Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons

被引:100
作者
Antonellis, Anthony
Lee-Lin, Shih-Queen
Wasterlain, Amy
Leo, Paul
Quezado, Martha
Goldfarb, Lev G.
Myung, Kyungjae
Burgess, Shawn
Fischbeck, Kenneth H.
Green, Eric D.
机构
[1] NHGRI, Gen Technol Branch, NIH, Bethesda, MD 20892 USA
[2] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA
[3] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA
[4] NHGRI, Pathol Lab, NIH, Bethesda, MD 20892 USA
[5] NINDS, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA
[6] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA
关键词
Charcot-Marie-Tooth disease; spinal muscular atrophy; peripheral neuropathy; axonopathy; tRNA synthetase; axonal translation;
D O I
10.1523/JNEUROSCI.1671-06.2006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are axonal neuropathies characterized by a phenotype that is more severe in the upper extremities. We previously implicated mutations in the gene encoding glycyl-tRNA synthetase (GARS) as the cause of CMT2D and dSMA-V. GARS is a member of the family of aminoacyl-tRNA synthetases responsible for charging tRNA with cognate amino acids; GARS ligates glycine to tRNAGly. Here, we present functional analyses of disease-associated GARS mutations and show that there are not any significant mutation-associated changes in GARS expression levels; that the majority of identified GARS mutations modeled in yeast severely impair viability; and that, in most cases, mutant GARS protein mislocalizes in neuronal cells. Indeed, four of the five mutations studied show loss-of-function features in at least one assay, suggesting that tRNA-charging deficits play a role in disease pathogenesis. Finally, we detected endogenous GARS-associated granules in the neurite projections of cultured neurons and in the peripheral nerve axons of normal human tissue. These data are particularly important in light of the recent identification of CMT-associated mutations in another tRNA synthetase gene [YARS(tyrosyl-tRNA synthetase gene)]. Together, these findings suggest that tRNA-charging enzymes play a key role in maintaining peripheral axons.
引用
收藏
页码:10397 / 10406
页数:10
相关论文
共 35 条
[1]  
[Anonymous], GENOME ANAL LAB MANU
[2]   Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V [J].
Antonellis, A ;
Ellsworth, RE ;
Sambuughin, N ;
Puls, I ;
Abel, A ;
Lee-Lin, SQ ;
Jordanova, A ;
Kremensky, I ;
Christodoulou, K ;
Middleton, LT ;
Sivakumar, K ;
Ionasescu, V ;
Funalot, B ;
Vance, JM ;
Goldfarb, LG ;
Fischbeck, KH ;
Green, ED .
AMERICAN JOURNAL OF HUMAN GENETICS, 2003, 72 (05) :1293-1299
[3]  
BIEDLER JL, 1978, CANCER RES, V38, P3751
[4]   A POSITIVE SELECTION FOR MUTANTS LACKING OROTIDINE-5'-PHOSPHATE DECARBOXYLASE ACTIVITY IN YEAST - 5-FLUORO-OROTIC ACID RESISTANCE [J].
BOEKE, JD ;
LACROUTE, F ;
FINK, GR .
MOLECULAR & GENERAL GENETICS, 1984, 197 (02) :345-346
[5]   MAPPING OF A DISTAL FORM OF SPINAL MUSCULAR-ATROPHY WITH UPPER-LIMB PREDOMINANCE TO CHROMOSOME 7P [J].
CHRISTODOULOU, K ;
KYRIAKIDES, T ;
HRISTOVA, AH ;
GEORGIOU, DM ;
KALAYDJIEVA, L ;
YSHPEKOVA, B ;
IVANOVA, T ;
WEBER, JL ;
MIDDLETON, LT .
HUMAN MOLECULAR GENETICS, 1995, 4 (09) :1629-1632
[6]   The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration [J].
Corti, O ;
Hampe, C ;
Koutnikova, H ;
Darios, F ;
Jacquier, S ;
Prigent, A ;
Robinson, JC ;
Pradier, L ;
Ruberg, M ;
Mirande, M ;
Hirsch, E ;
Rooney, T ;
Fournier, A ;
Brice, A .
HUMAN MOLECULAR GENETICS, 2003, 12 (12) :1427-1437
[7]   Coexistence of CMT-2D and distal SMA-V phenotypes in an Italian family with a GARS gene mutation [J].
Del Bo, R ;
Locatelli, F ;
Corti, S ;
Scarlato, M ;
Ghezzi, S ;
Prelle, A ;
Fagiolari, G ;
Moggio, M ;
Carpo, M ;
Bresolin, N ;
Comi, GP .
NEUROLOGY, 2006, 66 (05) :752-754
[8]   LOWER MOTOR AND PRIMARY SENSORY NEURON DISEASES WITH PERONEAL MUSCULAR ATROPHY .2. NEUROLOGIC GENETIC AND ELECTROPHYSIOLOGIC FINDINGS IN VARIOUS NEURONAL DEGENERATIONS [J].
DYCK, PJ ;
LAMBERT, EH .
ARCHIVES OF NEUROLOGY, 1968, 18 (06) :619-&
[9]   Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy [J].
Evgrafov, OV ;
Mersiyanova, I ;
Irobi, J ;
Van Den Bosch, L ;
Dierick, I ;
Leung, CL ;
Schagina, O ;
Verpoorten, N ;
Van Impe, K ;
Fedotov, V ;
Dadali, E ;
Auer-Grumbach, M ;
Windpassinger, C ;
Wagner, K ;
Mitrovic, Z ;
Hilton-Jones, D ;
Talbot, K ;
Martin, JJ ;
Vasserman, N ;
Tverskaya, S ;
Polyakov, A ;
Liem, RKH ;
Gettemans, J ;
Robberecht, W ;
De Jonghe, P ;
Timmerman, V .
NATURE GENETICS, 2004, 36 (06) :602-606
[10]  
Freist W, 1996, BIOL CHEM H-S, V377, P343