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

被引：89

作者：

Akizu, Naiara ^{[1
]}

Cantagrel, Vincent ^{[1
]}

Schroth, Jana ^{[1
]}

Cai, Na ^{[1
]}

Vaux, Keith ^{[1
]}

McCloskey, Douglas ^{[2
]}

Naviaux, Robert K. ^{[3
,4
,5
]}

Van Vleet, Jeremy ^{[6
]}

Fenstermaker, Ali G. ^{[1
]}

Silhavy, Jennifer L. ^{[1
]}

Scheliga, Judith S. ^{[7
]}

Toyama, Keiko ^{[8
,9
]}

Morisaki, Hiroko ^{[8
,9
]}

Sonmez, Fatma M. ^{[10
]}

Celep, Figen ^{[11
]}

Oraby, Azza ^{[12
]}

Zaki, Maha S. ^{[13
]}

Al-Baradie, Raidah ^{[14
]}

Faqeih, Eissa A. ^{[15
]}

Saleh, Mohammed A. M. ^{[15
]}

Spencer, Emily ^{[1
]}

Rosti, Rasim Ozgur ^{[1
]}

Scott, Eric ^{[1
]}

Nickerson, Elizabeth ^{[16
]}

Gabriel, Stacey ^{[16
]}

Morisaki, Takayuki ^{[8
,9
]}

Holmes, Edward W. ^{[17
]}

Gleeson, Joseph G. ^{[1
]}

机构：

[1] Univ Calif San Diego, Howard Hughes Med Inst, Rady Childrens Hosp, Neurogenet Lab,Inst Genom Med, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Mitochondrial & Metab Dis Ctr, Dept Med, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Mitochondrial & Metab Dis Ctr, Dept Pediat, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Mitochondrial & Metab Dis Ctr, Dept Pathol, La Jolla, CA 92093 USA

[6] Univ Calif San Diego, Glycotechnol Core Resource, La Jolla, CA 92093 USA

[7] Sanford Burnham Med Res Inst, Signal Transduct Program, La Jolla, CA 92037 USA

[8] Osaka Univ, Grad Sch Pharmaceut Sci, Dept Biosci & Genet, Natl Cerebral & Cardiovasc Ctr Res Inst, Osaka 5658565, Japan

[9] Osaka Univ, Grad Sch Pharmaceut Sci, Dept Mol Pathophysiol, Osaka 5658565, Japan

[10] Turgut Ozal Univ, Dept Pediat Neurol, TR-06510 Ankara, Turkey

[11] Karadeniz Tech Univ, Dept Med Biol, TR-61080 Trabzon, Turkey

[12] Cairo Univ, Childrens Hosp, Pediat Neurol Dept, Cairo 406, Egypt

[13] Natl Res Ctr, Human Genet & Genome Res Div, Dept Clin Genet, Cairo 12311, Egypt

[14] King Fahd Specialist Hosp, Dept Pediat Neurol, Dammam 31444, Saudi Arabia

[15] King Fahad Med City, Childrens Hosp, Dept Pediat, Med Genet Sect, Riyadh 11525, Saudi Arabia

[16] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA

[17] Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA

来源：

CELL | 2013年 / 154卷 / 03期

关键词：

PROTEIN-SYNTHESIS; PONTOCEREBELLAR HYPOPLASIA; NUCLEOTIDE DEPLETION; YEAST; DEFICIENCY; DEAMINASE; TOXICITY; PURINE; GENE; PHOSPHORIBOSYLTRANSFERASE;

D O I：

10.1016/j.cell.2013.07.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 neuro degenerative 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.

引用

页码：505 / 517

页数：13

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