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Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.


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 ?-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.

SUBMITTER: Ouyang Q 

PROVIDER: S-EPMC5035873 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.

Ouyang Qing Q   Nakayama Tojo T   Baytas Ozan O   Davidson Shawn M SM   Yang Chendong C   Schmidt Michael M   Lizarraga Sofia B SB   Mishra Sasmita S   Ei-Quessny Malak M   Niaz Saima S   Gul Butt Mirrat M   Imran Murtaza Syed S   Javed Afzal A   Chaudhry Haroon Rashid HR   Vaughan Dylan J DJ   Hill R Sean RS   Partlow Jennifer N JN   Yoo Seung-Yun SY   Lam Anh-Thu N AT   Nasir Ramzi R   Al-Saffar Muna M   Barkovich A James AJ   Schwede Matthew M   Nagpal Shailender S   Rajab Anna A   DeBerardinis Ralph J RJ   Housman David E DE   Mochida Ganeshwaran H GH   Morrow Eric M EM  

Proceedings of the National Academy of Sciences of the United States of America 20160906 38


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, yie  ...[more]

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