Genetic modification of prenatal lethality and dilated cardiomyopathy in Mn superoxide dismutase mutant mice

Mn superoxide dismutase (MnSOD), a mitochondrial antioxidant enzyme, has be en shown to be essential for animal survival. MnSOD mutant mice (Sod2(-/-)m ice) on the CD1 background develop severe dilated cardiomyopathy and usuall y die within 10 d after birth. To characterize better the phenotype and und erstand the mechanism of superoxide-mediated tissue damage in Sod2(-/-)mice , congenic Sod2(-/-)mice on inbred backgrounds were generated to ensure gen etic homogeneity. When generated on a C57BL/6J background (136 < Sod2(-/-)> ), more than half of the fetuses develop severe dilated cardiomyopathy by e mbryonic day 15 and die in the uterus. Those that survive to term usually d ie within 24 h. In contrast, Sod2(-/-)mice on DBA/2J (D2 < Sod2(-/-)>) and B6D2F1 (B6D2F1 < Sod2(-/-)>) backgrounds develop normally throughout gestat ion and do not develop dilated cardiomyopathy. However, the D2 < Sod2(-/-)> mice do develop a severe metabolic acidosis and survive for only up to 12 d after birth. B6D2F1 < Sod2(-/-)> mice have a milder form of metabolic aci dosis and can survive for up to 3 weeks. The marked difference in lifespans and the development of dilated cardiomyopathy in the B6 but not the D2 or B6D2F1 backgrounds indicate the possible existence of genetic modifiers tha t provide protection to the developing hearts in the absence of MnSOD. (C) 2001 Elsevier Science Inc.