A major QTL on mouse chromosome 17 resulting in lifespan variability in SOD1-G93A transgenic mouse models of amyotrophic lateral sclerosis

AbstractAmyotrophic 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.Key words:: Amyotrophic lateral sclerosisquantitative trait locilifespan Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.This work was supported by the ALS Hope Foundation (THP); DUCOM Cure Grant (THP, EPB, GAC, RS); Muscular Dystrophy Association (THP, EPB, GAC, RS); and the ALS Association (GAC).Notice of correctionInformation regarding the first authors of this article were updated after the article was published online.