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Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function. Mutations in three genes encoding aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT disease primarily associated with an axonal pathology. ARSs are ubiquitously expressed, essential enzymes responsible for charging tRNA molecules with their cognate amino acids. To further explore the role of ARSs in CMT disease, we performed a large-scale mutation screen of the 37 human ARS genes in a cohort of 355 patients with a phenotype consistent with CMT. Here we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort. Functional analyses revealed that two of these mutations (p.Leu133His and p.Tyr173SerfsX7) severely affect enzyme activity. Interestingly, both functional variants were found in a single patient with CMT disease and additional neurological and non-neurological sequelae. Based on these data, KARS becomes the fourth ARS gene associated with CMT disease, indicating that this family of enzymes is specifically critical for axon function.

Original publication

DOI

10.1016/j.ajhg.2010.09.008

Type

Journal article

Journal

Am J Hum Genet

Publication Date

08/10/2010

Volume

87

Pages

560 - 566

Keywords

Amino Acid Sequence, Base Sequence, Charcot-Marie-Tooth Disease, Cohort Studies, DNA Mutational Analysis, Heterozygote, Humans, Lysine-tRNA Ligase, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Peripheral Nervous System Diseases, Protein Conformation