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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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Major intrinsic protein of lens fiber (MIP) is one of the proteins essential for maintaining lens transparency while also contributing to dominant cataracts in humans. The Nodai cataract (Nat) mice harbor a spontaneous mutation in Mip and develop early-onset nuclear cataracts. The Nat mutation is a c.631G>A mutation (Mip Nat ), resulting in a glycine-to-arginine substitution (p.Gly211Arg) in the sixth transmembrane domain. The Mip Nat/Nat homozygotes exhibit congenital cataracts caused by the degeneration of lens fiber cells. MIP normally localizes to the lens fiber cell membranes. However, the Mip Nat/Nat mice were found to lack an organelle-free zone, and the MIP was mislocalized to the nuclear membrane and perinuclear region. Furthermore, the Mip Nat/+ mice exhibited milder cataracts than Mip Nat/Nat mice due to the slight degeneration of the lens fiber cells. Although there were no differences in the localization of MIP to the membranes of lens fiber cells in Mip Nat/+ mice compared to that in wild-type mice, the protein levels of MIP were significantly reduced in the eyes. These findings suggest that cataractogenesis in Mip Nat mutants are caused by defects in MIP expression. Overall, the Mip Nat mice offer a novel model to better understand the phenotypes and mechanisms for the development of cataracts in patients that carry missense mutations in MIP.

The Rinshoken cataract (rct) mutation, which causes congenital cataracts, is a recessive mutation found in SJL/J mice. All mutants present with opacity in the lens by 2 months of age. The rct locus was mapped to a 1.6-Mb region in Chr 4 that contains the Foxe3 gene. This gene is responsible for cataracts in humans and mice, and it plays a crucial role in the development of the lens. Furthermore, mutation of Foxe3 causes various ocular defects. We sequenced the genomic region of Foxe3, including the coding exons and UTRs; however, no mutations were discovered in these regions. Because there were no differences in Foxe3 sequences between the rct/rct and wild-type mice, we inferred that a mutation was located in the regulatory regions of the Foxe3 gene. To test this possibility, we sequenced a 5' noncoding region that is highly conserved among vertebrates and is predicted to be the major enhancer of Foxe3. This analysis revealed a deletion of 22-bp located approximately 3.2-kb upstream of the start codon of Foxe3 in rct mice. Moreover, we demonstrated by RT-PCR and in situ hybridization that the rct mutant has reduced expression of Foxe3 in the lens during development. We therefore suggest that cataracts in rct mice are caused by reduced Foxe3 expression in the lens and that this decreased expression is a result of a deletion in a cis-acting regulatory element.