The stretcher spontaneous neurodegenerative mutation models Charcot-Marie-Tooth disease type 4D.
Mice affected by a spontaneous mutation which arose within our colony exhibited a neuromuscular phenotype involving tremor and characteristic stretching of the rear limbs. The mutant, named stretcher, was used to breed a backcross cohort for genetic mapping studies. The gene responsible for the mutant phenotype was mapped to a small region on mouse chromosome 15, with a LOD score above 20. Candidate genes within the region included the Ndrg1 gene. Examination of this gene in the mutant mouse strain revealed that exons 10 to 14 had been deleted. Mutations in the human orthologue are known to result in Charcot-Marie-Tooth disease type 4D (CMT4D) a severe early-onset disorder involving Schwann cell dysfunction and extensive demyelination. The stretcher mutant mouse is more severely affected than mice in which the Ndrg1 gene had been knocked out by homologous recombination. Our results demonstrate that the Ndrg1 (str) mutation provides a new model for CMT4D, and demonstrate that exons 10 to 14 of Ndrg1 encode amino acids crucial to the appropriate function of Ndrg1 in the central nervous system.
Western Australian Institute for Medical Research and Centre for Diabetes Research, University of Western Australia, Perth, 6000, Australia ; Australian Genome Research Facility, Perth, 6000, Australia.
David
D
Chandler
The Walter and Eliza Hall Institute of Medical Research, Victoria, 3065, Australia.
Sash
S
Lopaticki
St Vincent's Institute of Medical Research, Victoria, 3010, Australia.
Dexing
D
Huang
Western Australian Institute for Medical Research and Centre for Diabetes Research, University of Western Australia, Perth, 6000, Australia ; Centre for Medical Research, University of Western Australia, Perth, 6000, Australia.
Michael
M
Hunter
Western Australian Institute for Medical Research and Centre for Diabetes Research, University of Western Australia, Perth, 6000, Australia ; Centre for Medical Research, University of Western Australia, Perth, 6000, Australia.
Dora
D
Angelicheva
Howard Florey Institute, Victoria, 3010, Australia.
Trevor
T
Kilpatrick
Department of Clinical Neurosciences, Institute of Neurology University College London, London, NW3 2PF, UK.
Rosalind Hm
RH
King
Western Australian Institute for Medical Research and Centre for Diabetes Research, University of Western Australia, Perth, 6000, Australia ; Centre for Medical Research, University of Western Australia, Perth, 6000, Australia.
Luba
L
Kalaydjieva
Western Australian Institute for Medical Research and Centre for Diabetes Research, University of Western Australia, Perth, 6000, Australia ; Centre for Medical Research, University of Western Australia, Perth, 6000, Australia ; The Walter and Eliza Hall Institute of Medical Research, Victoria, 3065, Australia.
Grant
G
Morahan