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Bo Chang, Jieping Wang, Bernard FitzMaurice, Patsy Nishina; A new mouse model of early-onset glaucoma.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2125.
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© ARVO (1962-2015); The Authors (2016-present)
To report the clinical characterization, genetic analysis and molecular basis of a new mutation named early-onset glaucoma 1 (egl1) in a mouse model with a significantly elevated intraocular pressure (IOP) and large eye size in early adulthood.
While screening mouse strains and stocks at The Jackson Laboratory for models of human ocular disorders, we identified a new mouse model of early-onset glaucoma. We characterized the clinical effects of the mutation using rebound tonometry to measure IOP, image-guided optical coherence tomography (OCT) to detect optic cupping, histological studies to observe retinal ganglion cell loss and electroretinography (ERG) to test for retinal function. Genetic analysis including linkage studies and comparison of whole exome sequences of mutant and wild-type (WT) controls identified the causative gene and mutation.
The egl1 mutation was discovered in mice with swollen eyes as a recessive mutation. IOP measurements using a rebound tonometer showed that at 5 weeks of age IOP levels were significantly higher in mutants than controls, a trend that continued as the mutants were aged. Examination of eyes of 3-month-old mice with OCT showed enlargement of the anterior chamber and optic cupping compared to controls. The optic cupping phenotype was observable at three months of age by indirect ophthalmoscopy as a ring-like feature around the optic nerve head and by histology as the optic head cupping, anterior synechia and a complete loss of inner retinal layers. ERG tests showed a normal rod a-wave, but a loss of rod b-waves and a lower cone ERG response at 3-months of age. Genetic analysis shows that this disorder is caused by an autosomal recessive mutation that maps to mouse Chromosome 3 between D3Mit106 and D3Mit216. By high throughput sequencing of a whole exome capture library of a egl1/egl1 mutant and subsequent sequence analysis, a missense mutation due to a single base pair substitution in exon 2 in the Pitx2 gene was detected. Specifically, in the egl1/egl1 mice, a single-base substitution at position 344 (G to T) in exon 2 was found that changes codon 115 from CGC to CTC (Arg115Leu).
Homozgyous egl1 mutants are a new glaucoma model, which exhibits early-onset, rapidly progressive, and fully penetrant phenotypic characteristics of glaucoma that has not been previously described in mice. The egl1 mutant will serve as an important model to test therapeutic methods for human glaucoma.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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