ABAT is a novel human mitochondrial DNA depletion syndrome gene linking gamma-aminobutyric acid (GABA) catabolism and mitochondrial nucleoside metabolism. P. Bonnen1, A. Besse1, P. Wu1, F. Bruni2, T. Donti1, B. Graham1, W. Craigen1, R. McFarland2, P. Moretti1, S. Lalani1, K. Scott1, R. Taylor2 1) Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 2) Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

   ABAT is a key enzyme responsible for catabolism of principal inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the mitochondrial matrix. We report a novel role for ABAT in a seemingly unrelated pathway, mitochondrial nucleoside salvage, and demonstrate that mutations in this enzyme cause neurometabolic dysfunction and are a novel cause of mtDNA depletion syndrome (MDS). MDS is a group of autosomal recessive disorders that share the hallmark of decreased copy number of the mitochondrial genome and clinically manifest as encephalopathy, encephalomyopathy or hepatocerebral. Whole exome sequencing of a child with severe psychomotor retardation, intractable seizures, hypotonia and hyperreflexia revealed a homozygous missense mutation in ABAT. Compromised neurometabolic activity was confirmed with in vivo proton magnetic resonance spectroscopy showing significantly increased levels of GABA in the subjects brain. Muscle biopsy exhibited abnormal mitochondrial morphology and global decrease of electron transport chain activity motivating investigations into additional potential roles for ABAT in mitochondrial function. RNAi-mediated inhibition of ABAT in fibroblasts caused depletion of mtDNA. By employing a first-in-kind lentiviral vector to simultaneously express ABAT-UTR-specific shRNA hairpins and mutant ABAT cDNA-sans-UTR in healthy cells we demonstrated that all ABAT mutations in known subjects cause mtDNA depletion. Nucleoside rescue and co-IP experiments pinpoint that ABAT functions in the mitochondrial nucleoside salvage pathway to facilitate conversion of dNDPs to dNTPs, binding other proteins (SUCLA2, SUCLG1, SUCLG2, and NME4) previously thought to participate in this process. This work reveals ABAT as a connection between GABA metabolism and nucleoside metabolism and defines a novel genetic cause of MDS.

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