Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis
Erik Schoenmakers, … , Dolph Hatfield, Krishna Chatterjee
Erik Schoenmakers, … , Dolph Hatfield, Krishna Chatterjee
Published February 8, 2016
Citation Information: J Clin Invest. 2016;126(3):992-996. https://doi.org/10.1172/JCI84747.
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Brief Report Genetics

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis

Abstract

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.

Authors

Erik Schoenmakers, Bradley Carlson, Maura Agostini, Carla Moran, Odelia Rajanayagam, Elena Bochukova, Ryuta Tobe, Rachel Peat, Evelien Gevers, Francesco Muntoni, Pascale Guicheney, Nadia Schoenmakers, Sadaf Farooqi, Greta Lyons, Dolph Hatfield, Krishna Chatterjee

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Figure 1

Pathways of Sec synthesis and incorporation into selenoproteins.

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Pathways of Sec synthesis and incorporation into selenoproteins. The syn...
The synthesis of Sec (upper pathway) occurs on its tRNA, with initial attachment of serine to tRNA[Ser]Sec by seryl-tRNA synthetase (SARS), phosphorylation of this residue by phosphoseryl-tRNA kinase (PSTK), subsequent conversion of this phosphoserine (PSer) to an intermediate by SEPSECS, and acceptance of selenophosphate to generate Sec-tRNA[Ser]Sec mcm5U. Selenophosphate is synthesized from selenide and ATP by selenophosphate synthetase 2 (SEPHS2) (2); Sec-tRNA[Ser]Sec mcm5U is partially methylated by an unidentified Um34 methylase, and the level of methylation is dependent on selenium status (7, 9). A multiprotein complex containing tRNA selenocysteine 1 associated protein 1 (TRNAU1AP), EEFSEC, and Sec-tRNA[Ser]Sec isoform by SECISBP2, wherein SECISBP2 is bound to the SECIS stem loop element located in the 3′ UTR of mammalian selenoprotein mRNAs decoding UGA Sec codons at the ribosomal acceptor site to mediate Sec incorporation into nascent polypeptide. Other factors, such as ribosomal protein L30 (RPL30), eukaryotic translation initiation factor 4A3 (EIF4A3), and nucleolin (NCL), also regulate the Sec insertion process (1, 2, 7).