title: A spontaneous mutation in Srebf2 leads to cataracts and persistent skin wounds in the lens opacity 13 (lop13) mouse.
abstract: Lens opacity 13 (lop13) is a spontaneous, autosomal recessive mouse mutant that exhibits nuclear cataracts. Histological analysis revealed swollen lens fiber cells and the presence of bladder cells within the lens cortex, as well as morgagnian globules and liquefied material at the lens posterior. At 3 months of age, in addition to cataracts, lop13 mice also develop persistent skin wounds. Linkage analysis assigned the lop13 locus to a 1.1-Mb region on mouse Chr 15, encompassing 19 candidate genes. Sequence analysis identified a C3112T mutation in exon 18 of Sterol Regulatory Element Binding-Transcription Factor 2 (Srebf2) resulting in the R1038C substitution of a highly conserved arginine within the Srebf2 regulatory domain. Srebf2 belongs to a family of membrane-bound basic helix-loop-helix leucine zipper transcription factors that control the expression of genes involved in the biosynthesis and uptake of cholesterol and fatty acids. The lack of complementation observed in Srebf2                         (                            lop13/GT                         ) compound heterozygotes carrying the Srebf2 gene trapped allele (Srebf2                         (                            GT                         )) provides genetic evidence that the identified C3112T substitution in Srebf2 is responsible for the lop13 phenotype. Gas chromatography analysis identified lower levels of cholesterol in the lop13 brain, liver, and lens when compared to wild-type mice. These findings suggest that lop13 is a hypomorphic mutation in Srebf2. As such, the lop13 mouse presents an invaluable in vivo model for studying the contribution of Srebf2 and cholesterol to maintaining the homeostasis of the lens and skin.
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, USA.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Merath
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Richard
authors.initials: R
authors.lastname: Dubielzig
authors.forename: Richard
authors.initials: R
authors.lastname: Jeannotte
authors.forename: Duska J
authors.initials: DJ
authors.lastname: Sidjanin
mesh_terms: D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002386:Cataract / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D005838:Genotype; D007908:Lens, Crystalline / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D017422:Sequence Analysis, DNA; D012867:Skin / Q000473:pathology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol