title: A major determinant for binding and aminoacylation of tRNA(Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease.
abstract: Charcot-Marie-Tooth disease (CMT) is the most common cause of inherited peripheral neuropathy, with an estimated frequency of 1/2500. We studied a large family with 17 patients affected by the axonal form of CMT (CMT2). Analysis of the 15 genes or loci known to date was negative. Genome-wide genotyping identified a CMT2 locus in 16q21-q23 between D16S3050 and D16S3106. The maximum two-point LOD score was 4.77 at theta = 0 for marker D16S3050. Sequencing of candidate genes identified a unique mutation, c.986G>A (p.Arg329His), affecting a totally conserved amino acid in the helical domain of cytoplasmic alanyl-tRNA synthetase (AlaRS). A second family with the same mutation and a different founder was then identified in a cohort of 91 CMT2 families. Although mislocation of mutant Arg329His-AlaRS in axons remains to be evaluated, experimental data point mostly to a quantitative reduction in tRNA(Ala) aminoacylation. Aminoacylation and editing functions closely cooperate in AlaRS, and Arg329His mutation could also lead to qualitative errors participating in neurodegeneration. Our report documents in 18 patients the deleterious impact of a mutation in human cytoplasmic AlaRS and broadens the spectrum of defects found in tRNA synthetases. Patients present with sensory-motor distal degeneration secondary to predominant axonal neuropathy, slight demyelination, and no atypical or additional CNS features.
authors.affiliation: Département de Biochimie, Centre de Biologie Est, Hospices Civils de Lyon, Bron, France. philippe.latour@chu-lyon.fr
authors.forename: Philippe
authors.initials: P
authors.lastname: Latour
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.forename: Chantal
authors.initials: C
authors.lastname: Baudelet-Méry
authors.forename: Pierre
authors.initials: P
authors.lastname: Soichot
authors.forename: Veronica
authors.initials: V
authors.lastname: Cusin
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Locatelli
authors.forename: Martine
authors.initials: M
authors.lastname: Mayençon
authors.forename: Annie
authors.initials: A
authors.lastname: Sarcey
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Broussolle
authors.forename: William
authors.initials: W
authors.lastname: Camu
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Robert
authors.initials: R
authors.lastname: Rousson
mesh_terms: D000293:Adolescent; D000328:Adult; D000412:Alanine-tRNA Ligase / Q000235:genetics*; D000595:Amino Acid Sequence; D049148:Aminoacylation; D001369:Axons / Q000378:metabolism*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D003593:Cytoplasm / Q000378:metabolism*; D005799:Genes, Dominant; D006801:Humans; D008126:Lod Score; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: D000412:Alanine-tRNA Ligase