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

Marisa W FriederichSharita TimalChristopher A PowellCristina DallabonaAlina KurolapSara Palacios-ZambranoDrago BratkovicTerry G J DerksDavid BickKatelijne BoumanKathryn C ChatfieldNadine Damouny-NaoumMegan K DishopTzipora C Falik-ZaccaiFuad FaresAyalla FedidaIleana FerreroRenata C GallagherRafael GaresseMicol GilbertiCristina GonzálezKatherine GowanClair HabibRebecca K HalliganLimor KalfonKaz KnightDirk LefeberLaura MamblonaHanna MandelAdi MoryJohn OttosonTamar PapernaGer J M PruijnPedro F Rebelo-GuiomarAnn SaadaBruno SainzHayley SalveminiMirthe H SchootsJan A M SmeitinkMaciej J SzuksztoHendrik J Ter HorstFrans van den BrandtFrancjan J van SpronsenJoris A VeltmanEric WartchowLiesbeth T WintjesYaniv ZoharMiguel A Fernández-MorenoHagit N BarisClaudia DonniniMichal MinczukRichard J T RodenburgJohan L K Van Hove
Published in: Nature communications (2018)
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-tRNAGln). mt-tRNAGln 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-tRNAGln 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.
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