ArticleAmerican journal of human genetics2019
Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy.
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Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 82 citations in OpenAlex.
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- Redox imbalance dictates dependence on GOT1 versus GOT2 for rod photoreceptor health during aging and stress.Redox biology · 2026Article
- The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes.The FEBS journal · 2026Article
- Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling.PLoS biology · 2026Article
- Oxaloacetate inhibition of succinate dehydrogenase: mechanism and physiological implications.American journal of physiology. Cell physiology · 2026Review
- GOT2-mediated suppression of CoQCommunications biology · 2026Article
- Redox imbalance dictates dependence on GOT1 versus GOT2 for rod photoreceptor health during aging and stress.bioRxiv : the preprint server for biology · 2026Article
- Modeling epilepsy by loss-of-function of the CUG-binding protein Elav-like family member 2 in zebrafish with multi-omics analysis.Chinese medical journal · 2026Article
- Pan-cancer molecular signatures connecting aspartate transaminase to cancer prognosis, metabolic and immune signatures.Frontiers in oncology · 2026Article
- Comprehensive genotypic, phenotypic, and biochemical characterization of GOT2 deficiency: A progressive neurodevelopmental disorder with epilepsy and abnormal movements.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
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- GOT2: a moonlighting enzyme at the crossroads of cancer metabolism and theranostics.Frontiers in immunology · 2025Review
- The Roles of White Adipose Tissue and Liver NADPH in Dietary Restriction-Induced Longevity.Antioxidants (Basel, Switzerland) · 2024Review
- Induced pluripotent stem cell-derived hepatocytes reveal TCA cycle disruption and the potential basis for triheptanoin treatment for malate dehydrogenase 2 deficiency.Molecular genetics and metabolism reports · 2024Article
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Authors and funding
33 authors at 14 institutions in 5 countries.
Clara D M van KarnebeekDepartments of Pediatrics & Clinical Genetics, Emma Children's Hospital, Amsterdam University Medical Centres, Amsterdam Gastro-enterology and Metabolism, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Department of Pediatrics / Medical Genetics, BC Children's Hospital Research Institute, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada; On behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Amalia Children's Hospital, Department of Pediatrics, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands. Electronic address: c.d.vankarnebeek@amsterdamumc.nl.
Rúben J RamosOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Genetics, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands.
Xiao-Yan WenZebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, Li Ka Sheng Knowledge Institute, St. Michael's Hospital, Toronto, ON M5B 1T8, Canada; Department of Medicine, Physiology and LMP & Institute of Medical Science, University of Toronto, Toronto, ON M5G 2C4, Canada.
Maja Tarailo-GraovacDepartments of Biochemistry, Molecular Biology and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
Joseph G GleesonDepartment Neurosciences and Pediatric, Howard Hughes Medical Institute, University of California; Rady Children's Institute for Genomic Medicine, San Diego, CA 92093, USA.
Cristina SkrypnykDepartment of Molecular Medicine and Al Jawhara Center for Molecular Medicine, Genetics and Inherited Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Postal Code 328, Bahrain.
Koroboshka Brand-ArzamendiZebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, Li Ka Sheng Knowledge Institute, St. Michael's Hospital, Toronto, ON M5B 1T8, Canada.
Farhad KarbassiZebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, Li Ka Sheng Knowledge Institute, St. Michael's Hospital, Toronto, ON M5B 1T8, Canada.
Mahmoud Y IssaClinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Robin van der LeeCentre for Molecular Medicine and Therapeutics, Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
Britt I DrögemöllerFaculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.
Janet KosterLaboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam Gastro-enterology and Metabolism, 1105 AZ Amsterdam, the Netherlands.
Justine RousseauCHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.
Philippe M CampeauCHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.
Youdong WangZebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, Li Ka Sheng Knowledge Institute, St. Michael's Hospital, Toronto, ON M5B 1T8, Canada.
Feng CaoDepartment of Neuroscience & Mental Health, The Hospital for Sick Children & Department of Physiology, University of Toronto, Toronto, ON M5G 1X8, Canada.
Meng LiZebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, Li Ka Sheng Knowledge Institute, St. Michael's Hospital, Toronto, ON M5B 1T8, Canada.
Jos RuiterLaboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam Gastro-enterology and Metabolism, 1105 AZ Amsterdam, the Netherlands.
Jolita CiapaiteOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Genetics, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands.
Leo A J KluijtmansOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Michel A A P WillemsenOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Amalia Children's Hospital, Department of Pediatrics, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Judith J JansOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Genetics, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands.
Colin J RossFaculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Liesbeth T WintjesOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Richard J RodenburgOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Amalia Children's Hospital, Department of Pediatrics, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Marleen C D G HuigenOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
Zhengping JiaDepartment of Neuroscience & Mental Health, The Hospital for Sick Children & Department of Physiology, University of Toronto, Toronto, ON M5G 1X8, Canada.
Hans R WaterhamOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam Gastro-enterology and Metabolism, 1105 AZ Amsterdam, the Netherlands.
Wyeth W WassermanCentre for Molecular Medicine and Therapeutics, Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
Ronald J A WandersOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam Gastro-enterology and Metabolism, 1105 AZ Amsterdam, the Netherlands.
Nanda M Verhoeven-DuifOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Genetics, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands.
Maha S ZakiClinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Ron A WeversOn behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands. Electronic address: ron.wevers@radboudumc.nl.
Radboud University Nijmegen · NLSt. Michael's Hospital · CAUniversity Medical Center Utrecht · NLUniversity of Amsterdam · NLRadboud University Medical Center · NLBC Children's Hospital · CACentre Hospitalier Universitaire Sainte-Justine · CANational Research Centre · EGUniversity of British Columbia · CAUniversity of Toronto · CAAlberta Children's Hospital · CAArabian Gulf University · BHHospital for Sick Children · CAHoward Hughes Medical Institute · US
Funding
Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MYale Center for Mendelian DisordersU54HG006504 · NHGRI · YALE UNIVERSITY · PI GERSTEIN, MARK BENDER, GUNEL, MURAT · 2012 to 2015
$11.0MMolecular Characterization of Joubert SyndromeR01NS048453 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G · 2004 to 2020
$6.0MMolecular Characterization of Pontocerebellar HypoplasiaR01NS098004 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI JOSEPH G GLEESON · 2016 to 2026
$4.6MPathogenesis of diseases caused by aberrant COPII megavesicle assemblyR01GM110373 · NIGMS · UNIVERSITY OF CALIFORNIA AT DAVIS · PI KIM, JINOH · 2015 to 2019
$1.8MHigh Performance Computing Instrumentation for the Yale Center for Genome AnalysiS10OD018521 · OD · YALE UNIVERSITY · PI MANE, SHRIKANT M · 2015 to 2015
$890kCharacterization of the interplay between SEC23A and the MAPK signaling pathwayR21DE022419 · NIDCR · UNIVERSITY OF CALIFORNIA AT DAVIS · PI KIM, JINOH · 2012 to 2013
$416kNHGRI NIH HHS U54 HG006504NHGRI NIH HHS UM1 HG008900NIH HHS S10 OD018521NINDS NIH HHS R01 NS048453NINDS NIH HHS R01 NS098004
Abstract
Early-infantile encephalopathies with epilepsy are devastating conditions mandating an accurate diagnosis to guide proper management. Whole-exome sequencing was used to investigate the disease etiology in four children from independent families with intellectual disability and epilepsy, revealing bi-allelic GOT2 mutations. In-depth metabolic studies in individual 1 showed low plasma serine, hypercitrullinemia, hyperlactatemia, and hyperammonemia. The epilepsy was serine and pyridoxine responsive. Functional consequences of observed mutations were tested by measuring enzyme activity and by cell and animal models. Zebrafish and mouse models were used to validate brain developmental and functional defects and to test therapeutic strategies. GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase. GOT2 enzyme activity was deficient in fibroblasts with bi-allelic mutations. GOT2, a member of the malate-aspartate shuttle, plays an essential role in the intracellular NAD(H) redox balance. De novo serine biosynthesis was impaired in fibroblasts with GOT2 mutations and GOT2-knockout HEK293 cells. Correcting the highly oxidized cytosolic NAD-redox state by pyruvate supplementation restored serine biosynthesis in GOT2-deficient cells. Knockdown of got2a in zebrafish resulted in a brain developmental defect associated with seizure-like electroencephalography spikes, which could be rescued by supplying pyridoxine in embryo water. Both pyridoxine and serine synergistically rescued embryonic developmental defects in zebrafish got2a morphants. The two treated individuals reacted favorably to their treatment. Our data provide a mechanistic basis for the biochemical abnormalities in GOT2 deficiency that may also hold for other MAS defects.
Indexed as
AllelesMutationAnimalsAspartic AcidBrain DiseasesChildChild, PreschoolExome SequencingFatty Acid-Binding ProteinsFemaleGene Knockdown TechniquesHEK293 CellsHumansMalatesMaleMiceAspartic AcidFatty Acid-Binding ProteinsMalatesmalic acidaspartate aminotransferaseEC 2.6.1.1.encephalopathyGOT2inborn error of metabolismmalate-aspartate shuttlemitochondriopathypyridoxine responsive epilepsyredox imbalancetreatment
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