title: A major QTL on mouse chromosome 17 resulting in lifespan variability in SOD1-G93A transgenic mouse models of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis is a late-onset degenerative disease affecting motor neurons in the spinal cord, brainstem, and motor cortex. There is great variation in the expression of ALS symptoms even between siblings who both carry the same Cu/Zn superoxide dismutase (SOD1) mutations. One important use of transgenic mouse models of SOD1-ALS is the study of genetic influences on ALS severity. We utilized multiple inbred mouse strains containing the SOD1-G93A transgene to demonstrate a major quantitative trait locus (QTL) on mouse chromosome 17 resulting in a significant shift in lifespan. Reciprocal crosses between long- and short-lived strains identified critical regions, and we have narrowed the area for potential genetic modifier(s) to < 2Mb of the genome. Results showed that resequencing of this region resulted in 28 candidate genes with potentially functional differences between strains. In conclusion, these studies provide the first major modifier locus affecting lifespan in this model of FALS and, once identified, these candidate modifier genes may provide insight into modifiers of human disease and, most importantly, define new targets for the development of therapies.
authors.affiliation: University of Maine , Orono, Maine.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Sher
authors.forename: Terry D
authors.initials: TD
authors.lastname: Heiman-Patterson
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Blankenhorn
authors.forename: Juliann
authors.initials: J
authors.lastname: Jiang
authors.forename: Guillermo
authors.initials: G
authors.lastname: Alexander
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Deitch
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000401:mortality; D000818:Animals; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D005065:Euthanasia; D006801:Humans; D008136:Longevity / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics*; D016019:Survival Analysis
chemical_list: C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
keywords: Amyotrophic lateral sclerosis; lifespan; quantitative trait loci