title: 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
authors: E
authors: Schoenmakers
authors: Bradley
authors: B
authors: Carlson
authors: Maura
authors: M
authors: Agostini
authors: Carla
authors: C
authors: Moran
authors: Odelia
authors: O
authors: Rajanayagam
authors: Elena
authors: E
authors: Bochukova
authors: Ryuta
authors: R
authors: Tobe
authors: Rachel
authors: R
authors: Peat
authors: Evelien
authors: E
authors: Gevers
authors: Francesco
authors: F
authors: Muntoni
authors: Pascale
authors: P
authors: Guicheney
authors: Nadia
authors: N
authors: Schoenmakers
authors: Sadaf
authors: S
authors: Farooqi
authors: Greta
authors: G
authors: Lyons
authors: Dolph
authors: D
authors: Hatfield
authors: Krishna
authors: K
authors: Chatterjee
mesh_terms: D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D056726:Genetic Association Studies; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis; D012345:RNA, Transfer, Amino Acid-Specific / Q000235:genetics*; D051140:Selenoproteins / Q000097:blood / Q000172:deficiency / Q000235:genetics*
chemical_list: D012345:RNA, Transfer, Amino Acid-Specific; D051140:Selenoproteins; C036928:tRNA, selenocysteine-