Editors' ChoiceMetabolism

Tracing the Fate of an Essential Element

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Science Translational Medicine  01 Dec 2010:
Vol. 2, Issue 60, pp. 60ec186
DOI: 10.1126/scitranslmed.3001965

Selenium is an essential trace element that plays a fundamental role in biology. Selenium deficiency in humans leads to a spectrum of diseases including myocarditis, osteoarthritis, immune defects, and severe hypothyroidism. Selenium, in the form of selenocysteine, is incorporated into ~25 different selenoproteins, most of which are enzymes, such as the glutathione peroxidases that break down reactive oxygen species or the deiodinases that metabolize thyroid hormone. Selenocysteine, often called the 21st amino acid, is encoded by a UGA codon that normally halts translation. There is a unique translation machinery that allows selenocysteine to be incorporated into selenoproteins, and part of this machinery includes the SBP2 protein. Now, Schoenmakers and colleagues show in two families that mutations in SBP2 result in the impaired synthesis of the majority of selenoproteins, leading to a severe multisystem disorder with many diverse symptoms.

The clue that these two families had a selenoprotein deficiency came from the observation that affected family members had hypothyroidism with low T3. There was also a diverse array of other symptoms, including lack of sperm (azoospermia) because of reduced spermatogenesis caused by the loss of selenoproteins in the testes. Affected individuals in the two families also showed an axial muscular dystrophy with features similar to myopathies caused by mutations in selenoprotein N. Patients also had increased skin photosensitivity, which is consistent with loss of the antioxidant selenoenzymes that normally break down damaging reactive oxygen species caused by ultraviolet light. A reduction in selenoproteins in peripheral blood cells resulted in defective proliferation of T lymphocytes, abnormal secretion of cytokines by mononuclear cells, and shortening of chromosome ends (an indicator of cellular aging). Intriguingly, an increase in reactive oxygen species in affected individuals was associated with enhanced sensitivity to insulin, reflecting the situation in mice that lack the antioxidant selenoprotein glutathione peroxidase. The case study of Schoenmakers et al. provides fascinating insights into selenium biology, the key role of SBP2 in selenoprotein synthesis, and the importance of selenoproteins to human health.

E. Schoenmakers et al., Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans. J. Clin. Invest. 15 November 2010 (10.1172/JCI43653). [Abstract]

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