Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism

Abstract

Selenocysteine is the 21st proteinogenic amino acid in mammals. The human genome contains 25 genes encoding selenoproteins, and their significance for human health is increasingly recognized through the identification of patients with inborn errors in selenoprotein biosynthetic factors or in individual selenoproteins. Mutations in selenoprotein N (SEPN1) lead to a spectrum of disorders collectively called SEPN1-related myopathy, and mutations in glutathione peroxidase 4 (GPX4) cause respiratory failure and bone defects, and mutations in thioredoxin reductase 2 (TXNRD2) are associated with familial glucocorticoid deficiency. Pathogenic mutations in selenocysteine synthase (SEPSECS) cause neurodevelopmental disorders, but also other factors epistatic to selenoprotein biosynthesis, such as SECIS-binding protein 2 (SECISBP2) and tRNA, are known to cause complex disorders. Mutations in the latter 2 genes involve impaired metabolism and action of thyroid hormones, which lead to delayed bone growth and maturation. Mutations in SECISBP2 sometimes affect nervous system development, muscle, inner ear, skin, and immune system function, underlining the significance of selenoproteins for the organism. Mouse models helped to delineate the functions of selenoproteins and explain pathomechanisms. For brevity, this review is focused on human genetic disorders associated with selenoprotein deficiency and only briefly touches on health effects of nutritional selenium deficiency.-Schweizer, U., Fradejas-Villar, N. Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism.

A selenoprotein T‐derived peptide protects the heart against ischaemia/reperfusion injury through inhibition of apoptosis and oxidative stress

“…In mammals, 25 selenoprotein‐encoding genes have been identified whose entire invalidation through Sec tRNA gene knockout leads to early embryonic lethality in rodents . Likewise, mutations in human Sec tRNA or SECIS binding protein lead to complex disorders …”

“…8 Likewise, mutations in human Sec tRNA or SECIS binding protein lead to complex disorders. 9 Due to the presence of Sec in their catalytic site, selenoproteins exert important oxidoreductase activities and include several major enzymes, such as glutathione peroxidases (GPx), thioredoxin reductases (TrxR) and iodothyronine deiodinases which protect cells from oxidative stress and catalyse key redox reactions. 10 In addition to their role in detoxification of free radicals, diverse essential functions were attributed to selenoproteins, such as the implication of deiodinases in thyroid hormone metabolism, 11 the selenoproteins N, M or K in Ca 2+ regulation 12 or TrxR in signal transduction and transcription regulation.…”

Selenoprotein Gene Nomenclature

“…2 Sec is co-translationally inserted into a polypeptide chain in response to in-frame UGA codons directed by the Sec insertion sequence element, a stem-loop structure in the 3Ј-UTRs of selenoprotein mRNAs. The human genome contains 25 selenoprotein genes (1), and selenoproteins are essential for embryo development and human health (2,3). Among the selenoproteins, 13 have known functions; at least 12 of them serve as oxidoreductases, wherein Sec is the catalytic redox-active residue.…”

Spontaneous premature birth as a target of genomic research

“…Both severe Se-excess and Se-deficiency cause serious symptoms (82,83). Inborn errors of Secproteins cause protein-specific traits (84). Male genitalia, thyroid, brain, and placenta have high Se-content and their Se-contents are resistant to acute Se-deficiency (79).…”