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A spontaneous mutation in Srebf2 leads to cataracts and persistent skin wounds in the lens opacity 13 (lop13) mouse

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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.

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Acknowledgments

This work was supported in part by National Institutes of Health grants EY15173 (DJS), P30EY001931 (DJS), and EY19943 (BC). The lipid analyses described in this work were performed at the Kansas Lipidomics Research Center Analytical Laboratory. Kansas Lipidomics Research Center was supported by National Science Foundation (EPS 0236913, MCB 0455318, DBI 0521587), Kansas Technology Enterprise Corporation, K-IDeA Networks of Biomedical Research Excellence (INBRE) of the National Institutes of Health (P20RR16475), and Kansas State University. We thank Drs. Sahoo and Drover from the Medical College of Wisconsin for their assistance with assays for measuring serum cholesterol levels.

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Authors and Affiliations

  1. Department of Cell Biology, Neurobiology, and Anatomy, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Kate M. Merath & Duska J. Sidjanin

  2. The Jackson Laboratory, Bar Harbor, ME, 04609, USA

    Bo Chang

  3. School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, 53706, USA

    Richard Dubielzig

  4. Kansas Lipidomics Research Center, Kansas State University, Manhattan, KS, 66506, USA

    Richard Jeannotte

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  1. Kate M. Merath
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Correspondence to Duska J. Sidjanin.

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Merath, K.M., Chang, B., Dubielzig, R. et al. A spontaneous mutation in Srebf2 leads to cataracts and persistent skin wounds in the lens opacity 13 (lop13) mouse. Mamm Genome 22, 661–673 (2011). https://doi.org/10.1007/s00335-011-9354-2

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