Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis

Erik Schoenmakers (1) , Bradley Carlson (2) , Maura Agostini (1) , Carla Moran (1) , Odelia Rajanayagam (1) , Elena Bochukova (1) , Ryuta Tobe (2) , Rachel Peat (3) , Evelien Gevers (4) , Francesco Muntoni (5) , Pascale Guicheney (3) , Nadia Schoenmakers (1) , Sadaf Farooqi (1) , Greta Lyons (1) , Dolph Hatfield (2) , Krishna Chatterjee (1)

1 Wellcome Trust - MRC Cambridge
2 Molecular Biology of Selenium Section, Bethesda
3 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
4 Royal London Hospital
5 Dubowitz Neuromuscular Center

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.

Domaines: Médecine humaine et pathologie

Erik Schoenmakers, Bradley Carlson, Maura Agostini, Carla Moran, Odelia Rajanayagam, et al.. Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis. Journal of Clinical Investigation, 2016, 126 (3), pp.992-996. ⟨10.1172/JCI84747⟩. ⟨hal-01295150⟩