Dominant Intermediate CMT - Disrupted function,axonal distribution of mutant tyr

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Nat Genet. 2006 Jan 22

Disrupted function and axonal distribution of mutant tyrosyl-tRNA

synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy.

Jordanova A, Irobi J, FP, Van Dijck P, Meerschaert K, Dewil M,

Dierick I, s A, De Vriendt E, Guergueltcheva V, Rao CV, Tournev

I, Gondim FA, D'Hooghe M, Van Gerwen V, Callaerts P, Van Den Bosch L,

Timmermans JP, Robberecht W, Gettemans J, Thevelein JM, De Jonghe P,

Kremensky I, Timmerman V.

[1] Department of Molecular Genetics, Flanders Interuniversity

Institute for Biotechnology, University of Antwerp,

Universiteitsplein 1, 2610 Antwerpen, Belgium. [2] Laboratory of

Molecular Pathology, Sofia Medical University, 1431 Sofia, Bulgaria.

Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the

peripheral nervous system caused by demyelination or axonal

degeneration, or a combination of both features. We previously

assigned the locus for autosomal dominant intermediate CMT neuropathy

type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two

heterozygous missense mutations (G41R and E196K) and one de novo

deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three

unrelated families affected with DI-CMTC. Biochemical experiments and

genetic complementation in yeast show partial loss of aminoacylation

activity of the mutant proteins, and mutations in YARS, or in its

yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal

termini in differentiating primary motor neuron and neuroblastoma

cultures. This specific distribution is significantly reduced in

cells expressing mutant YARS proteins. YARS is the second aminoacyl-

tRNA synthetase found to be involved in CMT, thereby linking protein-

synthesizing complexes with neurodegeneration.