Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.
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.
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;
Qing
Q
Ouyang
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;
Tojo
T
Nakayama
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912; Institute for Brain Science, Brown University, Providence, RI 02912;
Ozan
O
Baytas
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;
Shawn M
SM
Davidson
Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390;
Chendong
C
Yang
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;
Michael
M
Schmidt
Center for Childhood of Neurotherapeutics, Department of Biological Sciences, University of South Carolina, Columbia, SC 29208;
Sofia B
SB
Lizarraga
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912; Institute for Brain Science, Brown University, Providence, RI 02912;
Sasmita
S
Mishra
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;
Malak
M
Ei-Quessny
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;
Saima
S
Niaz
Pakistan Psychiatric Research Centre, Fountain House, Lahore, Pakistan; Department of Psychiatry, Fatima Jinnah Medical College/Sir Ganga Ram Hospital, Lahore, Pakistan;
Mirrat
M
Gul Butt
Pakistan Psychiatric Research Centre, Fountain House, Lahore, Pakistan;
Syed
S
Imran Murtaza
Pakistan Psychiatric Research Centre, Fountain House, Lahore, Pakistan;
Afzal
A
Javed
Pakistan Psychiatric Research Centre, Fountain House, Lahore, Pakistan; Department of Psychiatry, Fatima Jinnah Medical College/Sir Ganga Ram Hospital, Lahore, Pakistan;
Haroon Rashid
HR
Chaudhry
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;
Dylan J
DJ
Vaughan
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;
R Sean
RS
Hill
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;
Jennifer N
JN
Partlow
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;
Seung-Yun
SY
Yoo
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;
Anh-Thu N
AT
Lam
Department of Pediatrics, Harvard Medical School, Boston, MA 02115; Division of Developmental Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA 02115;
Ramzi
R
Nasir
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;
Muna
M
Al-Saffar
Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143;
A James
AJ
Barkovich
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912; Institute for Brain Science, Brown University, Providence, RI 02912;
Matthew
M
Schwede
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;
Shailender
S
Nagpal
National Genetic Centre, Directorate General of Royal Hospital, Ministry of Health, Muscat, Sultanate of Oman;
Anna
A
Rajab
Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390;
Ralph J
RJ
DeBerardinis
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; dhousman@mit.edu Ganesh.Mochida@childrens.harvard.edu Eric_Morrow@brown.edu.
David E
DE
Housman
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.
Ganeshwaran H
GH
Mochida
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.
Eric M
EM
Morrow
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D002952:Citric Acid Cycle / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D020125:Mutation, Missense; D009422:Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D019289:Pyruvic Acid / Q000378:metabolism; D000637:Transaminases / Q000235:genetics* / Q000378:metabolism
D007656:Ketoglutaric Acids; D019289:Pyruvic Acid; C000608785:GPT2 protein, human; D000637:Transaminases
GPT2; intellectual and developmental disability; metabolomics; mitochondria; spastic paraplegia