Validating a New Angle-Closure Glaucoma Gene

Julia Richards, PhD
University of Michigan (Ann Arbor, MI)

Co-Principal Investigators

Lev Prasov, MD, PhD
University of Michigan (Ann Arbor, MI)
Year Awarded:
Grant Duration:
July 1, 2015 to June 30, 2018
Award Amount:
Grant Reference ID:
Award Type:
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US Northeastern

Recipient of The Dr. Douglas H. Johnson Award

Julia Richards, PhD

Genetics of Homocysteine Metabolism in Glaucoma


Cysts in the iris can block the ability of fluid to flow out of the eye, leading to build up of pressure in the eye and glaucoma (damage to the optic nerve).  We will study a new angle closure glaucoma gene, MTRR, which we found by studying a large family with iris cysts. We will study the biochemical and functional changes to this protein that have been caused by the mutation. We also plan to study the role of the normal protein in the eye.  We will then screen for mutations in this gene in a different, common form of glaucoma which has been associated with this same biochemical pathway. These investigations will begin detailing the role of homocysteine metabolism in glaucoma and may lead to the development of future therapies. The discovery of this new angle closure glaucoma gene has raised the possibility that we might be able to develop dietary interventions to prevent or limit the severity of types of glaucoma that involve homocysteine metabolism.


Glaucoma is a leading cause of irreversible blindness worldwide. Among several forms of glaucoma involving elevation in intraocular pressure (IOP), angle-closure glaucoma involves obstruction of fluid access to the outflow facility. Recently, elevated levels of homocysteine and disruptions in in a pathway called one-carbon metabolism have been associated with pathogenesis of multiple subtypes of glaucoma, but it remains unclear how this metabolic abnormality is involved in each distinct kind of glaucoma. Also recently, through a combination of gene mapping and sequencing, we identified a mutation in a one-carbon metabolism gene called MTRR in a hereditary form of angle-closure glaucoma that results from multiple iridociliary cysts (MICC). In this condition, protein-rich fluids accumulate within the iris, forming cysts and blockage the ability of aqueous fluid to drain out of the front part of the eye. This leads to elevated IOP that can lead to glaucoma.  The underlying developmental mechanism of this disorder is unknown; however, we have identified a probable mechanism.

Our proposal seeks to validate the hypothesis that rare deleterious mutations in MTRR cause the formation of MICC, and to more broadly implicate MTRR in the pathogenesis of other glaucomas associated with similar defects in one-carbon metabolism. Aim 1 will carry out further genetic and clinic studies of  our large MICC family; screen cohorts of unrelated patients with iridociliary cysts; and evaluate the mechanisms by which MTRR plays a role in the family of homocysteine-metabolism glaucomas. Aim 2 will evaluate the ocular characteristics of a known mouse Mtrr mutant. Aim 3 will look for MTRR mutations in human populations with different types of glaucoma. Taken together, these studies will establish the role of MTRR in the pathogenesis of iridociliary cysts, and enhance our understanding of the developmental and genetic pathways that lead to the resulting angle-closure glaucoma.  Intriguingly, our studies may also provide a target for the development of nutritional therapies for a subset of glaucoma patients.

About the Researcher

I grew up in Seattle and earned a Bachelor of Science degree in microbiology at the University of Washington in 1971. After working as a technician at Cal Tech and then in Genetics at the University of Washington, I went to graduate school in genetics at the University of Wisconsin, Madison. Working with my thesis mentor, Frederick Blattner, PhD, and our collaborator, Oliver Smithies, PhD, it was an incredibly exciting time when we were involved in cloning some of the first single-copy mouse and human genes. I received my PhD in genetics in 1983, and then went on to do postdoctoral training with Patricia Jones, PhD, at Stanford University, studying the mouse invariant chain gene. When my husband took at faculty position in the School of Public Health at the University of Michigan, I continued my postdoctoral training in the lab of Francis Collins, MD, PhD, who at the time was a young assistant professor and now is director of the National Institutes of Health. While working with him on the genetics of Huntington Disease, I learned strategies for finding genes that cause inherited human diseases. While continuing to work on Huntington Disease, in the late 1980s, I met a new faculty member in the Department of Ophthalmology and Visual Sciences at the University of Michigan's Kellogg Eye Center, Paul Sieving, MD, PhD, who is now the director of the National Eye Institute. In 1988, he told me that the next big area of research in vision science was going to be ophthalmic genetics and that I should seriously consider making it my career. Thus I joined the faculty of the Kellogg Eye Center and took up doing ophthalmic genetics as the focus of my career. And much of my path along the way was shaped by interactions with some really amazing people, the mentors I studied with and the collaborators I have had.

Personal Story

"When I first started in the field of ophthalmic genetics in 1990, I thought I was coming to work on retina genetics. But shortly after I started my faculty position at the Kellogg Eye Center, University of Michigan, glaucoma specialist Paul Lichter, MD, came to me with a picture of a large pedigree drawn in tiny symbols so that it all would fit onto the small piece of paper he had folded up in his white coat pocket. "What would you do with this family with hereditary glaucoma?" he asked.

I wrote up a description of how to map the location of the glaucoma gene, then how to find the actual gene and study its properties. He gave my write-up back to me with a grant application form for the BrightFocus Foundation attached, and said, "great, go apply for the funds to find the gene." Thus it came to be that the BrightFocus Foundation was the very first organization to fund my faculty research. Its support helped me get my start my focus on glaucoma genetics that has been the central focus of my lab ever since.

There is another punchline here. I had been working on glaucoma genetics for three years before I found out that I am at risk for glaucoma. My mother called me up one day to say, "Did you know that your grandmother is using glaucoma eye drops?" No, I did not. As I had been taking family histories from so many of the patients who were participating in our studies, I had never bothered to ask my own relatives about my family history. So I started asking questions and by the time I had tracked it all down, I discovered that I have a family history of glaucoma in three of the four branches of my family!  There is a saying about hindsight being 20/20. In this case, my family history makes it seem like a really smart move for me to be studying glaucoma."

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