Disruption of circadian intraocular pressure fluctuations in mice by the Lyst beige-J mutation

Abstract

Intraocular pressure (IOP) follows a circadian rhythm. In both humans and mice, IOP is normally slightly elevated at night during the dark phase of the light cycle. In studying a strain of mice for possible indices of glaucoma, we incidentally discovered that C57BL/6J mice homozygous for the beige-J mutation of the Lyst gene lack a circadian fluctuation in IOP. Instead of having an elevated dark phase IOP, homozygotes exhibit a uniform IOP characteristic for light period values of C57BL/6J mice. The beige-J mutation results from deletion of a single isoleucine amino acid in the LYST WD40 motif likely to influence protein-protein interactions. Based on the literature, we hypothesized that CSNK2B (casein kinase 2, beta polypeptide) might be a relevant interacting protein, which we confirmed with a pulldown assay as a binding partner of wild-type, but not beige-J encoding, LYST protein. Treating wild-type mice with 4,5,6,7-tetrabromobenzotriazole (TBB), a casein kinase 2 inhibitor, recapitulated the beige-J mutant phenotype in preventing a rise in IOP during the dark period. Together, these results identify Lyst beige-J mice as a new strain for studying circadian IOP regulation and point to casein kinase 2 as a key molecule of interest.