Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy.,American Journal of Human Genetics

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Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2019-08-15 , DOI: 10.1016/j.ajhg.2019.07.015
Clara D M van Karnebeek ₁ , Rúben J Ramos ₂ , Xiao-Yan Wen ₃ , Maja Tarailo-Graovac ₄ , Joseph G Gleeson ₅ , Cristina Skrypnyk ₆ , Koroboshka Brand-Arzamendi ₇ , Farhad Karbassi ₇ , Mahmoud Y Issa ₈ , Robin van der Lee ₉ , Britt I Drögemöller ₁₀ , Janet Koster ₁₁ , Justine Rousseau ₁₂ , Philippe M Campeau ₁₂ , Youdong Wang ₇ , Feng Cao ₁₃ , Meng Li ₇ , Jos Ruiter ₁₁ , Jolita Ciapaite ₂ , Leo A J Kluijtmans ₁₄ , Michel A A P Willemsen ₁₅ , Judith J Jans ₂ , Colin J Ross ₁₆ , Liesbeth T Wintjes ₁₇ , Richard J Rodenburg ₁₈ , Marleen C D G Huigen ₁₄ , Zhengping Jia ₁₃ , Hans R Waterham ₁₉ , Wyeth W Wasserman ₉ , Ronald J A Wanders ₁₉ , Nanda M Verhoeven-Duif ₂ , Maha S Zaki ₈ , Ron A Wevers ₁₄

Affiliation

Departments 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.
On behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Genetics, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands.
Zebrafish 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.
Departments 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.
Department Neurosciences and Pediatric, Howard Hughes Medical Institute, University of California; Rady Children's Institute for Genomic Medicine, San Diego, CA 92093, USA.
Department 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.
Zebrafish 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.
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.
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.
CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.
Department of Neuroscience & Mental Health, The Hospital for Sick Children & Department of Physiology, University of Toronto, Toronto, ON M5G 1X8, Canada.
On 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.
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.
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
On 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.
On 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.
On 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.

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.

中文翻译：

双等位基因GOT2突变引起可治疗的苹果酸-天冬氨酸穿梭相关性脑病。

婴幼儿早期癫痫病是破坏性疾病，必须进行准确的诊断才能指导正确的治疗。全外显子组测序被用于调查来自智力残疾和癫痫的独立家庭的四个孩子的疾病病因，揭示了双等位基因GOT2突变。对个体1进行的深入代谢研究显示，血浆丝氨酸水平低，高瓜氨酸血症，高乳酸血症和高氨血症低。癫痫对丝氨酸和吡ido醇有反应。通过测量酶活性以及通过细胞和动物模型来测试观察到的突变的功能后果。斑马鱼和小鼠模型用于验证大脑发育和功能缺陷并测试治疗策略。GOT2编码线粒体谷氨酸草酰乙酸转氨酶。在具有双等位基因突变的成纤维细胞中，GOT2酶活性不足。苹果酸-天冬氨酸穿梭的成员GOT2在细胞内NAD（H）氧化还原平衡中起重要作用。从头丝氨酸的生物合成受到损害的成纤维细胞与GOT2突变和GOT2基因敲除HEK293细胞。通过补充丙酮酸来纠正高度氧化的胞质NAD氧化还原状态，可恢复GOT2缺陷型细胞中的丝氨酸生物合成。在斑马鱼中敲低got2a会导致与癫痫样脑电图峰值相关的大脑发育缺陷，可以通过在胚胎水中补充吡ido醇来挽救这种缺陷。吡ido醇和丝氨酸均可协同挽救斑马鱼got2a morphant的胚胎发育缺陷。两名接受治疗的人对其治疗反应良好。

更新日期：2019-09-30

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