Interacting loci cause severe iris atrophy and glaucoma in DBA/2J mice

Abstract

Glaucomas are a major cause of blindness. Visual loss typically involves retinal ganglion cell death and optic nerve atrophy subsequent to a pathologic elevation of intraocular pressure (IOP). Some human glaucomas are associated with anterior segment abnormalities such as pigment dispersion syndrome (PDS) and iris atrophy with associated synechiae. The primary causes of these abnormalities are unknown, and their aetiology is poorly understood. We recently characterized a mouse strain (DBA/2J) that develops glaucoma subsequent to anterior segment changes including pigment dispersion and iris atrophy. Using crosses between mouse strains DBA/2J (D2) and C57BL/6J (B6), we now show there are two chromosomal regions that contribute to the anterior segment changes and glaucoma. Progeny homozygous for the D2 allele of one locus on chromosome 6 (called ipd) develop an iris pigment dispersion phenotype similar to human PDS. ipd resides on a region of mouse chromosome 6 with conserved synteny to a region of human chromosome 7q that is associated with human PDS. Progeny homozygous for the D2 allele of a different locus on chromosome 4 (called isa) develop an iris stromal atrophy phenotype (ISA). The Tyrpl gene is a candidate for isa and likely causes ISA via a mechanism involving pigment production. Progeny homozygous for the D2 alleles of both ipd and isa develop an earlier onset and more severe disease involving pigment dispersion and iris stromal atrophy.

Calcineurin cleavage is triggered by elevated intraocular pressure, and calcineurin inhibition blocks retinal ganglion cell death in experimental glaucoma

“…Another mouse had both eyes with IOP Ͼ17. This IOP distribution is similar to what has been reported in the literature (25). These four mice (eight eyes) were harvested for analysis for CaN cleavage.…”

“…The rat model of glaucoma is well established as a chronic model with characteristic sustained elevation of IOP, ON atrophy, and apoptotic RGC death with apoptosis starting Ϸ1 week after elevation of IOP (22,37,38). The spontaneous model of glaucoma in the DBA͞2J mouse has also been demonstrated to have chronic elevation of IOP, ON atrophy, and RGC loss that occurs over several months (25,39). Although these two models share elevated IOP as the proximate cause of RGC death, the way in which the IOP is raised is distinct in each model.…”

“…Although these two models share elevated IOP as the proximate cause of RGC death, the way in which the IOP is raised is distinct in each model. The induction of elevated IOP in the rat usually occurs within 2-4 weeks of surgery, and in the mouse the IOP becomes spontaneously elevated between 6 and 9 months of age (25,39). These two models differ in their tempo of RGC death, with death occurring at a slower rate in the DBA͞2J mouse than in the rat.…”

“…Measuring IOP in DBA͞2J mice was performed by direct cannulation as described (25). After anesthesia with a mixture of 90 mg͞kg ketamine and 9 mg͞kg xylazine, a glass micropipette tip with an external diameter of 50 m and a length of 2 mm was introduced into the anterior chamber, taking care to avoid the lens, and connected to plastic tubing.…”

Involvement of Inflammation, Degradation, and Apoptosis in a Mouse Model of Glaucoma

“…The DBA/2J mouse has been described as an animal model of human pigmentary glaucoma (3,4). This mouse strain presents several hallmarks of the human pigmentary glaucoma including iris atrophy, pigment dispersion, peripheral anterior synechiae that are associated with development of elevated IOP, retinal ganglion cell loss, and optic nerve head excavation and is not representative of other forms of glaucoma (4 -6).…”