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-tRNAGlnis 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-tRNAGlnand 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.

Pathogenic variants in glutamyl-tRNAGlnamidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder / Friederich, 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 Jr; Salvemini, H; Schoots, Mh; Smeitink, Ja; Szukszto, Mj; Ter Horst, Hj; van den Brandt, F; van Spronsen, Fj; Veltman, Ja; Wartchow, E; Wintjes, Lt; Zohar, Y; Fernández-Moreno, Ma; Baris, Hn; Donnini, C; Minczuk, M; Rodenburg, Rj; Van Hove, Jlk.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 9:1(2018), pp. 4065-4078. [10.1038/s41467-018-06250-w]

Pathogenic variants in glutamyl-tRNAGlnamidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

Dallabona C;Ferrero I;Gilberti M;Donnini C;
2018

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-tRNAGln). mt-tRNAGlnis 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-tRNAGlnand 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.
Pathogenic variants in glutamyl-tRNAGlnamidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder / Friederich, 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 Jr; Salvemini, H; Schoots, Mh; Smeitink, Ja; Szukszto, Mj; Ter Horst, Hj; van den Brandt, F; van Spronsen, Fj; Veltman, Ja; Wartchow, E; Wintjes, Lt; Zohar, Y; Fernández-Moreno, Ma; Baris, Hn; Donnini, C; Minczuk, M; Rodenburg, Rj; Van Hove, Jlk.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 9:1(2018), pp. 4065-4078. [10.1038/s41467-018-06250-w]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2850979
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