DI CMT 2C: Drosophila as a platfrm to predict the pathogenicity of novel amino

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Amino Acids. 2011 Mar 8. [Epub ahead of print]

Drosophila as a platfrm to predict the pathogenicity of novel aminoacyl-tRNA

synthetase mutations in CMT.

Leitão-Gonçalves R, Ermanoska B, s A, De Vriendt E, Timmerman V, Lupski JR,

Callaerts P, Jordanova A.

Department of Molecular Genetics, VIB, University of Antwerp, Universiteitsplein

1, 2610, Antwerp, Belgium.

Abstract

Charcot-Marie-Tooth disease (CMT) is the major form of inherited peripheral

neuropathy in humans. CMT is clinically and genetically heterogeneous and four

aminoacyl-tRNA synthetases have been implicated in disease etiology. Mutations

in the YARS gene encoding a tyrosyl-tRNA synthetase (TyrRS) lead to Dominant

Intermediate CMT type C (DI-CMTC).

Three dominant YARS mutations were so far associated with DI-CMTC. To further

expand the spectrum of CMT causing genetic defects in this tRNA synthetase, we

performed DNA sequencing of YARS coding regions in a cohort of 181 patients with

various types of peripheral neuropathy.

We identified a novel K265N substitution that in contrast to all previously

described mutations is located at the anticodon recognition domain of the

enzyme. Further genetic analysis revealed that this variant represents a benign

substitution.

Using our recently developed DI-CMTC Drosophila model, we tested in vivo the

pathogenicity of this new YARS variant. We demonstrated that the developmental

and behavioral defects induced by all DI-CMTC causing mutations were not present

upon ubiquitous or panneuronal TyrRS K265N expression.

Thus, in line with our genetic studies, functional analysis confirmed that the

K265N substitution does not induce toxicity signs in Drosophila. The consistency

observed throughout this work underscores the robustness of our DI-CMTC animal

model and identifies Drosophila as a valid read-out platform to ascertain the

pathogenicity of novel mutations to be identified in the future.