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K. S. Nair, Z. Ali, S. W. M. John; Multiple Genes Determine Frequency and Severity of IOP Elevation in a Mouse Glaucoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2152. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Pigment dispersion syndrome (PDS) is characterized by deposition of abnormally liberated iris pigment onto anterior chamber structures and into the aqueous outflow pathway. In many but not all cases, PDS progresses to high intraocular pressure (IOP) and causes pigmentary glaucoma. The molecular mechanisms by which PDS progresses to pigmentary glaucoma are not known. We have shown that mutations in the genes Gpnmb and Tyrp1 lead to Pigment dispersion (PD) and elevation in IOP in DBA/2J (D2) mice. In a C57BL/6J (B6) background (B6 double mutants) these same mutations also lead to PD but elevation in IOP does not occur. This suggests that additional D2-derived genetic factors conspire with Gpnmb and Tyrp1 mutations to induce high IOP. Here, we performed genetic linkage analysis to determine additional genes that contribute to IOP elevation.
Multiple crosses between the less susceptible B6 double-mutants and D2 mice were established to identify additional genetic loci that co-operate with Gpnmb and Tyrp1 mutations to induce IOP elevation. The F1, N2 (from backcross to either parent) progenies were aged and Slit-lamp biomicroscopy was used to examine their eyes, ranging from 6 to 12 months of age. IOP was measured at various ages within this range. A genome wide haplotype analysis was performed to localize quantitative-trait loci (QTLs) modulating IOP elevation.
The F1 progeny from our cross develop a more severe phenotype that is characterized by an early age of onset and higher magnitude of IOP elevation compared to D2 mice. This data suggest that in addition to Gpnmb and Tyrp1 mutations, other D2 and B6-derived susceptible genes participate in the pathogenesis of IOP elevation. A genome-wide QTL analysis has localized dominant D2 loci on Chr 1, Chr 4 and Chr 5 and a dominant B6 locus on Chr 9 that contributes to IOP elevation. The N2 Progenies that carries all the 4 susceptible loci recapitulates the severe phenotype exhibited by the F1 mice. Importantly, these susceptible loci interact in a synergistic manner and the nature of their interactions dictates the frequency and magnitude of IOP elevation.
This study has identified multiple genetic loci that interact to modulate the frequency and magnitude of IOP elevation and hence dictate the progression from pigment dispersion to pigmentary glaucoma. It has allowed insight into the genetic complexity that underlies IOP elevation. There are good candidate genes present in these genetic regions, which are currently being tested to determine their role in modulating elevation in IOP.
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