TY - JOUR
T1 - Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy
AU - McLaughlin, Heather M.
AU - Sakaguchi, Reiko
AU - Liu, Cuiping
AU - Igarashi, Takao
AU - Pehlivan, Davut
AU - Chu, Kristine
AU - Iyer, Ram
AU - Cruz, Pedro
AU - Cherukuri, Praveen F.
AU - Hansen, Nancy F.
AU - Mullikin, James C.
AU - Biesecker, Leslie G.
AU - Wilson, Thomas E.
AU - Ionasescu, Victor
AU - Nicholson, Garth
AU - Searby, Charles
AU - Talbot, Kevin
AU - Vance, Jeffrey M.
AU - Züchner, Stephan
AU - Szigeti, Kinga
AU - Lupski, James R.
AU - Hou, Ya Ming
AU - Green, Eric D.
AU - Antonellis, Anthony
N1 - Funding Information:
We are indebted to the patients and their families for their participation in this study. We thank Ellen Pederson, Bob Lyons, and the University of Michigan DNA Sequencing Core for sequencing and genotyping assistance, Jeffrey Innis and the Michigan Medical Genetics Laboratory for anonymized DNA samples, Giovanni Manfredi and Kiyotaka Shiba for KARS cDNA constructs, and Jiqiang Ling and Dieter Söll for sharing unpublished data. We are also very grateful to the two anonymous reviewers for their helpful comments and suggestions, which dramatically improved the study. This work was supported in part by grant R00NS060983 from the National Institute of Neurological Diseases and Stroke (AA) and by the Intramural Research Program of the National Human Genome Research Institute (NIH). The ClinSeq cohort and sequencing were also supported by Intramural Funding from the National Human Genome Research Institute. H.M.M. was supported by the Rackham Merit Fellowship and the NIH Genetics Training Grant T32 GM007544-32. Y.-M.H. and R.S. were supported by a grant from the Muscular Dystrophy Association (157681 to Y.-M.H.).
PY - 2010/10/8
Y1 - 2010/10/8
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2010.09.008
DO - 10.1016/j.ajhg.2010.09.008
M3 - Article
C2 - 20920668
AN - SCOPUS:77957724879
VL - 87
SP - 560
EP - 566
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -