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

Journal: 
Cell
Publication Year: 
2013
Authors: 
Naiara Akizu
Vincent Cantagrel
Jana Schroth
Na Cai
Keith Vaux
Douglas McCloskey
Robert K Naviaux
Jeremy Van Vleet
Ali G Fenstermaker
Jennifer L Silhavy
Judith S Scheliga
Keiko Toyama
Hiroko Morisaki
Fatma M Sonmez
Figen Celep
Azza Oraby
Maha S Zaki
Raidah Al-Baradie
Eissa A Faqeih
Mohammed A M Saleh
Emily Spencer
Rasim Ozgur Rosti
Eric Scott
Elizabeth Nickerson
Stacey Gabriel
Takayuki Morisaki
Edward W Holmes
Joseph G Gleeson
PubMed link: 
23911318
Public Summary: 
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.
Scientific 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.