CAST;B6-GarsNmf249/JRwb mice have a severe axonal neuropathy of both sensory and motor axons. Mutant mice have abnormal neuromuscular junction morphology and impaired transmission, reduced nerve conduction velocities, and a loss of large-diameter peripheral axons, without defects in myelination. These mice may be useful in studies of inherited Charcot-Marie-Tooth peripheral neuropathies, type 2D (CMT2D).Read More +
NMF249 mice have a distal neuropathy in motor neurons with retracting axons (Figure 1) and poorly innervated or denervated neuromuscular junctions (Figure 2)visualized through immunohistochemistry of neuromuscular junctions; green labeling indicates the presence of neurofilament protein in axons (SMI31) and synaptic vesicle proteins at motor terminals (SV2); red labeling indicates ACh receptors visualized with rhodamine-labeled alpha-bungarotoxin; yellow color reveals the overlay of the presynaptic nerve with the motor terminal arborization). Large diameter myelinated fibers are absent and a significant number of unidentified cells is evident in the sciatic nerve of affected mice (Figure 3). No defects have been observed in the CNS.
On the mixed CAST;B6 background, motor nerves have a 26% reduction in axons, neuromuscular junctions are partially denervated and nerve conduction velocity is substantially reduced.
On the C57BL/6 background, heterozygous mice are smaller than their littermates and develop an unsteady gait about 3 weeks of age (average 3.5 weeks of age +/-0.5, n=22). The mice fail to thrive and die between 4-8 weeks of age. Homozygotes die before birth. Males and females are affected and do not live long enough to mate normally. Due to the difficulties in maintaining the strain, it is outcrossed to CAST/Ei every few generations.
Although the NMF249 mutation arose in an ENU mutagenized family, it is a spontaneous dominant mutation. This strain may be useful for studying Charcot-Marie-Tooth disease type 2D.
This phenotypic deviant was identified following multidose ethylnitrosourea (ENU) treatments to induce mutations in male founder C57BL/6J mice (Stock No. 000664), in the Neuroscience Mutagenesis Facility (NMF) at The Jackson Laboratory. The parents exhibited no overt phenotype and produced only 1 affected mouse in a total of 24 progeny. However, when this animal was mated to a wild-type male (using ovarian transplants), half the offspring was affected, suggesting that a spontaneous dominant mutation may have occurred. Ratios from subsequent matings are consistent with a fully penetrant dominant mutation. Sequence analysis indicates that the mutation is a nucleotide substitution resulting in the replacement of proline at codon 278 with a tyrosine and lysine. This highly conserved proline residue is near the second catalytic domain. Due to reproductive problems, the colony is outcrossed to CAST/Ei mice and is maintained by several generations of backcross to C57BL/6 followed by an outcross to CAST/Ei to improve breeding efficiency.
|Allele Name||neuroscience mutagenesis facility, 249|
|Allele Synonym(s)||GarsP278KY; Nmf249|
|Gene Symbol and Name||Gars, glycyl-tRNA synthetase|
|Gene Synonym(s)||CMT2D; DSMAV; GENA202; Gena201; Gena201; Genetics Harwell, 201; GlyRS; HMN5; Nmf249; RGD1559871; SMAD1; Sgrp23; Sgrp23; neuroscience mutagenesis facility, 249; storage granule protein 23|
|Strain of Origin||C57BL/6J|
|General Note||Although this phenotypic mutation was identified in an ENU mutagenesis screen, it is probably of spontaneous origin.|
|Molecular Note||Sequence analysis revealed that a CC pair in the open reading frame was changed to AAATA. This nucleotide substitution results in the proline at codon 278 to be replaced with a tyrosine and lysine residue without affecting the rest of the open reading frame. This highly conserved proline residue is near the second catalytic domain. Expression of transcript from this allele does not appear to be affected by this mutation. It is predicted to be a gain-of-function mutation.|
Homozygote mice die shortly after birth. The strain is maintained by mating heterozygotes to C57BL/6J (Stock No. 000664) mice for several backcross generations until breeding declines, and then outcrossing to CAST/EiJ (Stock No. 000928).
When using the GarsP278KY mouse strain in a publication, please cite the originating article(s) and include JAX stock #017540 in your Materials and Methods section.
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