van Karnebeek, Clara D. M. published the artcileBi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy, Synthetic Route of 97-67-6, the main research area is brain developmental defect seizure encephalopathy malate aspartate GOT2; EC 2.6.1.1.; GOT2; aspartate aminotransferase; encephalopathy; inborn error of metabolism; malate-aspartate shuttle; mitochondriopathy; pyridoxine responsive epilepsy; redox imbalance; treatment.
Whole-exome sequencing was used to investigate the disease etiol. 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. 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 electroencephalog. spikes, which could be rescued by supplying pyridoxine in embryo water. Both pyridoxine and serine synergistically rescued embryonic developmental defects in zebrafish got2a morphants. Our data provide a mechanistic basis for the biochem. abnormalities in GOT2 deficiency that may also hold for other MAS defects.
American Journal of Human Genetics published new progress about Alleles. 97-67-6 belongs to class alcohols-buliding-blocks, name is (S)-2-hydroxysuccinic acid, and the molecular formula is C4H6O5, Synthetic Route of 97-67-6.
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