Inherited Disorders of Thyroid Hormone Metabolism Defect Caused by the Dysregulation of Selenoprotein Expression

Abstract

Consistent activation and functioning of thyroid hormones are essential to the human body as a whole, especially in controlling the metabolic rate of all organs and systems. Impaired sensitivity to thyroid hormones describes any process that interferes with the effectiveness of thyroid hormones. The genetic origin of inherited thyroid hormone defects and the investigation of genetic defects upon the processing of thyroid hormones are of utmost importance. Impaired sensitivity to thyroid hormone can be categorized into three conditions: thyroid hormone cell membrane transport defect (THCMTD), thyroid hormone metabolism defect (THMD), and thyroid hormone action defect (THAD). THMD is caused by defects in the synthesis and processing of deiodinases that convert the prohormone thyroxine (T4) to the active hormone triiodothyronine (T3). Deiodinase, a selenoprotein, requires unique translation machinery that is collectively composed of the selenocysteine (Sec) insertion sequence (SECIS) elements, Sec-insertion sequence-binding protein 2 (SECISBP2), Sec-specific eukaryotic elongation factor (EEFSEC), and Sec-specific tRNA (TRU-TCA1-1), which leads to the recognition of the UGA codon as a Sec codon for translation into the growing polypeptide. In addition, THMD could be expanded to the defects of enzymes that are involved in thyroid hormone conjugation, such as glucuronidation and sulphation. Paucity of inherited disorders in this category leaves them beyond the scope of this review. This review attempts to specifically explore the genomic causes and effects that result in a significant deficiency of T3 hormones due to inadequate function of deiodinases. Moreover, along with SECISBP2, TRU-TCA1-1, and deiodinase type-1 (DIO1) mutations, this review describes the variants in DIO2 single nucleotide polymorphism (SNP) and thyroid stimulating hormone receptor (TSHR) that result in the reduced activity of DIO2 and subsequent abnormal conversion of T3 from T4. Finally, this review provides additional insight into the general functionality of selenium supplementation and T3/T4 combination treatment in patients with hypothyroidism, suggesting the steps that need to be taken in the future.

Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

“…Disorders of handling iodide along its path to TH, which impair the functions of TSHR, NIS, TG, TPO, DUOX/DUOXA2 and IYD, are known [ 19 ]. Similarly, (inherited) genetic disorders and variants of the selenoproteins required for TH biosynthesis and metabolism as well as the protection of the H 2 O 2 -exposed thyroid follicular structure have been identified [ 20 ]. Such alterations modify the sensitivity of the hypothalamus–pituitary–thyroid–periphery (HPTP) axis to its negative feedback regulation by TH and its adaptive response to nutritional, environmental, pharmacological and disease-related challenges.…”

Genetic Determinants of Selenium Availability, Selenium-Response, and Risk of Polycystic Ovary Syndrome

“…However, present study found signi cant association between rs11548 polymorphism and increased PCOS risk. Selenocysteine as structural amino acid for thyroid deiodinases (DIO1, DIO2) were dependent upon blood selenium concentration for their biological activities such as homeostasis and thyroid hormone regulation [45]. In vivo study evaluated the dietary selenium effect among selenoprotein genes which shows decreased mRNA expression of GPX2, GPX3, and DIO2 genes and no effect on DIO1 and TXNRD1 gene expression [46].…”

Effects of SARS-CoV-2 infection on hypothyroidism and subclinical hypothyroidism: a meta-analysis

“…Individuals with severe COVID-19 frequently experience a strong systemic inflammatory response, which may have an effect on how thyroid hormones are transformed and released ( 25 ). For instance, inflammation may cause cystosulfate deiodinase (DIO2) to function less efficiently, which may influence the conversion of T4 to T3 ( 26 ). Also, the virus might directly or indirectly invade thyroid tissues, causing inflammation and cellular damage ( 27 ).…”