Glutamate metabolism serves a critical role in a variety of processes that regulate cognition, including excitatory synaptic transmission, energetics, and biosynthesis. We and others have recently identified a new genetic disorder of human cognitive development that involves a mitochondrial enzyme with a role in glutamate metabolism (Celis et al, 2015; Lobo-Prada et al, 2017; Ouyang et al, 2016). Investigation of this new neurogenetic disease promises valuable insight into the multiple functions of mitochondria and glutamate metabolism in brain development and cognition.

Through linkage mapping to chromosome 16 and high-throughput sequencing, mutations in a mitochondrial enzyme, glutamate pyruvate transaminase 2 (GPT2), have been identified in pedigrees affected by intellectual disability and postnatal microcephaly (Celis et al, 2015; Lobo-Prada et al, 2017; Ouyang et al, 2016). Also, a subset of patients has a progressive motor dysfunction, termed spastic paraplegia (Ouyang et al, 2016). We reported two mutations, a missense (p.Pro272Leu) and a nonsense (p.Arg404*), that lead to enzyme loss-of-function. Several other mutations have been discovered, all of which appear to be loss-of-function: p.Ser153Arg (Celis et al, 2015); p.Gly96Arg (Lobo-Prada et al, 2017); p.Arg134Cys and p.Val479Met (compound heterozygote) (Kaymakçalan Çelebiler et al, 2017); and p.Gly412* (Pagnamenta et al, 2015). Most patients present similar clinical phenotypes, including intellectual disability and postnatal microcephaly, and the inheritance pattern is autosomal recessive. As postnatal microcephaly is a condition of attenuated brain growth that is limited to the early postnatal period, the underlying causes most likely involve mechanisms of brain development such as neuronal arborization, synaptogenesis, and gliogenesis (van Dyck and Morrow, 2017).

GPT2 reversibly transfers an amino group from glutamate to pyruvate yielding alanine and α-ketoglutarate. Subcellular localization of GPT2 to mitochondria shapes its function and control over its substrates. Further, this localization suggests a prominent role in synapses, which are enriched for mitochondria. Through expression of mutated GPT2 proteins in HeLa cells, we confirmed that mutations cause loss of enzyme activity, along with reduced protein levels. We also tested for protein levels and activity in the developing mouse brain. The highest peak of expression and corresponding activity was observed postnatally, coinciding with an active time of circuit development (Ouyang et al, 2016).

Given the loss-of-function of the mutations, a Gpt2-null mouse serves as an excellent model. Gpt2-null mice have diminished postnatal brain growth, recapitulating microcephaly in humans. In vitro, dissociated primary hippocampal cultures show reductions in synapse count, suggesting defective synaptogenesis. As GPT2 is involved in several metabolic pathways, we applied metabolomics to whole-brain tissue obtained from wild-type and Gpt2-null mice. There was a marked decrease in alanine and several of the tricarboxylic acid cycle (TCA) intermediates, accompanied by elevated levels of several amino acids (Ouyang et al, 2016). The overall metabolic signature of GPT2 deficiency points to defects in biosynthesis and bioenergetics.

In conclusion, the mutations in GPT2 present new insights into neurometabolism and its relevance to mechanisms for neurological and cognitive disorders. Studies into the function of the enzyme in animal models may have broad therapeutic value and produce preventive strategies involving alteration of metabolism, such as through diet modification or co-factor supplements.

Funding and Disclosure

Eric M. Morrow is supported by National Institute of Mental Health Grants R01MH105442 and R01MH102418, a Brown University Research Seed Fund Award, and the Hassenfeld Child Health Innovation Institute at Brown University. Ozan Baytaş is supported by the Suna and Inan Kiraç Foundation, and a Brown Institute for Brain Science Graduate Award in Brain Science supported by the Suna Kiraç Fellowship and Research Fund in Molecular Biology. The authors declare no conflict of interest.