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

Qing Ouyang, Tojo Nakayama, Ozan Baytas, Shawn M. Davidson, Chendong Yang, Michael Schmidt, Sofia B. Lizarraga, Sasmita Mishra, Malak Ei-Quessny, Saima Niaz, Mirrat Gul Butt, Syed Imran Murtaza, Afzal Javed, Haroon Rashid Chaudhry, Dylan J. Vaughan, R. Sean Hill, Jennifer N. Partlow, Seung Yun Yoo, Anh Thu N Lam, Ramzi Nasir & 9 others Muna Al-Saffar, A. James Barkovich, Matthew Schwede, Shailender Nagpal, Anna Rajab, Ralph J. DeBerardinis, David E. Housman, Ganeshwaran H. Mochida, Eric M. Morrow

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E5598-E5607
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number38
DOIs
StatePublished - Sep 20 2016

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Transaminases
Pyruvic Acid
Glutamic Acid
Mutation
Enzymes
Developmental Disabilities
Intellectual Disability
Alanine
Brain
Phenotype
Microcephaly
Metabolomics
Essential Amino Acids
Paraplegia
Brain Diseases
Alanine Transaminase
Isotopes
Neurodegenerative Diseases
Mitochondria
Amino Acids

Keywords

  • GPT2
  • Intellectual and developmental disability
  • Metabolomics
  • Mitochondria
  • Spastic paraplegia

ASJC Scopus subject areas

  • General

Cite this

Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features. / Ouyang, Qing; Nakayama, Tojo; Baytas, Ozan; Davidson, Shawn M.; Yang, Chendong; Schmidt, Michael; Lizarraga, Sofia B.; Mishra, Sasmita; Ei-Quessny, Malak; Niaz, Saima; Butt, Mirrat Gul; Murtaza, Syed Imran; Javed, Afzal; Chaudhry, Haroon Rashid; Vaughan, Dylan J.; Hill, R. Sean; Partlow, Jennifer N.; Yoo, Seung Yun; Lam, Anh Thu N; Nasir, Ramzi; Al-Saffar, Muna; Barkovich, A. James; Schwede, Matthew; Nagpal, Shailender; Rajab, Anna; DeBerardinis, Ralph J.; Housman, David E.; Mochida, Ganeshwaran H.; Morrow, Eric M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 38, 20.09.2016, p. E5598-E5607.

Research output: Contribution to journalArticle

Ouyang, Q, Nakayama, T, Baytas, O, Davidson, SM, Yang, C, Schmidt, M, Lizarraga, SB, Mishra, S, Ei-Quessny, M, Niaz, S, Butt, MG, Murtaza, SI, Javed, A, Chaudhry, HR, Vaughan, DJ, Hill, RS, Partlow, JN, Yoo, SY, Lam, ATN, Nasir, R, Al-Saffar, M, Barkovich, AJ, Schwede, M, Nagpal, S, Rajab, A, DeBerardinis, RJ, Housman, DE, Mochida, GH & Morrow, EM 2016, 'Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 38, pp. E5598-E5607. https://doi.org/10.1073/pnas.1609221113
Ouyang, Qing ; Nakayama, Tojo ; Baytas, Ozan ; Davidson, Shawn M. ; Yang, Chendong ; Schmidt, Michael ; Lizarraga, Sofia B. ; Mishra, Sasmita ; Ei-Quessny, Malak ; Niaz, Saima ; Butt, Mirrat Gul ; Murtaza, Syed Imran ; Javed, Afzal ; Chaudhry, Haroon Rashid ; Vaughan, Dylan J. ; Hill, R. Sean ; Partlow, Jennifer N. ; Yoo, Seung Yun ; Lam, Anh Thu N ; Nasir, Ramzi ; Al-Saffar, Muna ; Barkovich, A. James ; Schwede, Matthew ; Nagpal, Shailender ; Rajab, Anna ; DeBerardinis, Ralph J. ; Housman, David E. ; Mochida, Ganeshwaran H. ; Morrow, Eric M. / Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 38. pp. E5598-E5607.
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T1 - Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features

AU - Ouyang, Qing

AU - Nakayama, Tojo

AU - Baytas, Ozan

AU - Davidson, Shawn M.

AU - Yang, Chendong

AU - Schmidt, Michael

AU - Lizarraga, Sofia B.

AU - Mishra, Sasmita

AU - Ei-Quessny, Malak

AU - Niaz, Saima

AU - Butt, Mirrat Gul

AU - Murtaza, Syed Imran

AU - Javed, Afzal

AU - Chaudhry, Haroon Rashid

AU - Vaughan, Dylan J.

AU - Hill, R. Sean

AU - Partlow, Jennifer N.

AU - Yoo, Seung Yun

AU - Lam, Anh Thu N

AU - Nasir, Ramzi

AU - Al-Saffar, Muna

AU - Barkovich, A. James

AU - Schwede, Matthew

AU - Nagpal, Shailender

AU - Rajab, Anna

AU - DeBerardinis, Ralph J.

AU - Housman, David E.

AU - Mochida, Ganeshwaran H.

AU - Morrow, Eric M.

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N2 - 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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