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M. M. Jablonski, H. Lu, M. Pullen, X. Wang, L. Lu, R. W. Williams; Genetic Dissection of the Gpnmb Network in the Eye. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2153.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate variations in the gene expression of Gpnmb, a gene that contributes to pigmentary dispersion syndrome (PDS) and pigmentary glaucoma (PG) in the DBA/2J mouse. We also determined genes acting downstream of Gpnmb and constructed a genetic regulatory network for this gene.
An oligo microarray system was used to measure the gene expression levels in the eye and determine the expression differences across 68 strains BXD recombinant inbred (RI) mice, their two parental strains (C57BL/6J and DBA/2J), and two F1 strains (B6D2F1 and D2B6F1). We then combined these results with quantitative trait locus (QTL) mapping approaches (genetical genomics) and gene-set cohesion analysis to characterize the variation in expression and determine the regulatory network of Gpnmb in the eye.
Interval mapping detected an expression quantitative trait locus (eQTL) with a significant linkage score (LRS) of 33.13 on Chr 6 within 3 Mb of the location of the gene itself, demonstrating that Gpnmb is acting as a cis-QTL. We found multiple SNPs in both the 3’-UTR and intronic regions of the gene that provide some insights into the mechanism by which the gene may regulate its own expression. By controlling variation at this locus through composite interval mapping, a suggestive trans-QTL with LRS of 15.1 was found on distal Chr 7, flanked proximally by the marker rs13478757. Two genes within this interval (i.e., Ccdc101, and Ctbp2) showed statistically significant genetic and tissue correlation with Gpnmb (p<0.05) and are thus the highest priority candidate genes within this QTL region. Sixty-seven genes were identified as functioning downstream of Gpnmb. Included in this list are genes that relate to immunity and inflammation. Some of these gene products likely contribute to the PDS phenotype of D2 mice. The genetic regulatory network for Gpnmb included genes that are associated with dysfunction of pigment in the eye, are related to the development of glaucoma, and associated with T cell immune responses and inflammation.
These results demonstrate that the genetical genomics approach provides a powerful tool for constructing pathways that contribute to complex traits, such as PDS and PG. Genetic network analysis suggests that the dysfunction of the immune system may play an important role in PDS and PG.
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