The Foxe3(rct) mutation, which causes early-onset cataracts, is a recessive mutation found in SJL/J mice. A previous study reported that cataract phenotypes are modified by the genetic background of mouse inbred strains and that the Pde6b(rd1) mutation, which induced degeneration of the photoreceptor cells, is a strong candidate genetic modifier to accelerate the severity of cataractogenesis of Foxe3(rct) mice. We created congenic mice by transferring a genomic region including the Foxe3(rct) mutation to the B6 genetic background, which does not carry the Pde6b(rd1) mutation. In the congenic mice, the cataract phenotypes became remarkably mild, and the development of cataracts was suppressed for a long time. Moreover, we created transgenic mice by injecting BAC clones including the wild-type Pde6b gene into the eggs of SJL-Foxe3(rct) mice. Although the resistant effect for cataract phenotypes in transgenic mice was less than that in congenic mice, the severity and onset time of cataract phenotypes were clearly improved and delayed, respectively, compared with the phenotypes of the original SJL-Foxe3(rct) mice. These results clearly show that the development of early-onset cataracts requires at least two mutant alleles of Foxe3(rct) and Pde6b(rd1), and another modifier associated with the severity of cataract phenotypes in Foxe3(rct) mice underlies the genetic backgrounds in mice. (C) 2018 Elsevier Inc. All rights reserved.