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Nat Commun. 2018 Oct 3;9(1):4065. doi: 10.1038/s41467-018-06250-w.

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

Author information

1
Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, 80045, CO, USA.
2
Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center, Nijmegen, 6500 HB, The Netherlands.
3
Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, 6500 HB, The Netherlands.
4
Medical Research Council, Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 OXY, United Kingdom.
5
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, 43124, Italy.
6
The Genetics Institute, Rambam Health Care Campus, Haifa, 3109601, Israel.
7
The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, 3109601, Israel.
8
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, Madrid, 28029, Spain.
9
Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, 28041, Spain.
10
SA Pathology, Women and Children's Hospital Adelaide, Adelaide, 5006, Australia.
11
Division of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, 9700 RB, The Netherlands.
12
HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
13
Department of Genetics, University Medical Center of Groningen, University of Groningen, Groningen, 9700 RB, The Netherlands.
14
Department of Pediatrics, Section of Pediatric Cardiology, Children's Hospital Colorado, University of Colorado, Aurora, CO, 80045, USA.
15
Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Haifa, 3498838, Israel.
16
Department of Pathology, Children's Hospital Colorado, University of Colorado, Aurora, 80045, CO, USA.
17
Institute of Human Genetics, Galilee Medical Center, Nahariya, 22100, Israel.
18
The Azrieli Faculty of Medicine in the Galilee, Bar Ilan University, Safed, 1311502, Israel.
19
Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO, 80045, USA.
20
Department of Pediatrics, Bnai Zion Medical Center, Haifa, 3339419, Israel.
21
Metabolic Unit, Rambam Health Care Campus, Haifa, 3109601, Israel.
22
Department of Biomolecular Chemistry, Institute for Molecules and Materials, Radboud University, Nijmegen, 6500 HB, The Netherlands.
23
Graduate Program in Areas of Basic and Applied Biology (GABBA), University of Porto, Porto, 4200-135, Portugal.
24
Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
25
Enfermedades Crónicas y Cáncer Area, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, 28034, Spain.
26
Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB, Groningen, The Netherlands.
27
Division of Neonatology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, 9700 RB, The Netherlands.
28
Institute of Genetic Medicine, Newcastle University, Newcastle, NE1 3BZ, United Kingdom.
29
Institute of Pathology, Rambam Health Care Campus, 3109601, Haifa, Israel.
30
Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, 80045, CO, USA. Johan.Vanhove@ucdenver.edu.

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.

PMID:
30283131
PMCID:
PMC6170436
DOI:
10.1038/s41467-018-06250-w
[Indexed for MEDLINE]
Free PMC Article

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