Open AccessHuman Disorders Affecting the Selenocysteine Incorporation Pathway Cause Systemic Selenoprotein Deficiency
Author(s) -
Erik Schoenmakers,
Krishna Chatterjee
Publication year - 2020
Publication title -
antioxidants and redox signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.277
H-Index - 190
eISSN - 1557-7716
pISSN - 1523-0864
DOI - 10.1089/ars.2020.8097
Subject(s) - selenoprotein , selenocysteine , neurodegeneration , phenotype , selenium deficiency , deiodinase , proteostasis , biology , thyroid , endocrinology , oxidative stress , genetics , medicine , gene , superoxide dismutase , biochemistry , glutathione peroxidase , triiodothyronine , disease , cysteine , enzyme
Significance: Generalized selenoprotein deficiency has been associated with mutations in SECISBP2 , SEPSECS , and TRU-TCA1-1 , 3 factors that are crucial for incorporation of the amino acid selenocysteine (Sec) into at least 25 human selenoproteins. SECISBP2 and TRU-TCA1-1 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. SEPSECS mutations are associated with a predominantly neurological phenotype with progressive cerebello-cerebral atrophy. Recent Advances: 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. Critical Issues: 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. Future Directions: 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 ( e.g ., neoplasia, aging) or consequences of deficiency of selenoproteins whose function remains to be elucidated. The role of antioxidant therapies requires evaluation. Antioxid. Redox Signal. 33, 481-497.