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Subspecialties Glaucoma, Basic & Translational Research, Pediatric

Digging into Glaucoma’s Genetic Roots

Janey Wiggs – Professor of Ophthalmology and Vice Chair for Clinical Research at Harvard Medical School – and her team at Massachusetts Eye and Ear have identified a new mutation of interest in their search for genetic drivers of congenital glaucoma.

Exploring a dataset of more than 34,000 adults with glaucoma, the team found a striking and novel variant in the thrombospondin-1 (THBS1) gene in an American family of European-Caucasian descent (1). Notably, the mutated gene was not found in family members without childhood glaucoma nor in large, population genetic databases. Further research conducted at Flinders University, Australia, found another two families – one of mixed European descent and one Sudanese family originally from Africa – with an alteration in the same amino acid and a history of primary congenital, adding further strength to the correlation. Additionally, a mouse model with the THBS1 mutation was developed by Robert J. D’Amato – the Judah Folkman Chair in Surgery in the Vascular Biology Program at Boston Children's Hospital – to explore pathogenesis.

Here, Wiggs sheds additional light on the research and its potential impact.

What are the implications of finding this new variant?

Identifying genes responsible for inheritable conditions can help define the underlying disease pathogenesis, which can lead to new therapies. Additionally, finding genes that cause these conditions makes it possible to use genetic testing to find mutation carriers who are at high disease risk. Follow up research on a mouse model with the same mutation demonstrated that the thrombospondin mutation caused accumulation of aggregated protein in the trabecular meshwork, resulting in a reduction in intraocular fluid outflow. This novel disease mechanism for congenital glaucoma could potentially impact the development of novel treatments.

How important is collaboration when digging deeper into complex conditions?

Well, this was a very exciting study that involved international collaborations between clinicians, clinician scientists, and basic scientists. Without these collaborations, the project would simply not have been possible.

What does this research mean for the future of childhood glaucoma care?

As noted, adding a new gene for congenital glaucoma improves genetic testing for this condition and also could help identify novel approaches to treatment. Genetic testing is very important for glaucoma; people who have high risk of disease can be identified before the disease becomes manifest, allowing for preemptive treatment.

Where should additional research efforts be directed?

We still need to identify more genes and mutations responsible for early-onset glaucoma.  Currently, we have only a few genes known to cause these conditions, so genetic testing using these genes only provides a molecular diagnosis in about 20 percent of individuals.  Finding additional genes could help provide useful testing for the remaining 80 percent.

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  1. JL Wiggs et al., “Thrombospondin 1 missense alleles induce extracellular matrix protein aggregation and TM dysfunction in congenital glaucoma,” J Clin Invest, [Online ahead of print] (2022). PMID: 36453543.
About the Author
Sarah Healey

Communicating stories in a way that is accessible to all was one of the focal points of my Creative Writing degree. Although writing magical realism is a fun endeavor (and one I still dabble in), getting to the heart of human stories has always been the driving motivator behind my writing. At Texere, I am able to connect with the people behind scientific breakthroughs and share their stories in a way that is impactful and engaging.

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