A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N).
Charcot-Marie-Tooth (CMT) disease comprises a heterogeneous group of peripheral neuropathies characterized by muscle weakness and wasting, and impaired sensation in the extremities. Four genes encoding an aminoacyl-tRNA synthetase (ARS) have been implicated in CMT disease. ARSs are ubiquitously expressed, essential enzymes that ligate amino acids to cognate tRNA molecules. Recently, a p.Arg329His variant in the alanyl-tRNA synthetase (AARS) gene was found to segregate with dominant axonal CMT type 2N (CMT2N) in two French families; however, the functional consequence of this mutation has not been determined. To investigate the role of AARS in CMT, we performed a mutation screen of the AARS gene in patients with peripheral neuropathy. Our results showed that p.Arg329His AARS also segregated with CMT disease in a large Australian family. Aminoacylation and yeast viability assays showed that p.Arg329His AARS severely reduces enzyme activity. Genotyping analysis indicated that this mutation arose on three distinct haplotypes, and the results of bisulfite sequencing suggested that methylation-mediated deamination of a CpG dinucleotide gives rise to the recurrent p.Arg329His AARS mutation. Together, our data suggest that impaired tRNA charging plays a role in the molecular pathology of CMT2N, and that patients with CMT should be directly tested for the p.Arg329His AARS mutation.
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-5618, USA.
Heather M
HM
McLaughlin
Reiko
R
Sakaguchi
William
W
Giblin
Thomas E
TE
Wilson
Leslie
L
Biesecker
James R
JR
Lupski
Kevin
K
Talbot
Jeffery M
JM
Vance
Stephan
S
Züchner
Yi-Chung
YC
Lee
Marina
M
Kennerson
Ya-Ming
YM
Hou
Garth
G
Nicholson
Anthony
A
Antonellis
D000412:Alanine-tRNA Ligase / Q000235:genetics* / Q000378:metabolism; D049148:Aminoacylation; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D001315:Australia; D001369:Axons; D016022:Case-Control Studies; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands; D005260:Female; D005602:France; D005799:Genes, Dominant; D008040:Genetic Linkage; D006239:Haplotypes; D006639:Histidine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D046249:Transfer RNA Aminoacylation / Q000235:genetics*; D015003:Yeasts
D006639:Histidine; D001120:Arginine; D000412:Alanine-tRNA Ligase