Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy

Clara D. M. van Karnebeek, R. ben J. Ramos, Xiao-Yan Wen, Maja Tarailo-Graovac, Joseph G. Gleeson, Cristina Skrypnyk, Koroboshka Brand-Arzamendi, Farhad Karbassi, Mahmoud Y. Issa, Robin van der Lee, Britt I. Drögemöller, Janet Koster, Justine Rousseau, Philippe M. Campeau, Youdong Wang, Feng Cao, Meng Li, Jos Ruiter, Jolita Ciapaite, Leo A. J. Kluijtmans & 13 others Michel A. A. P. Willemsen, Judith J. Jans, Colin J. Ross, Liesbeth T. Wintjes, Richard J. Rodenburg, Marleen C. D. G. Huigen, Zhengping Jia, Hans R. Waterham, Wyeth W. Wasserman, Ronald J. A. Wanders, Nanda M. Verhoeven-Duif, Maha S. Zaki, Ron A. Wevers

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)534-548
JournalAmerican journal of human genetics
Volume105
Issue number3
DOIs
Publication statusPublished - 5 Sep 2019

Cite this

van Karnebeek, C. D. M., Ramos, R. B. J., Wen, X-Y., Tarailo-Graovac, M., Gleeson, J. G., Skrypnyk, C., ... Wevers, R. A. (2019). Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy. American journal of human genetics, 105(3), 534-548. https://doi.org/10.1016/j.ajhg.2019.07.015
van Karnebeek, Clara D. M. ; Ramos, R. ben J. ; Wen, Xiao-Yan ; Tarailo-Graovac, Maja ; Gleeson, Joseph G. ; Skrypnyk, Cristina ; Brand-Arzamendi, Koroboshka ; Karbassi, Farhad ; Issa, Mahmoud Y. ; van der Lee, Robin ; Drögemöller, Britt I. ; Koster, Janet ; Rousseau, Justine ; Campeau, Philippe M. ; Wang, Youdong ; Cao, Feng ; Li, Meng ; Ruiter, Jos ; Ciapaite, Jolita ; Kluijtmans, Leo A. J. ; Willemsen, Michel A. A. P. ; Jans, Judith J. ; Ross, Colin J. ; Wintjes, Liesbeth T. ; Rodenburg, Richard J. ; Huigen, Marleen C. D. G. ; Jia, Zhengping ; Waterham, Hans R. ; Wasserman, Wyeth W. ; Wanders, Ronald J. A. ; Verhoeven-Duif, Nanda M. ; Zaki, Maha S. ; Wevers, Ron A. / Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy. In: American journal of human genetics. 2019 ; Vol. 105, No. 3. pp. 534-548.
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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.",
author = "{van Karnebeek}, {Clara D. M.} and Ramos, {R. ben J.} and Xiao-Yan Wen and Maja Tarailo-Graovac and Gleeson, {Joseph G.} and Cristina Skrypnyk and Koroboshka Brand-Arzamendi and Farhad Karbassi and Issa, {Mahmoud Y.} and {van der Lee}, Robin and Dr{\"o}gem{\"o}ller, {Britt I.} and Janet Koster and Justine Rousseau and Campeau, {Philippe M.} and Youdong Wang and Feng Cao and Meng Li and Jos Ruiter and Jolita Ciapaite and Kluijtmans, {Leo A. J.} and Willemsen, {Michel A. A. P.} and Jans, {Judith J.} and Ross, {Colin J.} and Wintjes, {Liesbeth T.} and Rodenburg, {Richard J.} and Huigen, {Marleen C. D. G.} and Zhengping Jia and Waterham, {Hans R.} and Wasserman, {Wyeth W.} and Wanders, {Ronald J. A.} and Verhoeven-Duif, {Nanda M.} and Zaki, {Maha S.} and Wevers, {Ron A.}",
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van Karnebeek, CDM, Ramos, RBJ, Wen, X-Y, Tarailo-Graovac, M, Gleeson, JG, Skrypnyk, C, Brand-Arzamendi, K, Karbassi, F, Issa, MY, van der Lee, R, Drögemöller, BI, Koster, J, Rousseau, J, Campeau, PM, Wang, Y, Cao, F, Li, M, Ruiter, J, Ciapaite, J, Kluijtmans, LAJ, Willemsen, MAAP, Jans, JJ, Ross, CJ, Wintjes, LT, Rodenburg, RJ, Huigen, MCDG, Jia, Z, Waterham, HR, Wasserman, WW, Wanders, RJA, Verhoeven-Duif, NM, Zaki, MS & Wevers, RA 2019, 'Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy' American journal of human genetics, vol. 105, no. 3, pp. 534-548. https://doi.org/10.1016/j.ajhg.2019.07.015

Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy. / van Karnebeek, Clara D. M.; Ramos, R. ben J.; Wen, Xiao-Yan; Tarailo-Graovac, Maja; Gleeson, Joseph G.; Skrypnyk, Cristina; Brand-Arzamendi, Koroboshka; Karbassi, Farhad; Issa, Mahmoud Y.; van der Lee, Robin; Drögemöller, Britt I.; Koster, Janet; Rousseau, Justine; Campeau, Philippe M.; Wang, Youdong; Cao, Feng; Li, Meng; Ruiter, Jos; Ciapaite, Jolita; Kluijtmans, Leo A. J.; Willemsen, Michel A. A. P.; Jans, Judith J.; Ross, Colin J.; Wintjes, Liesbeth T.; Rodenburg, Richard J.; Huigen, Marleen C. D. G.; Jia, Zhengping; Waterham, Hans R.; Wasserman, Wyeth W.; Wanders, Ronald J. A.; Verhoeven-Duif, Nanda M.; Zaki, Maha S.; Wevers, Ron A.

In: American journal of human genetics, Vol. 105, No. 3, 05.09.2019, p. 534-548.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy

AU - van Karnebeek, Clara D. M.

AU - Ramos, R. ben J.

AU - Wen, Xiao-Yan

AU - Tarailo-Graovac, Maja

AU - Gleeson, Joseph G.

AU - Skrypnyk, Cristina

AU - Brand-Arzamendi, Koroboshka

AU - Karbassi, Farhad

AU - Issa, Mahmoud Y.

AU - van der Lee, Robin

AU - Drögemöller, Britt I.

AU - Koster, Janet

AU - Rousseau, Justine

AU - Campeau, Philippe M.

AU - Wang, Youdong

AU - Cao, Feng

AU - Li, Meng

AU - Ruiter, Jos

AU - Ciapaite, Jolita

AU - Kluijtmans, Leo A. J.

AU - Willemsen, Michel A. A. P.

AU - Jans, Judith J.

AU - Ross, Colin J.

AU - Wintjes, Liesbeth T.

AU - Rodenburg, Richard J.

AU - Huigen, Marleen C. D. G.

AU - Jia, Zhengping

AU - Waterham, Hans R.

AU - Wasserman, Wyeth W.

AU - Wanders, Ronald J. A.

AU - Verhoeven-Duif, Nanda M.

AU - Zaki, Maha S.

AU - Wevers, Ron A.

PY - 2019/9/5

Y1 - 2019/9/5

N2 - 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.

AB - 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.

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van Karnebeek CDM, Ramos RBJ, Wen X-Y, Tarailo-Graovac M, Gleeson JG, Skrypnyk C et al. Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy. American journal of human genetics. 2019 Sep 5;105(3):534-548. https://doi.org/10.1016/j.ajhg.2019.07.015