A deletion in a cis element of Foxe3 causes cataracts and microphthalmia in rct mice.

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.

Phylogenetic development of a regulatory gene for the core 2 GlcNAc transferase in Mus musculus.

In our previous study, we identified a mouse gene, Gsl5, that controls the expression of a glycolipid, GL-Y [Galbeta1-4(Fucalpha1-3)GlcNAcbeta1-6(Galbeta1-3)GalNAcbeta1-3Galalpha1-4Galbeta1-4Glcbeta1-Cer], and the core 2 structure of O-linked glycans of glycoproteins, GlcNAcbeta1-6(Galbeta1-3)GalNAcalpha-Ser/Thr, in a kidney tubular cell-specific manner through the regulation of UDP-GlcNAc beta-1,6-GlcNAc transferase (GNT). Regulation by the Gsl5 gene occurs at the level of GNT mRNA and the recessive allele of Gsl5 is rare and carried by DBA/2 and its related strains. Here, we report a sequence comparison of the 5' flanking region of the GNT gene among 5 laboratory strains and 10 wild-derived strains, demonstrating that the DBA/2 allele sequence is similar to the sequence carried by Asian Mus m. musculus and differs substantially from the East European M. m. musculus. These results suggest that the DBA/2 allele of Gsl5 was introduced into laboratory mouse strains by Asian wild-derived mice. Phylogenetic comparison of the 5' flanking region sequences between the recessive and dominant Gsl5 alleles indicates that mutations to create a functional Gsl5 gene occurred approximately one million years ago during the subspeciation of M. musculus, and provides a case for studies on the creation of functional genes involved in tissue-specific transcriptional regulation.