Purchase this article with an account.
H. Lu, H. Guan, L. Lu, R. W. Williams, M. M. Jablonski; Genetic Dissection of Iris Transillumination Defects and Pigmentary Dispersion Syndrome. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2148.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
To find the dominant factors and molecular biology mechanisms contributing to pigment dispersion syndrome in DBA/2J mice, a natural model of pigmentary dispersion syndrome (PDS) and pigmentary glaucoma (PG). We also constructed a genetic regulatory network for this phenotype.
Using a five level grading scale, we characterized the iris transillumination defect, a measure of iris atrophy and pigmentation loss, in 3564 mice. Because the integrity of the iris varies significantly during the life of a DBA/2J mouse, all mice were grouped according to age (1-2 months, 2-5 months, 6-9 months, 10-13 months and >13 months) and were comprised of 71 strains of BXD RI mice, two parental strains, and two F1 strains. We also measured gene expression levels in the eyes from these mice using an oligo microarray system. Subsequently we used quantitative trait locus (QTL) analysis for iris transillumination defects. Candidate genes were identified using filters such as the density of SNPs and the mean expression levels. Moreover, correlation analyses were made and a gene regulatory network was constructed.
Interval mapping identified a highly significant QTL on Chr 4 for all age groups. A second significant QTL was identified on Chr 5 in mice aged 1-2 months. All other age groups showed a suggestive QTL the same location. We also detected a significant QTL on Chr 6 in mice aged >13 months. The highest priority candidate genes for the loci on Chrs 4 and 6 are Tyrp1 and Gpnmb, respectively. The highest priority candidate genes on Chr 5 are Bri3bp, Aacs, Slc15a4, and Tmem132d. The genetic regulatory network for the iris tranillumination defect included Tyrp1 and Gpnmb along with other genes.
This study demonstrates that the genetical genomics approach provides a powerful tool for mapping genes that regulate iris transillumination defects. Our results demonstrated that Tyrp1 is the major gene responsible for the iris pathology in all ages of DBA/2J mice. In contrast, Gpnmb contributes to the disease in its most advanced stages. Both of these genes are known to be causative for PDS. Importantly, the third QTL that we discovered on Chr 5 demonstrates that one or more additional genes may also be involved in the pathologic processes of PDS.
This PDF is available to Subscribers Only