Toward a Genetic Understanding of Glaucoma—Breakthroughs and Challenges
mice allow the opportunity to identify genetic and environmental factors with even modest phenotypic contributions. Once defined in mice, research gains can then be brought back into focused human studies where there is direct relevance to patient care. However, to apply these advantages to the study of exfoliation syndrome a challenge arises: few, if any, mouse models of exfoliation syndrome have previously been described. However, recent reports indicate that many exciting opportunities are now available.
Multiple advances are being made with animal models relevant to pathways of exfoliation syndrome. Mice with a genetic defect in the lysosomal trafficking regulator (Lyst) gene recapitulate multiple aspects of human exfoliation syndrome.21,22
Our consideration of Lyst as a
candidate impacting exfoliation began from the observation that Lyst mutation results in an unusual pattern of iris transillumination defects. The iris transillumination defects occurring in Lyst mutant mice are a known, but often overlooked, aspect of exfoliation syndrome.23
Building
on this initial finding, we have also observed the presence of an exfoliative-like material and pronounced iris pigment dispersion in eyes of Lyst mutant mice. The Lyst gene has not previously been considered a candidate for exfoliation syndrome, and the LYST protein is not known to be a member of a LOXL1 pathway. Thus, this phenotype-driven approach in mice has led us to a novel hypothesis that would otherwise not have been considered: the Lyst gene is a potential contributor to exfoliation syndrome in humans. Experiments to test this hypothesis directly are under way.
Another significant opportunity using mouse genetics pertains to mouse models of Loxl1. Interestingly, mice containing a targeted knockout of
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2. Wolfs RC, Klaver CC, Ramrattan RS, et al., Genetic risk of primary open-angle glaucoma. Population-based familial aggregation study, Arch Ophthalmol, 1998;116:1640–5.
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Loxl1 have existed for several years,24 but, curiously, there has been no
mention of exfoliation syndrome-like phenotypes. This may indicate that Loxl1 knockout mice have a different phenotype from what is caused by the non-synonymous mutations found in humans. Simply stated, mutations resulting in proteins with defective function often behave differently from mutations that result in no protein at all. Alternatively, Loxl1-dependent phenotypes may be subtle and will require detailed examination to detect. In considering the findings with Lyst mutant mice, it will be particularly interesting to determine whether Loxl1 mutant mice also exhibit iris transillumination defects. It will also be important to determine whether Loxl1-dependent phenotypes in mice are genetic background dependent, perhaps differing when the same mutant allele is studied in different inbred strains of mice. Such a finding could serve as an important first step toward identification of additional genetic factors interacting with LOXL1.
Conclusion
The genetic pathways involved in susceptibility to many common diseases are intricate and often difficult to dissect. Glaucoma is no exception. The recent discovery of the LOXL1 gene as a genetic risk factor for exfoliation syndrome has suggested that some glaucoma genes with very large influence remain to be identified. Given the power of recent technologic advances, the overall future appears bright for glaucoma genetics. However, the example of LOXL1 also emphasizes what most geneticists have long suspected: glaucoma is a multifactorial disease. Thus, in moving forward, it will be important to use experimental approaches that reduce complexity, including the synergistic use of genetic approaches in mice to identify additional genes of importance. n
9. Wiggs JL, Allingham RR, Vollrath D, et al., Prevalence of mutations in TIGR/Myocilin in patients with adult and juvenile primary open-angle glaucoma, Am J Hum Genet, 1998;63:1549–52.
10. Gould DB, Reedy M, Wilson LA, et al., Mutant myocilin nonsecretion in vivo is not sufficient to cause glaucoma, Mol Cell Biol, 2006;26:8427–36.
11. Paper W, Kroeber M, Heersink S, et al., Elevated amounts of myocilin in the aqueous humor of transgenic mice cause significant changes in ocular gene expression, Exp Eye Res, 2008;87:257–67.
12. Shepard AR, Jacobson N, Millar JC, et al., Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure, Hum Mol Genet, 2007;16:609–17.
13. Zhou Y, Grinchuk O, Tomarev SI, Transgenic mice expressing the Tyr437His mutant of human myocilin protein develop glaucoma, Invest Ophthalmol Vis Sci, 2008;49:1932–9.
14. Wiggs JL, Genetic etiologies of glaucoma, Arch Ophthalmol, 2007;125:30–7.
15. Gottfredsdottir MS, Sverrisson T, Musch DC, Stefansson E, Chronic open-angle glaucoma and associated ophthalmic findings in monozygotic twins and their spouses in Iceland, J Glaucoma, 1999;8:134–9.
16. Allingham RR, Loftsdottir M, Gottfredsdottir MS, et al., Pseudoexfoliation syndrome in Icelandic families, Br J Ophthalmol, 2001;85:702–7.
17. Thorleifsson G, Magnusson KP, Sulem P, et al., Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma, Science, 2007;317:1397–400.
18. Fingert JH, Alward WL, Kwon YH, et al., LOXL1 mutations are associated with exfoliation syndrome in patients from the Midwestern United States, Am J Ophthalmol, 2007;144:974–5.
19. Hayashi H, Gotoh N, Ueda Y, Nakanishi H, Yoshimura N, Lysyl oxidase-like 1 polymorphisms and exfoliation syndrome in the Japanese population, Am J Ophthalmol, 2008;145:582–5.
20. Libby RT, Gould DB, Anderson MG, John SW, Complex genetics of glaucoma susceptibility, Annu Rev Genomics Hum Genet, 2005;6:15–44.
21. Trantow CM, Mao M, Petersen GE, et al., Lyst mutation in mice recapitulates iris defects of human exfoliation syndrome, Invest Ophthalmol Vis Sci, 2009;50:1205–14.
22. Trantow CM, Hedberg-Buenz A, Iwashita S, et al., Elevated oxidative membrane damage associated with genetic modifiers of Lyst-mutant phenotypes, PLoS Genet, 2010;6:e1001008.
23. Foos RY, Iris in pseudoexfoliation, Ophthalmology, 1991;98:1486–7. 24. Liu X, Zhao Y, Gao J, et al., Elastic fiber homeostasis requires lysyl oxidase-like 1 protein, Nat Genet, 2004;36:178–82.
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