Dominant Axonal CMT: A Major Determinant for Binding and Aminoacylation of tRNA(

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Am J Hum Genet. 2009 Dec 30.

A Major Determinant for Binding and Aminoacylation of tRNA(Ala) in Cytoplasmic

Alanyl-tRNA Synthetase Is Mutated in Dominant Axonal Charcot-Marie-Tooth

Disease.

Latour P, Thauvin-Robinet C, Baudelet-Méry C, Soichot P, Cusin V, Faivre L,

Locatelli MC, Mayençon M, Sarcey A, Broussolle E, Camu W, A, Rousson R.

Département de Biochimie, Centre de Biologie Est, Hospices Civils de Lyon,

F-69500 Bron, France.

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.