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Biological and Clinical Consequences of a de Novo Mutation in Glutaminase

出版	University of Washington Libraries, 2019
URL	http://books.google.com.hk/books?id=7AdIzQEACAAJ&hl=&source=gbs_api

註釋The causes of bipolar disorder have been a mystery for as long as people have been writing about mental illness. Bipolar disorder is clearly familial but is not inherited in a simple way. Genetic studies have implicated genes involved in inhibitory transmission and genes involved in excitatory neurotransmission. In our studies of severe mental illness in patients with no suggestive family history, we identified a damaging de novo mutation in GLS in a young man with bipolar disorder with psychosis that onset at age 16. GLS encodes glutaminase, the enzyme that converts glutamine to glutamate, the excitatory neurotransmitter. Very recently, other mutations in GLS have been reported, leading to severe neurological manifestations. The goal of this project was to functionally characterize the patient's de novo mutation, GLS p.L606R. I undertook three types of analyses for this purpose. First, I tested activity of purified mutant and wild-type glutaminase proteins. These assays yielded a marginally significantly higher Kcat/Km ratio for the L606R mutant enzyme than for the wildtype enzyme (P = 0.057). Second, I compared the glutamate / glutamine ratios in lymphoblast cells of the patient versus his unaffected parents. The glutamate/glutamine ratio in patient cells was higher than that in comparable cells of his unaffected parents. Third, I compared profiles of>150 metabolites in lymphoblast cells of the patient to his unaffected parents. Eight metabolites differed significantly between the patient and his parents. The most significant differences were in levels of N-acetyl-aspartyl-glutamate (NAAG) and of glutamine, both elevated in the patient's cells. NAAG is a peptide neurotransmitter that inhibits the release of both inhibitory and excitatory neurotransmitters. The total cellular glutamate (consisting of glutamic acid and NAAG) was significantly elevated in the patient's cells compared to his unaffected parents. Metabolites from several other pathways were also significantly different in the patient. Inosine monophosphate, the first nucleoside produced during purine synthesis, was elevated in the patient. In contrast, the pyrimidine derivative uracil was decreased in the patient. The B-vitamins thiamine (B1) and pantothenate (B5) were both decreased in the patient. Lactate was increased in the patient, potentially caused by the thiamine deficiency. Finally, methionine sulfoxide which is a marker of oxidative stress was increased in the patient. I propose that excess of total cellular glutamate is caused by the increase in glutaminase activity and is modulated by the increase in NAAG and the patient's successful treatment with lithium.