Glaucoma is the leading cause of irreversible blindness worldwide. Pigmentary glaucoma is caused by a release of iris pigment known as pigment dispersion syndrome. Pigment dispersion syndrome is a common disorder that affects about 1 in 40 (2.5%) Americans. As many as 10 to 20% of those with pigment dispersion syndrome develop high intraocular pressure (ocular hypertension) and a secondary glaucoma - pigmentary glaucoma. Young to middle-aged people are affected by pigmentary glaucoma and consequently the visual disability it causes may lead to decades more loss of function and productivity than late-onset forms of glaucoma. Thus, research to determine the cause of pigmentary glaucoma is an important public concern. Strong evidence indicates that pigmentary glaucoma has a genetic basis. DBA/2J mice are an inbred strain of mice that develop pigmentary glaucoma that is a clearly inherited trait. Large human pedigrees have also been reported, in which pigmentary glaucoma is dominantly inherited. Cases of pigmentary glaucoma are also frequently clustered within families and ethnic groups. These data provide strong evidence for the existence of genes that cause or predispose pigmentary glaucoma. However, no genes that cause pigmentary glaucoma have been identified to date. The largely unknown genetic basis of pigmentary glaucoma has been an obstacle to discovery of the mechanisms that cause this disease and has also hindered development of new more effective therapies for this potentially blinding disease. As a result, there is critical need to identify and study the genes that cause pigmentary glaucoma. Aberrant release of iris pigment is a defining feature of pigmentary glaucoma. Moreover, mutations in genes involved in melanin synthesis and melanosomes (Gpnmb and Typr1) are known to cause pigmentary glaucoma in DBA/2J mice. Based on these observations, we hypothesize that some cases of pigmentary glaucoma are caused by mutations in genes involved in melanin synthesis. We will evaluate our hypothesis by studying whole exome data collected from 5 pigmentary glaucoma pedigrees and a cohort of pigmentary glaucoma patients (n=214) and matched controls (n=354) with the aims described below:
AIM 1 PEDIGREE-BASED exome analysis of several large pigmentary glaucoma pedigrees.
AIM 2 POPULATION-BASED exome analysis of a cohort of pigmentary glaucoma patients (n=214) and matched controls (n=254) We will validate our human studies with analyses of pigmentary glaucoma in mice using 1) publicly available strains of mice from The Jackson Laboratory and 2) our inducible pigmentary glaucoma mouse model. Identifying the first human pigmentary glaucoma genes will provide new insights into the pathogenesis of this important disease and may advance development of sight-saving therapies.
Pigmentary glaucoma is a common eye disease in which release of iris pigment causes high pressure in the eye and ultimately leads to optic nerve damage, glaucoma, and vision loss. We have proposed a series of experiments with our unique clinical and DNA resources from large cohorts of unrelated pigmentary glaucoma patients and our large pigmentary glaucoma pedigrees to identify the first genes that cause pigmentary glaucoma. Such discoveries will help facilitate early diagnoses, improve the accuracy of prognoses, and provide key insights into the basic biology of pigmentary glaucoma necessary to develop new sight-saving therapies.