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AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

ABSTRACT: Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease.

SUBMITTER: Akizu N

PROVIDER: S-EPMC3815927 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

Akizu Naiara N Cantagrel Vincent V Schroth Jana J Cai Na N Vaux Keith K McCloskey Douglas D Naviaux Robert K RK Van Vleet Jeremy J Fenstermaker Ali G AG Silhavy Jennifer L JL Scheliga Judith S JS Toyama Keiko K Morisaki Hiroko H Sonmez Fatma M FM Celep Figen F Oraby Azza A Zaki Maha S MS Al-Baradie Raidah R Faqeih Eissa A EA Saleh Mohammed A M MA Spencer Emily E Rosti Rasim Ozgur RO Scott Eric E Nickerson Elizabeth E Gabriel Stacey S Morisaki Takayuki T Holmes Edward W EW Gleeson Joseph G JG

Cell 20130801 3

Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypopl ...[more]

PMID: 23911318

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Dataset Information

AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

Publications

AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

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