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[Ser]Sec, 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.