Consequences of mutations and inborn errors of selenoprotein biosynthesis and functions

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In its 200 years of history, selenium has been defined first as a toxic element and finally as a micronutrient. Selenium is incorporated into selenoproteins as selenocysteine (Sec), the 21st proteinogenic amino acid codified by a stop codon. Specific biosynthetic factors recode UGA stop codon as Sec. The significance of selenoproteins in human health is manifested through the identification of patients with inborn errors in selenoproteins or their biosynthetic factors. Selenoprotein N-related myopathy was the first disease identified due to mutations in a selenoprotein gene. Mutations in GPX4 were linked to Sedaghatian disease, characterized by bone and brain anomalies and cardiorespiratory failure. Mutations in TXNRD2 produced familial glucocorticoid deficiency (FGD) and dilated cardiomyopathy (DCM). Genetic generalized epilepsy was associated with mutations in TXNRD1 gene. Mutations in biosynthetic factors as SEPSECS, SECISBP2 and even tRNA[Ser]Sec, have been also related to diseases. Thus, SEPSECS mutations produce a neurodegenerative disease called now pontocerebellar hypoplasia type 2D (PCH2D). SECISBP2 syndrome, caused by SECISBP2 mutations, is a multifactorial disease affecting mainly thyroid metabolism, bone, inner ear and muscle. Similar symptoms were reproduced in a patient carrying a mutation in tRNA[Ser]Sec gene, TRU-TCA1-1. This review describes human genetic disorders caused by selenoprotein deficiency. Human phenotypes will be compared with mouse models to explain the pathologic mechanisms of lack of selenoproteins.Graphical abstractHighlightsSelenoproteins are important for human health.Mutations in SECISBP2 or tRNA[Ser]Sec gene cause a similar multisystemic disease.Effect of some selenoprotein mutations is more severe than selenoprotein deficiency.Wide expression of selenoproteins leads to impact on most organs.

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