Metabolic dysfunction and neurological disease from mutations in a mitochondrial enzyme

Metabolic dysfunction and neurological disease from mutations in a mitochondrial enzyme

Intellectual and developmental disabilities (IDDs) occur in 2% of people worldwide and rank first in the United States as a cause of lifelong disability. IDD can be accompanied by various associated features, including motor disability. Hereditary spastic paraplegia (HSP) is a unique form of motor disability that is characterized by progressive spasticity and weakness of the lower extremities. In addition, postnatal microcephaly may occur with IDD and complicated forms of HSP, and likely reflects failures in processes driving postnatal brain growth such as neuronal arborization, synaptogenesis, and gliogenesis.

In this study published in the journal PNAS, authors present the discovery of loss-of-function (homozygous nonsense p.Arg404* and missense p.Pro272Leu) mutations in the gene encoding the enzyme glutamate pyruvate transaminase 2 (GPT2) in autosomal recessive IDD with postnatal microcephaly and motor findings consistent with progressive spastic paraplegia.

GPT2 [also known as alanine transaminase 2 (ALT2) or alanine aminotransferase 2 (ALAT2)] is one of two related enzymes that catalyze the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and α-ketoglutarate. GPT2 and highly related GPT are among several transaminases that regulate critical metabolic processes, including amino acid metabolism and the tricarboxylic acid (TCA) cycle.

In addition to identification of mutations in GPT2 in human neurological disease, authors have developed a mouse model of Gpt2 deficiency. Akin to the human phenotype, they see reduced brain growth in this mouse model.

Metabolomics studies in Gpt2-null mouse brains reveal reduced TCA metabolites consistent with a defect in anaplerosis. They also identify metabolomic signatures reflecting abnormalities in amino acid metabolism (these include defects in amino acid metabolism such as low alanine levels and elevated essential amino acids.), as well as in neuroprotective mechanisms previously implicated in neurodegenerative disease.

Overall, the data support an important role for GPT2 in mitochondria-based metabolism and neurological disease with both developmental and progressive features.