The C57BL/6J Mouse Strain Background Modifies the Effect of a Mutation in Bcl2l2

Bcl2l2 encodes BCL-W, an antiapoptotic member of the BCL-2 family of proteins. Intercross of Bcl2l2 +/- mice on a mixed C57BL/6J, 129S5 background produces Bcl2l2 -/- animals with the expected frequency. In contrast, intercross of Bcl2l2 +/- mice on a congenic C57BL/6J background produces relatively few live-born Bcl2l2 -/- animals. Genetic modifiers alter the effect of a mutation. C57BL/6J mice (Mus musculus) have a mutant allele of nicotinamide nucleotide transhydrogenase (Nnt) that can act as a modifier. Loss of NNT decreases the concentration of reduced nicotinamide adenine dinucleotide phosphate within the mitochondrial matrix. Nicotinamide adenine dinucleotide phosphate is a cofactor for glutathione reductase, which regenerates reduced glutathione, an important antioxidant. Thus, loss of NNT activity is associated with increased mitochondrial oxidative damage and cellular stress. To determine whether loss of Bcl2l2 -/- mice on the C57BL/6J background was mediated by the Nnt mutation, we outcrossed Bcl2l2 congenic C57BL/6J (Nnt -/-) mice with the closely related C57BL/6JEiJ (Nnt +/+) strain to produce Bcl2l2 +/-; Nnt +/+ and Bcl2l2 +/-; Nnt -/- animals. Intercross of Bcl2l2 +/-; Nnt +/+ mice produced Bcl2l2 -/- with the expected frequency, whereas intercross of Bcl2l2 +/-; Nnt -/- animals did not. This finding indicates the C57BL/6J strain background, and possibly the Nnt mutation, modifies the Bcl2l2 mutant phenotype. This and previous reports highlight the importance of knowing the genetic composition of mouse strains used in research studies as well as the accurate reporting of mouse strains in the scientific literature.