Abstract
Purpose: :
Pigmentary glaucoma is a significant cause of human blindness. Abnormally liberated iris pigment and cell debris enter the ocular drainage structures, leading to increased intraocular pressure (IOP) and glaucoma. Here, we characterize pigment dispersion and iris atrophy in the mouse strain YBR/Ei (YBR). Further, we determine that these mice develop elevated intraocular pressure (IOP) and glaucoma and perform initial genetic analyses.
Methods: :
Slit-lamp biomicroscopy and histology were used to examine the eyes of YBR mice ranging from 3 to 16 months of age. IOP was measured at various ages within this range. Retinal ganglion cell death and optic nerve degeneration was assessed using histological examination. Genetic crosses were established to identify loci controlling distinct phenotypes that dictate glaucoma.
Results: :
YBR mice develop pigment dispersion, iris transillumination, iris atrophy and anterior synechiae. Subsequently, these mice exhibit elevated IOP starting at 9 months of age. These changes were followed by the death of retinal ganglion cells, optic nerve atrophy, and optic nerve cupping. Genetic experiments demonstrate segregation of the iris disease and elevated IOP phenotypes in progeny derived by interbreeding the YBR strain with control C57BL/6J mice. Preliminary data suggest that a recessive locus on Chromosome (Chr) 4 (68-90 Mb) is responsible for the iris disease. By itself this locus is typically insufficient to induce high IOP. A different locus on Chr17 (73-85 Mb) contributes to the high IOP phenotype, even in mice that do not have the iris disease. Progeny homozygous for both of the YBR alleles on Chrs 4 and 17 develop an earlier onset glaucoma with higher penetrance than that in mice with the Chr 17 loci alone.
Conclusions: :
The YBR strain represents a new model to identify genes controlling IOP elevation and to evaluate mechanisms of pressure-related ganglion cell death and optic nerve atrophy. Although further experiments are needed to determine the causative gene, the YBR strain has the Tyrpb mutation on Chr 4 that is known to contribute to iris disease and IOP elevation in the widely used glaucoma strain DBA/2J. In addition, a genetic locus on Chr 17 causes high IOP independent of iris disease. Identifying the Chr17 mutation is a priority with potential to further our understanding of mechanisms of IOP elevation in glaucoma.
Keywords: intraocular pressure • iris • gene mapping