ArticleProceedings of the National Academy of Sciences of the United States of America2016
Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 66 citations in OpenAlex.
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- Mitochondria at the intersections of RNA modifications and metabolism reprogramming implications in cell death, tumor microenvironment, and immunotherapy.Journal of hematology & oncology · 2025Review
- Genome-wide association study for Kleiber ratio and growth efficiency traits in Lori-Bakhtiari sheep.Tropical animal health and production · 2025Article
- Serum ALT activity and its isoenzymes as potential biomarkers for diagnosis of Sarcopenia in older adults: a retrospective, cross-sectional study.BMC geriatrics · 2025Article
- Early life microbiome disbalance impacts neuroendocrine outcomes in pre-pubertal mice in a sexually dimorphic manner.Frontiers in microbiology · 2025Article
- Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.Molecular brain · 2024Article
- miR-124 coordinates metabolic regulators acting at early stages of human neurogenesis.Communications biology · 2024Article
- Disruption of hepatic mitochondrial pyruvate and amino acid metabolism impairs gluconeogenesis and endurance exercise capacity in mice.American journal of physiology. Endocrinology and metabolism · 2024Article
- Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila.Nature metabolism · 2023Article
- Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult.Molecular metabolism · 2023Article
- Disruption of Hepatic Mitochondrial Pyruvate and Amino Acid Metabolism Impairs Gluconeogenesis and Endurance Exercise Capacity in Mice.bioRxiv : the preprint server for biology · 2023Article
- Metabolites as signalling molecules.Nature reviews. Molecular cell biology · 2023Review
- Plasma metabolomics by nuclear magnetic resonance reveals biomarkers and metabolic pathways associated with the control of HIV-1 infection/progression.Frontiers in molecular biosciences · 2023Article
- Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease.Cellular and molecular gastroenterology and hepatology · 2023Article
- Loss of mitochondrial enzyme GPT2 causes early neurodegeneration in locus coeruleus.Neurobiology of disease · 2022Article
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- Contribution of Mitochondria to Insulin Secretion by Various Secretagogues.Antioxidants & redox signaling · 2022Review
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Authors and funding
29 authors at 13 institutions in 5 countries.
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Abstract
Mutations that cause neurological phenotypes are highly informative with regard to mechanisms governing human brain function and disease. We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD). GPT2 [also known as alanine transaminase 2 (ALT2)] is one of two related transaminases that catalyze the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and α-ketoglutarate. In addition to IDD, all affected individuals show postnatal microcephaly and ∼80% of those followed over time show progressive motor symptoms, a spastic paraplegia. Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to be loss of function. The GPT2 gene demonstrates increasing expression in brain in the early postnatal period, and GPT2 protein localizes to mitochondria. Akin to the human phenotype, Gpt2-null mice exhibit reduced brain growth. Through metabolomics and direct isotope tracing experiments, we find a number of metabolic abnormalities associated with loss of Gpt2. These include defects in amino acid metabolism such as low alanine levels and elevated essential amino acids. Also, we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle intermediates. Finally, mutant brains demonstrate misregulated metabolites in pathways implicated in neuroprotective mechanisms previously associated with neurodegenerative disorders. Overall, our data reveal an important role for the GPT2 enzyme in mitochondrial metabolism with relevance to developmental as well as potentially to neurodegenerative mechanisms.
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