TY - JOUR
T1 - Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis
T2 - A window of opportunity in the search for genetic modifiers
AU - Heiman-Patterson, Terry D.
AU - Sher, Roger B.
AU - Blankenhorn, Elizabeth A.
AU - Alexander, Guillermo
AU - Deitch, Jeffrey S.
AU - Kunst, Catherine B.
AU - Maragakis, Nicholas
AU - Cox, Gregory
N1 - Funding Information:
The authors wish to thank David Schroeder for general laboratory practices and colony maintenance.We also thank Denise Figlewicz for her comments and shared data. The collaboration and meetings of the authors was supported by the ALS Hope Foundation.
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
KW - Amyotrophic lateral sclerosis
KW - genetic background
KW - genetic modifiers
UR - http://www.scopus.com/inward/record.url?scp=79951754463&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79951754463&partnerID=8YFLogxK
U2 - 10.3109/17482968.2010.550626
DO - 10.3109/17482968.2010.550626
M3 - Review article
C2 - 21241159
AN - SCOPUS:79951754463
SN - 1748-2968
VL - 12
SP - 79
EP - 86
JO - Amyotrophic Lateral Sclerosis
JF - Amyotrophic Lateral Sclerosis
IS - 2
ER -