AMPD2 regulates de novo GTP synthesis and is mutated in a new form of pontocerebellar hypoplasia. V. Cantagrel1, 2, N. Akizu2, J. Schroth2, J. Van Vleet3, N. Cai2, K. Vaux2, A. Crawford2, J. S. Silhavy2, F. M. Sonmez4, F. Celep5, A. Oraby6, M. Zaki7, R. Al-Baradie8, E. Faqeih9, E. Nickerson10, S. Gabriel10, T. Morisaki11, E. W. Holmes12, J. G. Gleeson2 1) INSERM U781-Institut IMAGINE, H˘pital Necker-Enfants Malades, Paris, France; 2) Neurogenetics Laboratory, Institute for Genomic Medicine, Rady Childrens Hospital, Howard Hughes Medical Institute, University of California, San Diego, CA 92093, USA; 3) Glycotechnology Core Resource, University of California, San Diego, CA 92093, USA; 4) Department of Pediatric Neurology, Turgut Ozal University, Ankara, Turkey; 5) Medical Biology Department, Karadeniz Technical University, Trabzon, 61080, Turkey; 6) Pediatric Neurology Department, Cairo University Childrens Hospital, Cairo 406, Egypt; 7) Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt; 8) Division of Pediatric Neurology, King Fahd University Hospital, Dammam, 31444, Kingdom of Saudi Arabia; 9) Division of Medical Genetics, Department of Pediatrics, King Fahad Medical City, Childrens Hospital, Riyadh 11525, Kingdom of Saudi Arabia; 10) The Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA; 11) National Cerebral and Cardiovascular Center Research Institute, Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Osaka, 565-0871 Japan; 12) Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.

   AMP deaminase (AMPD) enzymes play a role in the maintenance of purine nucleotide homeostasis by converting adenosine monophosphate (AMP) into inosine monophosphate (IMP), the common precursor for both adenine and guanine nucleotides. Using a combination of whole-exome sequencing and linkage analysis, we identified a new distinct early-onset neurodegenerative condition with characteristic brain imaging features of pontocerebellar hypoplasia (PCH), which we propose to be called PCH type 8. We identified recessive mutations in the AMPD2 gene in five unrelated families. All affected individuals present atrophy of the cerebellum and the pons and corpus callosum hypoplasia. Among the three human AMPD genes, AMPD2 is the only one highly expressed in the cerebellum. Functional conservation of the human AMPD2 enzyme was demonstrated in yeast, however none of the patients' mutations were able to rescue the yeast phenotype. The study of Ampd2/Ampd3 double knockout mice revealed a neurodegenerative phenotype in the hippocampus and the cerebellum. This observation supports a role for AMP deaminase activity in neuroprotection through adenosine nucleotide metabolism and/or maintenance of the guanine nucleotide pool. Using yeast and patient-derived cell lines, we quantified nucleotides levels and investigated the underlying mechanism. In the presence of precursor of adenosine, patients cells are not able to control the feedback inhibition caused by the accumulation of adenine nucleotide which cannot get converted into guanine nucleotides. This exacerbated regulatory loop strongly inhibits the de novo purine biosynthesis pathway and leads to a severe depletion of guanine nucleotide resulting in a defective GTP-dependent initiation of protein translation. Administration of a purine precursor allowed us to rescue the cellular defects associated with this nucleotide imbalance.

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