title: 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.
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine, Rady Children's Hospital, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Naiara
authors.initials: N
authors.lastname: Akizu
authors.forename: Vincent
authors.initials: V
authors.lastname: Cantagrel
authors.forename: Jana
authors.initials: J
authors.lastname: Schroth
authors.forename: Na
authors.initials: N
authors.lastname: Cai
authors.forename: Keith
authors.initials: K
authors.lastname: Vaux
authors.forename: Douglas
authors.initials: D
authors.lastname: McCloskey
authors.forename: Robert K
authors.initials: RK
authors.lastname: Naviaux
authors.forename: Jeremy
authors.initials: J
authors.lastname: Van Vleet
authors.forename: Ali G
authors.initials: AG
authors.lastname: Fenstermaker
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Silhavy
authors.forename: Judith S
authors.initials: JS
authors.lastname: Scheliga
authors.forename: Keiko
authors.initials: K
authors.lastname: Toyama
authors.forename: Hiroko
authors.initials: H
authors.lastname: Morisaki
authors.forename: Fatma M
authors.initials: FM
authors.lastname: Sonmez
authors.forename: Figen
authors.initials: F
authors.lastname: Celep
authors.forename: Azza
authors.initials: A
authors.lastname: Oraby
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.forename: Raidah
authors.initials: R
authors.lastname: Al-Baradie
authors.forename: Eissa A
authors.initials: EA
authors.lastname: Faqeih
authors.forename: Mohammed A M
authors.initials: MA
authors.lastname: Saleh
authors.forename: Emily
authors.initials: E
authors.lastname: Spencer
authors.forename: Rasim Ozgur
authors.initials: RO
authors.lastname: Rosti
authors.forename: Eric
authors.initials: E
authors.lastname: Scott
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nickerson
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.forename: Takayuki
authors.initials: T
authors.lastname: Morisaki
authors.forename: Edward W
authors.initials: EW
authors.lastname: Holmes
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000659:AMP Deaminase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001933:Brain Stem / Q000473:pathology; D002531:Cerebellum / Q000473:pathology; D002648:Child; D005260:Female; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism; D009849:Olivopontocerebellar Atrophies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis; D011687:Purines / Q000096:biosynthesis*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism
chemical_list: D011687:Purines; D006160:Guanosine Triphosphate; D000659:AMP Deaminase; C475566:AMPD2 protein, human
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