Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations.

Authors

Laurie B Griffin, Cellular and Molecular Biology Program, University of Michigan Medical School; Medical Scientist Training Program, University of Michigan Medical School
Reiko Sakaguchi, Department of Biochemistry and Molecular Biochemistry, Thomas Jefferson UniversityFollow
David McGuigan, Department of Biochemistry and Molecular Biochemistry, Thomas Jefferson University
Michael A Gonzalez, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine
Charles Searby, Department of Pediatrics, Division of Medical Genetics, University of Iowa
Stephan Züchner, Hussman Institute for Human Genomics, University of Miami Miller School of MedicineFollow
Ya-Ming Hou, Department of Biochemistry and Molecular Biochemistry, Thomas Jefferson UniversityFollow
Anthony Antonellis, Cellular and Molecular Biology Program, University of Michigan Medical School; Department of Human Genetics, University of Michigan Medical School; Department of Neurology, University of Michigan Medical School

Document Type

Article

Publication Date

11-1-2014

Comments

This article has been peer reviewed. It was published in: Human Mutation.

Volume 35, Issue 11, 1 November 2014, Pages 1363-1371.

The published version is available at DOI: 10.1002/humu.22681

Copyright © 2014 Wiley Periodicals, Inc.

Abstract

Charcot-Marie-Tooth disease type 2D (CMT2D) is an autosomal-dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D. GARS is a member of the ubiquitously expressed aminoacyl-tRNA synthetase (ARS) family and is responsible for charging tRNA with glycine. To date, 13 GARS mutations have been identified in patients with CMT disease. While functional studies have revealed loss-of-function characteristics, only four GARS mutations have been rigorously studied. Here, we report the functional evaluation of nine CMT-associated GARS mutations in tRNA charging, yeast complementation, and subcellular localization assays. Our results demonstrate that impaired function is a common characteristic of CMT-associated GARS mutations. Additionally, one mutation previously associated with CMT disease (p.Ser581Leu) does not demonstrate impaired function, was identified in the general population, and failed to segregate with disease in two newly identified families with CMT disease. Thus, we propose that this variant is not a disease-causing mutation. Together, our data indicate that impaired function is a key component of GARS-mediated CMT disease and emphasize the need for careful genetic and functional evaluation before implicating a variant in disease onset.

Recommended Citation

Griffin, Laurie B; Sakaguchi, Reiko; McGuigan, David; Gonzalez, Michael A; Searby, Charles; Züchner, Stephan; Hou, Ya-Ming; and Antonellis, Anthony, "Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations." (2014). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 92.
https://jdc.jefferson.edu/bmpfp/92

PubMed ID

25168514