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

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

  • Proc Natl Acad Sci U S A. 2016 Sep 20;113(38):E5598-607. doi: 10.1073/pnas.1609221113.
Qing Ouyang 1,  Tojo Nakayama 2,  Ozan Baytas 3,  Shawn M Davidson 4,  Chendong Yang 5,  Michael Schmidt 1,  Sofia B Lizarraga 6,  Sasmita Mishra 3,  Malak Ei-Quessny 7,  Saima Niaz 8,  Mirrat Gul Butt 9,  Syed Imran Murtaza 10,  Afzal Javed 10,  Haroon Rashid Chaudhry 9,  Dylan J Vaughan 7,  R Sean Hill 7,  Jennifer N Partlow 11,  Seung-Yun Yoo 11,  Anh-Thu N Lam 11,  Ramzi Nasir 12,  Muna Al-Saffar 13,  A James Barkovich 14,  Matthew Schwede 3,  Shailender Nagpal 1,  Anna Rajab 15,  Ralph J DeBerardinis 5,  David E Housman 16,  Ganeshwaran H Mochida 17,  Eric M Morrow 18
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912; Institute for Brain Science, Brown University, Providence, RI 02912; Developmental Disorders Genetics Research Program, Emma Pendleton Bradley Hospital and Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, East Providence, RI 02915;
  • 2 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115; Department of Pediatrics, Harvard Medical School, Boston, MA 02115;
  • 3 Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912; Institute for Brain Science, Brown University, Providence, RI 02912;
  • 4 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;
  • 5 Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390;
  • 6 Center for Childhood of Neurotherapeutics, Department of Biological Sciences, University of South Carolina, Columbia, SC 29208;
  • 7 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115;
  • 8 Pakistan Psychiatric Research Centre, Fountain House, Lahore, Pakistan; North London Forensic Service, Chase Farm Hospital, Barnet, Enfield and Haringey Mental Health National Health Service Trust, Enfield EN2 8JL, United Kingdom;
  • 9 Pakistan Psychiatric Research Centre, Fountain House, Lahore, Pakistan; Department of Psychiatry, Fatima Jinnah Medical College/Sir Ganga Ram Hospital, Lahore, Pakistan;
  • 10 Pakistan Psychiatric Research Centre, Fountain House, Lahore, Pakistan;
  • 11 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115;
  • 12 Department of Pediatrics, Harvard Medical School, Boston, MA 02115; Division of Developmental Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA 02115;
  • 13 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115; Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates;
  • 14 Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143;
  • 15 National Genetic Centre, Directorate General of Royal Hospital, Ministry of Health, Muscat, Sultanate of Oman;
  • 16 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; dhousman@mit.edu Ganesh.Mochida@childrens.harvard.edu Eric_Morrow@brown.edu.
  • 17 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115; Department of Pediatrics, Harvard Medical School, Boston, MA 02115; Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114 dhousman@mit.edu Ganesh.Mochida@childrens.harvard.edu Eric_Morrow@brown.edu.
  • 18 Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912; Institute for Brain Science, Brown University, Providence, RI 02912; Developmental Disorders Genetics Research Program, Emma Pendleton Bradley Hospital and Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, East Providence, RI 02915; dhousman@mit.edu Ganesh.Mochida@childrens.harvard.edu Eric_Morrow@brown.edu.
PMID: 27601654 DOI: 10.1073/pnas.1609221113
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.

Keywords

GPT2; intellectual and developmental disability; metabolomics; mitochondria; spastic paraplegia.

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