Abstract
Intellectual disability is genetically heterogeneous, and it is likely that many of the responsible genes have not yet been identified. We describe three siblings with isolated, severe developmental encephalopathy. After extensive uninformative genetic and metabolic testing, whole exome sequencing identified a homozygous novel variant in glutamic pyruvate transaminase 2 (GPT2) or alanine transaminase 2 (ALT2), c.459 C > G p.Ser153Arg that segregated with developmental encephalopathy in the family. This variant was predicted to be damaging by all in silico prediction algorithms. GPT2 is the gene encoding ALT2 which is responsible for the reversible transamination of alanine and 2-oxoglutarate to form pyruvate and glutamate. GPT2 is expressed in brain and is in the pathway to generate glutamate, an excitatory neurotransmitter. Functional assays of recombinant wild-type and mutant ALT2 proteins demonstrated the p.Ser153Arg mutation resulted in a severe loss of enzymatic function. We suggest that recessively inherited loss of function GPT2 mutations are a novel cause of intellectual disability.
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Acknowledgments
We thank the patients and their family for their contribution. Research reported in this publication was supported by the National Institutes of Health under award number: T32GM082771, Maryland Clinical Nutrition Research Unit (DK072488), and The Baltimore Diabetes Research and Training Center (P60-DK-079637). Authors acknowledge Alan Shuldiner for helpful discussions and critical review of the manuscript.
Conflicts of Interest
Eden Haverfield is an employee of GeneDx, Inc. Wendy K. Chung is a consultant to BioReference Laboratories.
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This article does not contain any studies with human or animal subjects performed by the any of the authors.
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Communicated by: Gajja Salomons
Katrina Celis, Scott Shuldiner, Da-Wei Gong and Wendy K. Chung contributed equally to this work.
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Celis, K., Shuldiner, S., Haverfield, E.V. et al. Loss of function mutation in glutamic pyruvate transaminase 2 (GPT2) causes developmental encephalopathy. J Inherit Metab Dis 38, 941–948 (2015). https://doi.org/10.1007/s10545-015-9824-x
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DOI: https://doi.org/10.1007/s10545-015-9824-x