Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels.

Authors

William W Motley
Kevin L Seburn
Mir Hussain Nawaz
Kathy E Miers
Jun Cheng
Anthony Antonellis
Eric D Green
Kevin Talbot
Xiang-Lei Yang
Kenneth H Fischbeck
Robert W BurgessFollow

Document Type

Article

Publication Date

12-1-2011

Keywords

Animals, Axons, Charcot-Marie-Tooth Disease, Disease Models, Animal, Glycine-tRNA Ligase, Heterozygote, Homozygote, Humans, Mice, Mice, Transgenic, Mutation, Missense, Neurons, Peripheral Nervous System, Schwann Cells, Sciatic Nerve

JAX Source

PLoS Genet 2011 Dec; 7(12):e1002399.

PMID

22144914

Volume

7

Issue

12

First Page

1002399

Last Page

1002399

ISSN

1553-7404

Abstract

Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). In addition to GARS, mutations in three other tRNA synthetase genes cause similar neuropathies, although the underlying mechanisms are not fully understood. To address this, we generated transgenic mice that ubiquitously over-express wild-type GARS and crossed them to two dominant mouse models of CMT2D to distinguish loss-of-function and gain-of-function mechanisms. Over-expression of wild-type GARS does not improve the neuropathy phenotype in heterozygous Gars mutant mice, as determined by histological, functional, and behavioral tests. Transgenic GARS is able to rescue a pathological point mutation as a homozygote or in complementation tests with a Gars null allele, demonstrating the functionality of the transgene and revealing a recessive loss-of-function component of the point mutation. Missense mutations as transgene-rescued homozygotes or compound heterozygotes have a more severe neuropathy than heterozygotes, indicating that increased dosage of the disease-causing alleles results in a more severe neurological phenotype, even in the presence of a wild-type transgene. We conclude that, although missense mutations of Gars may cause some loss of function, the dominant neuropathy phenotype observed in mice is caused by a dose-dependent gain of function that is not mitigated by over-expression of functional wild-type protein.

Recommended Citation

Motley W, Seburn K, Nawaz M, Miers K, Cheng J, Antonellis A, Green E, Talbot K, Yang X, Fischbeck K, Burgess R. Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels. PLoS Genet 2011 Dec; 7(12):e1002399.