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Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy |
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| Authors: | McLaughlin Heather M,Sakaguchi Reiko,Liu Cuiping,Igarashi Takao,Pehlivan Davut,Chu Kristine,Iyer Ram,Cruz Pedro,Cherukuri Praveen F,Hansen Nancy F,Mullikin James C NISC Comparative Sequencing Program,Biesecker Leslie G,Wilson Thomas E,Ionasescu Victor,Nicholson Garth,Searby Charles,Talbot Kevin,Vance Jeffrey M,Züchner Stephan,Szigeti Kinga,Lupski James R,Hou Ya-Ming,Green Eric D,Antonellis Anthony |
| Affiliation: | 1 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA 2 Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, PA 19107, USA 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA 4 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA 5 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA 6 NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA 7 Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA 8 Division of Medical Genetics, Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA 9 Northcott Neuroscience Laboratory, ANZAC Research Institute and Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales 2139, Australia 10 Faculty of Medicine, University of Sydney, Camperdown, New South Wales 2006, Australia 11 Department of Clinical Neurology, University of Oxford, OX1 3QX Oxford, UK 12 Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA 13 Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA 14 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA 15 Texas Children's Hospital, Houston, TX 77030, USA 16 Department of Neurology, 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. |
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