Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: A window of opportunity in the search for genetic modifiers

Abstract Transgenic (Tg) mouse models of FALS containing mutant human SOD1 genes (G37R, G85R, D90A, or G93A missense mutations or truncated SOD1) exhibit progressive neurodegeneration of the motor system that bears a striking resemblance to ALS, both clinically and pathologically. The most utilized...

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Published in:Amyotrophic lateral sclerosis 2011-03, Vol.12 (2), p.79-86
Main Authors: Heiman-Patterson, Terry D., Sher, Roger B., Blankenhorn, Elizabeth A., Alexander, Guillermo, Deitch, Jeffrey S., Kunst, Catherine B., Maragakis, Nicholas, Cox, Gregory
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - pathology
Amyotrophic Lateral Sclerosis - physiopathology
Animals
Disease Models, Animal
Drug Design
Female
genetic background
genetic modifiers
Genotype
Humans
Male
Mice
Mice, Transgenic
Nerve Degeneration - genetics
Nerve Degeneration - pathology
Phenotype
Protein Isoforms - genetics
Superoxide Dismutase - genetics
Superoxide Dismutase-1
Survival Rate
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Summary:Abstract Transgenic (Tg) mouse models of FALS containing mutant human SOD1 genes (G37R, G85R, D90A, or G93A missense mutations or truncated SOD1) exhibit progressive neurodegeneration of the motor system that bears a striking resemblance to ALS, both clinically and pathologically. The most utilized and best characterized Tg mice are the G93A mutant hSOD1 (Tg(hSOD1-G93A)1GUR mice), abbreviated G93A. In this review we highlight what is known about background-dependent differences in disease phenotype in transgenic mice that carry mutated human or mouse SOD1. Expression of G93A-hSOD1Tg in congenic lines with ALR, NOD.Rag1KO, SJL or C3H backgrounds show a more severe phenotype than in the mixed (B6xSJL) hSOD1Tg mice, whereas a milder phenotype is observed in B6, B10, BALB/c and DBA inbred lines. We hypothesize that the background differences are due to disease-modifying genes. Identification of modifier genes can highlight intracellular pathways already suspected to be involved in motor neuron degeneration; it may also point to new pathways and processes that have not yet been considered. Most importantly, identified modifier genes provide new targets for the development of therapies.
ISSN:1748-2968
1471-180X
DOI:10.3109/17482968.2010.550626