Genetics of IOP Elevation and Glaucoma

Glaucoma is a leading cause of blindness affecting an estimated 70 million people. Elevated intraocular pressure (IOP) is a major risk factor for human glaucoma and can induce glaucoma in animals. Most forms of glaucoma have a genetic component. Characterizing glaucoma genes can provide new insights about the causes of glaucoma, and provides opportunities for developing new interventions, preventative measures and diagnostic tests. Despite the identification of several genes that cause glaucoma, the genes and molecular processes responsible for glaucoma in most glaucoma patients are not known. Current evidence suggests that many different genes can cause glaucoma, and that in many patients multiple genes are important. Therefore, the identification and characterization of new glaucoma genes is a top priority of our research. In addition to studying human glaucoma, we use mouse models. Mice have essentially the same genes as people and develop similar diseases. They are proving to be very valuable in understanding glaucoma. We have pioneered the use of mice to study glaucoma by developing mouse models of glaucoma and the tools to study them. An important strategy to understand the molecular basis of elevated IOP and glaucoma is discovering and testing genes for inherited forms of these conditions in mice.

On this page:

Candidate gene approaches

Key Resources for glaucoma gene characterization

Unbiased genetic approach

RNA granules, oxidative stress and glaucoma

Angle-closure glaucoma

Complex genetics of IOP elevation

Genetics of developmental glaucoma

Candidate Gene Approaches

We are expert in using a variety of approaches to study the genetics of glaucoma. This section discusses these methods. One approach for linking specific genes to glaucoma is to test the effects of altering these genes on IOP and glaucoma in mice. The tested genes are known as functional candidate genes as they are selected because available information about their functions makes it plausible that they may affect IOP. The tests are necessary to determine if these genes actually affect the phenotypes, as many will not. Although this gene-driven approach is very valuable, it is limited by current knowledge and hypotheses.

Another version of the candidate gene approach tests genes that are known to associate with glaucoma. For example, the effects of altering genes that reside in chromosomal intervals associated with IOP and glaucoma phenotypes in human families can be tested. These genes are called positional candidate genes, and we actively collaborate with human geneticists and ophthalmologists (nationally and internationally) to identify and assess such genes. Candidate genes are also identified as genes with specific variant forms (alleles) that are more common in glaucoma patients than in control individuals. These candidate genes are identified by both genome wide association studies (GWAS) and recently developed genome-wide DNA sequencing methods (important genomic approaches). Genome-wide assessment of the amount of RNA made by each gene (gene expression) is another important tool and can help to both identify and prioritize candidate genes for further evaluation.

Key Resources for Glaucoma Gene Characterization

Modern genomic technologies--especially genome sequencing--are rapidly maturing to the point of identifying many candidate genes that associate with human disease. Thus, subsequent testing to determine if specific candidate genes actually impact glaucoma phenotypes will become increasingly important. Many of these candidate genes will have subtle DNA differences between patients and controls. Therefore, it often will be difficult to distinguish glaucoma causing candidate genes from other candidate genes that are associated with glaucoma but which have no impact on the disease. The testing of candidate genes with subtle DNA changes, known as point mutations, will become a major roadblock in advancing the understanding of glaucoma. In answer to this roadblock, we have devised an important strategy for developing mouse resources that will greatly facilitate both the prioritization and testing of candidate genes with point mutations, and the generation of new animal models with alterations in these genes. Once developed, the resources will allow testing of many more genes than is currently possible and in an efficient and relatively cost effective way. In addition to IOP and glaucoma, these resources will facilitate studies of many biological processes and diseases.

Unbiased Genetic Approach

An alternative approach for discovering new glaucoma genes starts with phenotypes not genes. This phenotype-driven approach detects genes with mutations that have a strong and clear affect on glaucoma phenotypes. An important aspect of this approach is that effort is directed specifically at discovering genes that have significant affects on IOP and glaucoma, regardless of the identity of the underlying genes or biases of current knowledge. In one variation of this approach, screening a population of mice with different mutations in many genes identifies mice with the desired IOP and glaucoma phenotypes. Identifying these mice allows the subsequent characterization of the underlying glaucoma genes. Additionally, it provides new glaucoma models that will become a valuable community resource. This approach is an important complement to human studies for understanding disease etiology, and it greatly enhances the use of comparative genomics to identify human glaucoma genes. We are heavily vested in this approach and have successfully identified several glaucoma-relevant genes. Mutations in both the mouse and human equivalents of most of these genes cause glaucoma-relevant phenotypes in mice and people respectively. We are currently focused on identifying and characterizing several new mutants that appear to affect different molecular pathways.

RNA Granules, Oxidative Stress, and Glaucoma

Recently, we determined that mutations in a gene, which makes a molecule present in intracellular structures known as RNA granules, cause pediatric cataracts, high IOP and glaucoma. Mutations in this gene impede the formation of structures known as stress granules, which appear to protect from oxidative stress. Oxidative stress is believed to contribute to IOP elevation with increasing age in human patients. Although we plan more experiments to test these ideas, our findings suggest that the mutated gene causes increased susceptibility to oxidative stress and IOP elevation with age, and that it alters susceptibility to glaucoma following pediatric cataract extraction.

Angle-closure Glaucoma

Angle closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people. ACG also is known as both primary angle-closure glaucoma and closed-angle glaucoma. It is estimated to blind more people worldwide than other common forms of glaucoma. The genetic and molecular mechanisms of IOP elevation in ACG are not understood, but the eyes of individuals with ACG often have a reduced size. We identified a mouse mutant with a phenotype that strongly resembles ACG including a similar mild reduction of ocular size. The phenotype of the mutant mice differs between different mouse strains that have a different genetic makeup, with a severe alteration of ocular dimensions in some strains. We have identified the gene responsible for this condition, and are investigating its normal functions and role in disease. A collaborative study has already determined that mutations in the same gene affect patients in families with substantially altered ocular size and glaucoma. We are also collaborating with human geneticists and ophthalmologists to identify and characterize other ACG genes and to characterize ACG-relevant mutant mice.

Complex Genetics of IOP Elevation

In most cases, glaucoma is a multifactorial disease. This means that multiple genes and possibly environmental factors are important in determining the age of onset and severity of disease. Some individuals who have forms of genes that predispose to glaucoma do not develop glaucoma, as other genes protect them from developing glaucoma. Genes that alter the phenotypic effects of other genes are known as modifier genes. We have great experience using mice to understand complex genetic interactions and to identify the genes that underlie them. A major project is studying the complex genetics of intraocular pressure elevation following pigment dispersion (see below). Future studies will determine if the genes we are identifying contribute to IOP elevation in other forms of glaucoma, including glaucoma due to uveitis and exfoliation syndrome. Another project aims to identify mutant genes that interact with the Cyp1b1 gene to cause high IOP and glaucoma. The human equivalent of Cyp1b1 causes primary congenital glaucoma, a particularly severe glaucoma that affects infants.

Pigment dispersion occurs when iris cells are damaged, resulting in dispersal of iris pigment into the ocular drainage structure. In some people the pigment dispersion induces high IOP and pigmentary glaucoma, while in others it does not. Understanding the genetic differences that confer susceptibility or resistance to IOP elevation and glaucoma following pigment dispersion will suggest new interventions to prevent or alleviate pigmentary glaucoma. DBA/2J mice develop a form of pigmentary glaucoma. We have shown that their disease starts as an iris disease that results in severe pigment dispersion. Previously, we have determined important mechanisms that underlie the iris pigment dispersion. We are now focusing studies on the subsequent elevation of IOP. We have developed important resources and genetic strategies for studying this genetically complex process. Currently, our efforts have led to the identification of 7 genetic loci that contribute to the pigment dispersion and IOP elevation. These loci interact with one another and modulate both the presence and severity of IOP elevation. Of these 7 loci, we have already identified three causal mutations.

Genetics of Developmental Glaucoma

In developmental glaucomas, abnormal formation of the eye results in glaucoma, which can manifest at different ages. Ocular drainage structures are located in a region of the eye called the angle, and angle abnormalities contribute to IOP elevation. We have studied a number of genes and processes that contribute to developmental glaucomas. Briefly, we have characterized genes that results in dysgenesis of structures in the anterior segment of the eye, including the forkhead transcription factor (Foxc2), bone morphogenetic protein (Bmp4), and collagen type IV alpha 1 (Col4a1). We have also studied mice with mutations in the genes for cytochrome P450 1b1 (Cyp1b1) and forkhead box transcription factor C1 (Foxc1). Most of these genes cause anterior segment dysgenesis and developmental glaucoma in people.

Because of extensive variability in the human disease, we used mice to identify a modifier gene that alters ocular abnormalities due to mutations in Cyp1b1 and Foxc1. Genetic deficiency of tyrosinase exacerbates defects in both Cyp1b1 and Foxc1 mutant mice. We have shown that Tyrosinase provides L-DOPA that protects against angle malformation. Importantly, administering L-DOPA in the drinking water of female mice has a profound protective effect and substantially alleviates the ocular abnormalities.

In the future, we plan to further study the role of L-DOPA in ocular development and glaucoma, and evaluate if and how dietary DOPA modulates the severity of human glaucoma. We are interested in determining if bean consumption alleviates glaucoma, as some beans are rich in L-DOPA. We are currently working to identify further genes that modify the phenotype in Cyp1b1 mutant mice. We are also working with collaborators to characterize mice with a mutation in the Lmx1b gene, and we are mapping modifier genes that influence the phenotype. The human gene causes open-angle glaucoma in patients with Nail-patella syndrome.

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