreno and Visser, 2010;Targovnik et al, 2017) TG is a large glycosylated protein secreted by the thyrocytes into the follicular lumen by exocytosis and it plays an essential role in the process of thyroid hormone synthesis. The human TG gene is a single copy gene of 270 kb long that maps on chromosome 8q24.…”

Section: A N U S C R I P Tmentioning

confidence: 99%

Molecular analysis of thyroglobulin mutations found in patients with goiter and hypothyroidism

Siffo

Adrover

Citterio

et al. 2018

Molecular and Cellular Endocrinology

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Thyroid dyshormonogenesis due to thyroglobulin (TG) gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism. Up to now, one hundred seventeen deleterious mutations in the TG gene have been identified and characterized. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report eight patients from seven unrelated families with goiter, hypothyroidism and low levels of serum TG. All patients underwent clinical, biochemical and image evaluation. Sequencing of DNA, genotyping, as well as bioinformatics analysis were performed. Molecular analyses revealed three novel inactivating TG mutations: c.5560G>T [p.E1835*], c.7084G>C [p.A2343P] and c.7093T>C [p.W2346R], and four previously reported mutations: c.378C>A [p.Y107*], c.886C>T [p.R277*], c.1351C>T [p.R432*] and c.7007G>A [p.R2317Q]. Two patients carried homozygous mutations (p.R277*/p.R277*, p.W2346R/p.W2346R), four were compound heterozygous mutations (p.Y107*/p.R277* (two unrelated patients), p.R432*/p.A2343P, p.Y107*/p.R2317Q) and two siblings from another family had a single p.E1835* mutated allele. Additionally, we include the analysis of 48 patients from 31 unrelated families with TG mutations identified in our present and previous studies. Our observation shows that mutations in both TG alleles were found in 27 families (9 as homozygote and 18 as heterozygote compound), whereas in the remaining four families only one mutated allele was detected. The majority of the detected mutations occur in exons 4, 7, 38 and 40. 28 different mutations were identified, 33 of the 96 TG alleles encoded the change p.R277*. In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiological importance of the predicted TG misfolding and therefore thyroid hormone formation as a consequence of truncated TG proteins and/or missense mutations located within its ACHE-like domain.

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Iodide handling disorders (NIS, TPO, TG, IYD)

Cited by 86 publications

References 92 publications

DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

Specific alteration of gene expression profile in rats by treatment with thyroid toxicants that inhibit thyroid hormone synthesis

Molecular analysis of thyroglobulin mutations found in patients with goiter and hypothyroidism

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