Pathogenic variants in glutamyl-tRNA amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder.

TitlePathogenic variants in glutamyl-tRNA amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder.
Publication TypeJournal Article
Year of Publication2018
AuthorsFriederich, MW, Timal, S, Powell, CA, Dallabona, C, Kurolap, A, Palacios-Zambrano, S, Bratkovic, D, Derks, TGJ, Bick, D, Bouman, K, Chatfield, KC, Damouny-Naoum, N, Dishop, MK, Falik-Zaccai, TC, Fares, F, Fedida, A, Ferrero, I, Gallagher, RC, Garesse, R, Gilberti, M, González, C, Gowan, K, Habib, C, Halligan, RK, Kalfon, L, Knight, K, Lefeber, D, Mamblona, L, Mandel, H, Mory, A, Ottoson, J, Paperna, T, Pruijn, GJM, Rebelo-Guiomar, PF, Saada, A, Sainz, B, Salvemini, H, Schoots, MH, Smeitink, JA, Szukszto, MJ, Horst, HJTer, van den Brandt, F, van Spronsen, FJ, Veltman, JA, Wartchow, E, Wintjes, LT, Zohar, Y, Fernández-Moreno, MA, Baris, HN, Donnini, C, Minczuk, MA, Rodenburg, RJ, Van Hove, JLK
JournalNat Commun
Volume9
Issue1
Pagination4065
Date Published2018 10 03
ISSN2041-1723
KeywordsAmino Acid Sequence, Cardiomyopathies, Female, Fibroblasts, Humans, Infant, Infant, Newborn, Lentivirus, Male, Mitochondrial Diseases, Models, Molecular, Mutation, Myocardium, Nitrogenous Group Transferases, Oxidative Phosphorylation, Pedigree, Protein Biosynthesis, Protein Subunits, RNA, Transfer, Saccharomyces cerevisiae
Abstract

Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNA). mt-tRNA is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNA and mitochondrial protein translation are deficient in patients' fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.

DOI10.1038/s41467-018-06250-w
Alternate JournalNat Commun
Citation Key10.1038/s41467-018-06250-w
PubMed ID30283131
PubMed Central IDPMC6170436
Grant ListMC_U105697135 / / Medical Research Council (MRC) / International
MC_UU_00015/4 / / Medical Research Council (MRC) / International
MC_U105697135 / / Medical Research Council (MRC) / International
MC_UU_00015/4 / / Medical Research Council (MRC) / International
MC_U105697135 / / Medical Research Council (MRC) / International
MC_UU_00015/4 / / Medical Research Council (MRC) / International
MC_UU_00015/4 / / Medical Research Council (MRC) / International
GGP15041 / / Fondazione Telethon (Telethon Foundation) / International