Defective i6A37 Modification of Mitochondrial and Cytosolic tRNAs Results from Pathogenic Mutations in TRIT1 and Its Substrate tRNA

• DOI: 10.1371/journal.pgen.1004424
• Publication Date: 2014-06-05T20:34:17Z
• Authors: John W. Yarham; Tek N. Lamichhane; Angela Pyle; Sandy Mattijssen; Enrico Baruffini; Francesco Bruni; Claudia Donnini; Alex Vassilev; Langping He; Emma L. Blakely; Helen Griffin; Mauro Santibanez-...; Laurence A. Bindoff; Ileana Ferrero; Patrick F. Chinnery; Robert McFarland; Richard J. Maraia; Robert W. Taylor
• Keywords: Mitochondrial disease

Identifying the genetic basis for mitochondrial diseases is technically challenging given size of proteome and heterogeneity disease presentations. Using next-generation exome sequencing, we identified in a patient with severe combined respiratory chain defects corresponding perturbation protein synthesis, homozygous p.Arg323Gln mutation TRIT1. This gene encodes human tRNA isopentenyltransferase, which responsible i6A37 modification anticodon loops small subset cytosolic tRNAs. Deficiency was previously shown yeast to decrease translational efficiency fidelity codon-specific manner. Modelling on co-crystal structure homologous isopentenyltransferase bound substrate tRNA, indicates that it one series adjacent basic side chains interact backbone stem, somewhat removed from catalytic center. We show cells bearing TRIT1 are severely deficient both Complete complementation deficiency tRNAs achieved by transduction fibroblasts wild-type Moreover, previously-reported pathogenic m.7480A>G mt-tRNASer(UCN) loop sequence A36A37A38 recognised causes loss modification. These data demonstrate deficiencies should be considered potential mechanism caused nuclear DNA mutations while providing insight into function