The GPT2 gene is located at chromosome 16q11.2 (NCBI Gene ID: 84706). GPT2-syndrome is an autosomal recessive disorder, i.e., both copies of the GPT2 gene contain pathogenic mutations. Mutations detected to date are located throughout the protein and are of various types – missense (i.e., change in amino acid), nonsense (i.e., shorten the overall protein), splicing (i.e., affect piecing together of the protein). As an autosomal recessive disorder, the mutations result in inactivation of both copies of the GPT2 gene in affected individuals. Various companies offer clinical tests, based in sequence analysis, for detection of GPT2 mutations.
GPT2 is an enzyme that catalyzes (speeds up) a cellular biochemical reaction involved in mitochondrial metabolism. Many of the mutations detected to date are in the catalytic domain and, thus, likely render the protein unable to perform its cellular functions. Indeed, results from laboratory studies suggest that many of the disease-causing GPT2 mutations detected to date result in lack of enzyme activity. The mutations may also affect protein folding and/or substrate binding, thereby negatively affecting GPT2’s ability to function appropriately within cells. This lack of function may affect, particularly in brain cells, mitochondrial metabolism, amino acid metabolism, and generation of cellular antioxidants and neuroprotective metabolites. For individuals affected by GPT2-syndrome, the location of the mutation within the GPT2 protein, as well as other factors, may affect the specific clinical phenotypes that manifest and the severity of disease.
