Nature Communications (Oct 2018)
Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
- 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 González,
- 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. Fernández-Moreno,
- Hagit N. Baris,
- Claudia Donnini,
- Michal Minczuk,
- Richard J. Rodenburg,
- Johan L. K. Van Hove
Affiliations
- Marisa W. Friederich
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado
- Sharita Timal
- Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center
- Christopher A. Powell
- Medical Research Council, Mitochondrial Biology Unit, University of Cambridge
- Cristina Dallabona
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma
- Alina Kurolap
- The Genetics Institute, Rambam Health Care Campus
- Sara Palacios-Zambrano
- Departamento de Bioquímica, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER). Facultad de Medicina, Universidad Autónoma de Madrid
- Drago Bratkovic
- SA Pathology, Women and Children’s Hospital Adelaide
- Terry G. J. Derks
- Division of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen
- David Bick
- HudsonAlpha Institute for Biotechnology
- Katelijne Bouman
- Department of Genetics, University Medical Center of Groningen, University of Groningen
- Kathryn C. Chatfield
- Department of Pediatrics, Section of Pediatric Cardiology, Children’s Hospital Colorado, University of Colorado
- Nadine Damouny-Naoum
- The Genetics Institute, Rambam Health Care Campus
- Megan K. Dishop
- Department of Pathology, Children’s Hospital Colorado, University of Colorado
- Tzipora C. Falik-Zaccai
- Institute of Human Genetics, Galilee Medical Center
- Fuad Fares
- Department of Human Biology, Faculty of Natural Sciences, University of Haifa
- Ayalla Fedida
- Institute of Human Genetics, Galilee Medical Center
- Ileana Ferrero
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma
- Renata C. Gallagher
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado
- Rafael Garesse
- Departamento de Bioquímica, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER). Facultad de Medicina, Universidad Autónoma de Madrid
- Micol Gilberti
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma
- Cristina González
- Departamento de Bioquímica, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER). Facultad de Medicina, Universidad Autónoma de Madrid
- Katherine Gowan
- Department of Biochemistry and Molecular Genetics, University of Colorado
- Clair Habib
- Department of Pediatrics, Bnai Zion Medical Center
- Rebecca K. Halligan
- SA Pathology, Women and Children’s Hospital Adelaide
- Limor Kalfon
- Institute of Human Genetics, Galilee Medical Center
- Kaz Knight
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado
- Dirk Lefeber
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center
- Laura Mamblona
- Departamento de Bioquímica, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER). Facultad de Medicina, Universidad Autónoma de Madrid
- Hanna Mandel
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology
- Adi Mory
- The Genetics Institute, Rambam Health Care Campus
- John Ottoson
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado
- Tamar Paperna
- The Genetics Institute, Rambam Health Care Campus
- Ger J. M. Pruijn
- Department of Biomolecular Chemistry, Institute for Molecules and Materials, Radboud University
- Pedro F. Rebelo-Guiomar
- Medical Research Council, Mitochondrial Biology Unit, University of Cambridge
- Ann Saada
- Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center
- Bruno Sainz
- Departamento de Bioquímica, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER). Facultad de Medicina, Universidad Autónoma de Madrid
- Hayley Salvemini
- SA Pathology, Women and Children’s Hospital Adelaide
- Mirthe H. Schoots
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen
- Jan A. Smeitink
- Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center
- Maciej J. Szukszto
- Medical Research Council, Mitochondrial Biology Unit, University of Cambridge
- Hendrik J. ter Horst
- Division of Neonatology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen
- Frans van den Brandt
- Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center
- Francjan J. van Spronsen
- Division of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen
- Joris A. Veltman
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center
- Eric Wartchow
- Department of Pathology, Children’s Hospital Colorado, University of Colorado
- Liesbeth T. Wintjes
- Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center
- Yaniv Zohar
- Institute of Pathology, Rambam Health Care Campus
- Miguel A. Fernández-Moreno
- Departamento de Bioquímica, Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER). Facultad de Medicina, Universidad Autónoma de Madrid
- Hagit N. Baris
- The Genetics Institute, Rambam Health Care Campus
- Claudia Donnini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma
- Michal Minczuk
- Medical Research Council, Mitochondrial Biology Unit, University of Cambridge
- Richard J. Rodenburg
- Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center
- Johan L. K. Van Hove
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado
- DOI
- https://doi.org/10.1038/s41467-018-06250-w
- Journal volume & issue
-
Vol. 9,
no. 1
pp. 1 – 14
Abstract
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-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.
