Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 38, Pages E5598-E5607Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1609221113
Keywords
GPT2; intellectual and developmental disability; mitochondria; metabolomics; spastic paraplegia
Categories
Funding
- Burroughs Wellcome Fund Career Award for Medical Scientists [1006815.01]
- Manton Center for Orphan Disease Research
- National Institute of Neurological Disorders and Stroke [R01NS035129]
- National Institutes of Health/Fogarty International Center [R21TW008223]
- Dubai Harvard Foundation for Medical Research
- F. Hoffmann-La Roche Ltd.
- Qatar National Research Fund
- Boston Children's Hospital Faculty Career Development Award
- National Cancer Institute [R01CA157996]
- Suna and Inan Kirac Foundation
- Japan Foundation for Pediatric Research
- Japan Society for the Promotion of Science
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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 alpha-ketoglutarate. In addition to IDD, all affected individuals show postnatal microcephaly and similar to 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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