Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis.
Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis.
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DOI：
10.1172/jci84747
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发表时间：
2016-03
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通讯作者：
E. Schoenmakers;B. Carlson;M. Agostini;C. Moran;O. Rajanayagam;E. Bochukova;Ryuta Tobe;Rachel A. Peat;E. Gevers;F. Muntoni;P. Guicheney;N. Schoenmakers;S. Farooqi;G. Lyons;D. Hatfield;K. Chatterjee
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作者：
E. Schoenmakers;B. Carlson;M. Agostini;C. Moran;O. Rajanayagam;E. Bochukova;Ryuta Tobe;Rachel A. Peat;E. Gevers;F. Muntoni;P. Guicheney;N. Schoenmakers;S. Farooqi;G. Lyons;D. Hatfield;K. Chatterjee
Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome-encoded, transfer RNA (tRNA[Ser]Sec). Here, we have identified a human tRNA[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins. Evaluation of primary cells from the homozygous proband and a heterozygous parent indicated that the observed deficit in stress-related selenoprotein production is likely mediated by reduced expression and diminished 2'-O-methylribosylation at uridine 34 in mutant tRNA[Ser]Sec. Moreover, this methylribosylation defect was restored by cellular complementation with normal tRNA[Ser]Sec. This study identifies a tRNA mutation that selectively impairs synthesis of stress-related selenoproteins and demonstrates the importance of tRNA modification for normal selenoprotein synthesis.
