Mapping and Phenotype information for this QTL, its variants and associated markers

(J:108213)
The mitochondrial superoxide dismutase mutation Sod2<tm1Cje> results in lethality, but phenotype and survival time is modified by genetic background. C57BL/6J animals with Sod2<tm1Cje> develop dilated cardiomyopathy and die at 15 days gestation, whereas DBA/2J animals with Sod2<tm1Cje> develop metabolic acidosis and die at approximately 8 days after birth.

Genome scan performed on animals from a C57BL/6-Sod2<tm1Cje> x (C57BL/6 x DBA/2-Sod2<tm1Cje>)F1 backcross detected preliminary linkage to survival time on mouse Chromosomes 9, 13, and 17. 217 microsatellite markers at an average spacing of 6.8 cM were used for the genome scan. Recombinant congenic Sod2<tm1Cje> strains derived from C57BL/6 and DBA/2J were constructed to map putative survival time QTLs.

Significant linkage to increased survival time in the presence of Sod2<tm1Cje> mapped to distal mouse Chromosome 13 between D13Mit288 and D13Mit35. This locus was further narrowed to a 10 Mb region around D13Mit35 (17 cM; 116.1 Mb) andis named Svtms (survival time modifier of Sod2). The presence of a DBA/2J-derived allele at Svtms confers increased lifespan of Sod2<tm1Cje> recombinant congenic animals to a degree similar to DBA/2J-Sod2<tm1Cje> animals. Potential candidate genes mapping to this region are Nln, Ndufs4, Mrps30, and Nnt (64 cM). Few SNPs have have been identified between C57BL/6J and DBA/2J for Nln, Ndufs4, and Mrps30.

C57BL/6J was found to have shorter Nnt cDNA lacking exons 7 - 11 compared to DBA/2J, due to a 17.8 kb deletion. Western blot analysis revealed an absence of Nnt protein in C57BL/6 tissues, whereas Nnt protein was present in tissues from DBA/2J, FVB/NJ, and C3H/HeJ. The null mutation is present only in C57BL/6J animals from The Jackson Laboratory, and is not found in other closely related C57BL/6 strains. The evidence supports Nnt as a candidate gene for Svtms.