Compound Heterozygosity for Loss-of-Function Lysyl-tRNA Synthetase Mutations in

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Am J Hum Genet. 2010 Oct 8;87(4):560-6

Compound Heterozygosity for Loss-of-Function Lysyl-tRNA Synthetase Mutations in

a Patient with Peripheral Neuropathy.

McLaughlin HM, Sakaguchi R, Liu C, Igarashi T, Pehlivan D, Chu K, Iyer R, Cruz

P, Cherukuri PF, Hansen NF, Mullikin JC; NISC Comparative Sequencing Program,

Biesecker LG, TE, Ionasescu V, Nicholson G, Searby C, Talbot K, Vance JM,

Züchner S, Szigeti K, Lupski JR, Hou YM, Green ED, Antonellis A.

Department of Human Genetics, University of Michigan Medical School, Ann Arbor,

MI 48109, USA.

Abstract

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.