Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

Friederich, M. W., Timal, S., Powell, C. A., Dallabona, C., Kurolap, A., Palacios-Zambrano, S., Bratkovic, D., Derks, T. G. J., Bick, D., Bouman, K., Chatfield, K. C., Damouny-Naoum, N., Dishop, M. K., Falik-Zaccai, T. C., Fares, F., Fedida, A., Ferrero, I., Gallagher, R. C., Garesse, R., Gilberti, M., Gonzalez, C., Gowan, K., Habib, C., Halligan, R. K., Kalfon, L., Knight, K., Lefeber, D., Mamblona, L., Mandel, H., Mory, A., Ottoson, J., Paperna, T., Pruijn, G. J. M., Rebelo-Guiomar, P. F., Saada, A., Sainz, B., Salvemini, H., Schoots, M. H., Smeitink, J. A., Szukszto, M. J., ter Horst, H. J., van den Brandt, F., van Spronsen, F. J., Veltman, J. A., Wartchow, E., Wintjes, L. T., Zohar, Y., Fernandez-Moreno, M. A., Baris, H. N. & Donnini, C., 3-Oct-2018, In : Nature Communications. 9, 1, 14 p., 4065.

Research output: Contribution to journalArticleAcademicpeer-review

  • Marisa W. Friederich
  • Sharita Timal
  • Christopher A. Powell
  • Cristina Dallabona
  • Alina Kurolap
  • Sara Palacios-Zambrano
  • Drago Bratkovic
  • Terry G. J. Derks
  • David Bick
  • Katelijne Bouman
  • Kathryn C. Chatfield
  • Nadine Damouny-Naoum
  • Megan K. Dishop
  • Tzipora C. Falik-Zaccai
  • Fuad Fares
  • Ayalla Fedida
  • Ileana Ferrero
  • Renata C. Gallagher
  • Rafael Garesse
  • Micol Gilberti
  • Cristina Gonzalez
  • Katherine Gowan
  • Clair Habib
  • Rebecca K. Halligan
  • Limor Kalfon
  • Kaz Knight
  • Dirk Lefeber
  • Laura Mamblona
  • Hanna Mandel
  • Adi Mory
  • John Ottoson
  • Tamar Paperna
  • Ger J. M. Pruijn
  • Pedro F. Rebelo-Guiomar
  • Ann Saada
  • Bruno Sainz
  • Hayley Salvemini
  • Mirthe H. Schoots
  • Jan A. Smeitink
  • Maciej J. Szukszto
  • Hendrik J. ter Horst
  • Frans van den Brandt
  • Francjan J. van Spronsen
  • Joris A. Veltman
  • Eric Wartchow
  • Liesbeth T. Wintjes
  • Yaniv Zohar
  • Miguel A. Fernandez-Moreno
  • Hagit N. Baris
  • Claudia Donnini

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(Gln)). mt-tRNA(Gln) 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.

Original languageEnglish
Article number4065
Number of pages14
JournalNature Communications
Issue number1
Publication statusPublished - 3-Oct-2018



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