AMPD2 Regulates GTP Synthesis and Is Mutated in a Potentially Treatable Neurodegenerative Brainstem Disorder

详细信息    查看全文

• 作者：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 ; et al.
• 刊名：Cell
• 出版年：2013
• 出版时间：1 August, 2013
• 年：2013
• 卷：154
• 期：3
• 页码：505-517
• 全文大小：3380 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

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.