Defects of Thyroid Hormone Synthesis and Action

Hannoush, Zeina; Weiss, Roy E.

doi:10.1016/j.ecl.2017.01.005

Cited by 31 publications

(21 citation statements)

References 81 publications

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“…Dyshormonogenic congenital hypothyroidism is caused by functional deficiency of thyroid hormone synthesis as a consequence of loss-of-function mutations in any of the genes involved in the biosynthesis of thyroid hormones [24]. Very recently, mutations in the SLC26A7 gene were associated with thyroid dyshormonogenesis [25, 26].…”

Section: I− Transport Defects Cause Dyshormonogenic Congenital Hypmentioning

confidence: 99%

Implications of Na+/I- Symporter Transport to the Plasma Membrane for Thyroid Hormonogenesis and Radioiodide Therapy

Martín

Geysels

Peyret

et al. 2018

Journal of the Endocrine Society

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Iodine is a crucial component of thyroid hormones; therefore, a key requirement for thyroid hormone biosynthesis is that iodide (I−) be actively accumulated in the thyroid follicular cell. The ability of the thyroid epithelia to concentrate I− is ultimately dependent on functional Na+/ I− symporter (NIS) expression at the plasma membrane. Underscoring the significance of NIS for thyroid physiology, loss-of-function mutations in the NIS-coding SLC5A5 gene cause an I− transport defect, resulting in dyshormonogenic congenital hypothyroidism. Moreover, I− accumulation in the thyroid cell constitutes the cornerstone for radioiodide ablation therapy for differentiated thyroid carcinoma. However, differentiated thyroid tumors often exhibit reduced (or even undetectable) I− transport compared with normal thyroid tissue, and they are diagnosed as cold nodules on thyroid scintigraphy. Paradoxically, immunohistochemistry analysis revealed that cold thyroid nodules do not express NIS or express normal, or even higher NIS levels compared with adjacent normal tissue, but NIS is frequently intracellularly retained, suggesting the presence of posttranslational abnormalities in the transport of the protein to the plasma membrane. Ultimately, a thorough comprehension of the mechanisms that regulate NIS transport to the plasma membrane would have multiple implications for radioiodide therapy, opening the possibility to identify new molecular targets to treat radioiodide-refractory thyroid tumors. Therefore, in this review, we discuss the current knowledge regarding posttranslational mechanisms that regulate NIS transport to the plasma membrane under physiological and pathological conditions affecting the thyroid follicular cell, a topic of great interest in the thyroid cancer field.

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Section: I− Transport Defects Cause Dyshormonogenic Congenital Hypmentioning

confidence: 99%

Implications of Na+/I- Symporter Transport to the Plasma Membrane for Thyroid Hormonogenesis and Radioiodide Therapy

Martín

Geysels

Peyret

et al. 2018

Journal of the Endocrine Society

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“…Insufficient hormone production secondary to TD is mainly due to defects in genes that encode enzymes that participate in iodine organification, thyroglobulin synthesis or transport, iodine transport or iodotyrosine deiodination during thyroid hormone synthesis (10). Although gland-in-situ (GIS) with normal thyroid morphology and goiter were once thought to be present in only 20-30% of CH patients, an increase in the frequency of CH with GIS has been reported, with the incidence more than doubled to ∼1 in 1,500 live newborns, which accounted for almost two-thirds of diagnosed cases in Italy at the time (11,12). Increasing evidence has shown that the pathogenesis of CH is complex, and this disease is considered to be influenced by environmental factors and genetic causes; genetic factors play an important role in the pathogenesis of CH (13).…”

Section: Introductionmentioning

confidence: 99%

DUOX2 and DUOXA2 Variants Confer Susceptibility to Thyroid Dysgenesis and Gland-in-situ With Congenital Hypothyroidism

Wang

Zang

et al. 2020

Front. Endocrinol.

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Background: Thyroid dysgenesis (TD), which is caused by gland developmental abnormalities, is the most common cause of congenital hypothyroidism (CH). In addition, advances in diagnostic techniques have facilitated the identification of mild CH patients with a gland-in-situ (GIS) with normal thyroid morphology. Therefore, TD and GIS account for the vast majority of CH cases. Methods: Sixteen known genes to be related to CH were sequenced and screened for variations by next-generation sequencing (NGS) in a cohort of 377 CH cases, including 288 TD cases and 89 GIS cases. Results: In our CH cohort, we found that DUOX2 (21.22%) was the most commonly variant pathogenic gene, while DUOXA2 was prominent in TD (18.75%) and DUOX2 was prominent in GIS (34.83%). Both biallelic and triple variants of DUOX2 were found to be most common in children with TD and children with GIS. The most frequent combination was DUOX2 with DUOXA1 among the 61 patients who carried digenic variants. We also found for the first time that biallelic TG, DUOXA2, and DUOXA1 variants participate in the pathogenesis of TD. In addition, the variant p.Y246X in DUOXA2 was the most common variant hotspot, with 58 novel variants identified in our study. Conclusion: We meticulously described the types and characteristics of variants from sixteen known gene in children with TD and GIS in the Chinese population, suggesting that DUOXA2 and DUOX2 variants may confer susceptibility to TD and GIS via polygenic inheritance and multiple factors, which further expands the genotype-phenotype spectrum of CH in China.

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“…Since then, 15 mutations in SLC5A5 have been reported in the Human Gene Mutation Database (HGMD), and these show autosomal recessive inheritance [20]. Clinically, these mutations cause hypothyroidism accompanied by goiter with eutopic thyroid on thyroid ultrasonography but show low or absent radioactive iodine uptake (RAIU) in thyroid scintigraphy [21]. In addition, the stomach and salivary glands, which also contain NIS, are unable to uptake radioiodine [5].…”

Section: Nis (Slc5a5) Mutations: Basolateral Iodide Transport Defectmentioning

confidence: 99%

“…When thyroid scintigraphy shows low or absent RAIU, this finding is suggestive of basolateral iodide transport defect ( NIS mutations). Normal or high RAIU is suggestive of one of the dyshormonogenesis beyond iodide trapping [5,21]. In neonates and children, 99m pertechnetate is preferred for thyroid scintigraphy, since it results in less radiation exposure [47].…”

Section: Thyroid Imaging For the Diagnosis Of Thyroid Dyshormonogenesismentioning

confidence: 99%

Clinical genetics of defects in thyroid hormone synthesis

Kwak

2018

Ann Pediatr Endocrinol Metab

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Thyroid dyshormonogenesis is characterized by impairment in one of the several stages of thyroid hormone synthesis and accounts for 10%–15% of congenital hypothyroidism (CH). Seven genes are known to be associated with thyroid dyshormonogenesis: SLC5A5 (NIS), SCL26A4 (PDS), TG, TPO, DUOX2, DUOXA2, and IYD (DHEAL1). Depending on the underlying mechanism, CH can be permanent or transient. Inheritance is usually autosomal recessive, but there are also cases of autosomal dominant inheritance. In this review, we describe the molecular basis, clinical presentation, and genetic diagnosis of CH due to thyroid dyshormonogenesis, with an emphasis on the benefits of targeted exome sequencing as an updated diagnostic approach.

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Defects of Thyroid Hormone Synthesis and Action

Cited by 31 publications

References 81 publications

Implications of Na+/I- Symporter Transport to the Plasma Membrane for Thyroid Hormonogenesis and Radioiodide Therapy

Implications of Na+/I- Symporter Transport to the Plasma Membrane for Thyroid Hormonogenesis and Radioiodide Therapy

DUOX2 and DUOXA2 Variants Confer Susceptibility to Thyroid Dysgenesis and Gland-in-situ With Congenital Hypothyroidism

Clinical genetics of defects in thyroid hormone synthesis

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