Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay,movement disorder,and metabolic abnormalities |
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| Institution: | 1. Genetics Section, Molecular and Clinical Sciences Research Institute, St. George’s, University of London, London, United Kingdom;2. Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK;3. Innovative Medical Research Centre, Faculty of Medicine, Islamic Azad University-Mashhad Branch, Mashhad, Iran;4. Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Center, Department of Human Genetics, McGill University, Montreal, Canada;5. Division of Inborn Errors of Metabolism, Department of Pediatrics, Izmir Katip Çelebi University Faculty of Medicine, Izmir, Turkey;6. Mitochondrial Medicine Frontier Program, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA;7. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;8. Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran;9. Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran;10. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad Iran;11. Children’s Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran;12. Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Canada;13. GeneDx, Gaithersburg, MD;14. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX;15. Department of Neuromuscular Disorders, UCL Institute of Neurology, University College London, London, United Kingdom;16. Division of Child Neurology, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;17. Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, and Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom |
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| Abstract: | PurposeThis study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.MethodsWe performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells.ResultsIn the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells.ConclusionWe established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities. |
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| Keywords: | α-ketoglutarate dehydrogenase deficiency Mitochondria Neurodevelopmental disease OGDH Oxoglutarate dehydrogenase |
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