Human Disorders Affecting the Selenocysteine Incorporation Pathway Cause Systemic Selenoprotein Deficiency.

Generalized selenoprotein deficiency has been associated with mutations in , , and , 3 factors that are crucial for incorporation of the amino acid selenocysteine (Sec) into at least 25 human selenoproteins. and defects are characterized by a multisystem phenotype due to deficiencies of antioxidant and tissue-specific selenoproteins, together with abnormal thyroid hormone levels reflecting impaired hormone metabolism by deiodinase selenoenzymes. mutations are associated with a predominantly neurological phenotype with progressive cerebello-cerebral atrophy. The recent identification of individuals with defects in genes encoding components of the selenocysteine insertion pathway has delineated complex and multisystem disorders, reflecting a lack of selenoproteins in specific tissues, oxidative damage due to lack of oxidoreductase-active selenoproteins and other pathways whose nature is unclear. Abnormal thyroid hormone metabolism in patients can be corrected by triiodothyronine (T3) treatment. No specific therapies for other phenotypes (muscular dystrophy, male infertility, hearing loss, neurodegeneration) exist as yet, but their severity often requires supportive medical intervention. These disorders provide unique insights into the role of selenoproteins in humans. The long-term consequences of reduced cellular antioxidant capacity remain unknown, and future surveillance of patients may reveal time-dependent phenotypes (., neoplasia, aging) or consequences of deficiency of selenoproteins whose function remains to be elucidated. The role of antioxidant therapies requires evaluation. 33, 481-497.