Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis

J Clin Invest. 2016 Mar 1;126(3):992-6. doi: 10.1172/JCI84747. Epub 2016 Feb 8.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Child
  • DNA Mutational Analysis
  • Genetic Association Studies
  • Genetic Diseases, Inborn / diagnosis*
  • Genetic Diseases, Inborn / genetics
  • Humans
  • Male
  • Molecular Sequence Data
  • Point Mutation
  • Polymorphism, Single Nucleotide
  • Protein Biosynthesis
  • RNA, Transfer, Amino Acid-Specific / genetics*
  • Selenoproteins / blood
  • Selenoproteins / deficiency
  • Selenoproteins / genetics*


  • RNA, Transfer, Amino Acid-Specific
  • Selenoproteins
  • tRNA, selenocysteine-