Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
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 ami...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2018-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-018-06250-w |
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English |
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Article |
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DOAJ |
| author |
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 |
| spellingShingle |
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 Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder Nature Communications |
| author_facet |
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 |
| author_sort |
Marisa W. Friederich |
| title |
Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder |
| title_short |
Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder |
| title_full |
Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder |
| title_fullStr |
Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder |
| title_full_unstemmed |
Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder |
| title_sort |
pathogenic variants in glutamyl-trnagln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder |
| publisher |
Nature Publishing Group |
| series |
Nature Communications |
| issn |
2041-1723 |
| publishDate |
2018-10-01 |
| description |
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. |
| url |
https://doi.org/10.1038/s41467-018-06250-w |
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doaj-5e2c03b6081043e5add48aba3812d0592021-05-11T10:16:37ZengNature Publishing GroupNature Communications2041-17232018-10-019111410.1038/s41467-018-06250-wPathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorderMarisa W. Friederich0Sharita Timal1Christopher A. Powell2Cristina Dallabona3Alina Kurolap4Sara Palacios-Zambrano5Drago Bratkovic6Terry G. J. Derks7David Bick8Katelijne Bouman9Kathryn C. Chatfield10Nadine Damouny-Naoum11Megan K. Dishop12Tzipora C. Falik-Zaccai13Fuad Fares14Ayalla Fedida15Ileana Ferrero16Renata C. Gallagher17Rafael Garesse18Micol Gilberti19Cristina González20Katherine Gowan21Clair Habib22Rebecca K. Halligan23Limor Kalfon24Kaz Knight25Dirk Lefeber26Laura Mamblona27Hanna Mandel28Adi Mory29John Ottoson30Tamar Paperna31Ger J. M. Pruijn32Pedro F. Rebelo-Guiomar33Ann Saada34Bruno Sainz35Hayley Salvemini36Mirthe H. Schoots37Jan A. Smeitink38Maciej J. Szukszto39Hendrik J. ter Horst40Frans van den Brandt41Francjan J. van Spronsen42Joris A. Veltman43Eric Wartchow44Liesbeth T. Wintjes45Yaniv Zohar46Miguel A. Fernández-Moreno47Hagit N. Baris48Claudia Donnini49Michal Minczuk50Richard J. Rodenburg51Johan L. K. Van Hove52Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of ColoradoRadboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical CenterMedical Research Council, Mitochondrial Biology Unit, University of CambridgeDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of ParmaThe Genetics Institute, Rambam Health Care CampusDepartamento 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 MadridSA Pathology, Women and Children’s Hospital AdelaideDivision of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, University of GroningenHudsonAlpha Institute for BiotechnologyDepartment of Genetics, University Medical Center of Groningen, University of GroningenDepartment of Pediatrics, Section of Pediatric Cardiology, Children’s Hospital Colorado, University of ColoradoThe Genetics Institute, Rambam Health Care CampusDepartment of Pathology, Children’s Hospital Colorado, University of ColoradoInstitute of Human Genetics, Galilee Medical CenterDepartment of Human Biology, Faculty of Natural Sciences, University of HaifaInstitute of Human Genetics, Galilee Medical CenterDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of ParmaSection of Clinical Genetics and Metabolism, Department of Pediatrics, University of ColoradoDepartamento 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 MadridDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of ParmaDepartamento 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 MadridDepartment of Biochemistry and Molecular Genetics, University of ColoradoDepartment of Pediatrics, Bnai Zion Medical CenterSA Pathology, Women and Children’s Hospital AdelaideInstitute of Human Genetics, Galilee Medical CenterSection of Clinical Genetics and Metabolism, Department of Pediatrics, University of ColoradoDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical CenterDepartamento 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 MadridThe Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of TechnologyThe Genetics Institute, Rambam Health Care CampusSection of Clinical Genetics and Metabolism, Department of Pediatrics, University of ColoradoThe Genetics Institute, Rambam Health Care CampusDepartment of Biomolecular Chemistry, Institute for Molecules and Materials, Radboud UniversityMedical Research Council, Mitochondrial Biology Unit, University of CambridgeMonique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical CenterDepartamento 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 MadridSA Pathology, Women and Children’s Hospital AdelaideDepartment of Pathology and Medical Biology, University Medical Center Groningen, University of GroningenRadboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical CenterMedical Research Council, Mitochondrial Biology Unit, University of CambridgeDivision of Neonatology, Beatrix Children’s Hospital, University Medical Center Groningen, University of GroningenRadboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical CenterDivision of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, University of GroningenDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical CenterDepartment of Pathology, Children’s Hospital Colorado, University of ColoradoRadboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical CenterInstitute of Pathology, Rambam Health Care CampusDepartamento 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 MadridThe Genetics Institute, Rambam Health Care CampusDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of ParmaMedical Research Council, Mitochondrial Biology Unit, University of CambridgeRadboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical CenterSection of Clinical Genetics and Metabolism, Department of Pediatrics, University of ColoradoAbstract 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.https://doi.org/10.1038/s41467-018-06250-w |