Researchers discover gene mutation behind childhood glaucoma

Despite its rarity, childhood glaucoma is responsible for 5% of cases of child blindness worldwide.

Five Australians are among an international team of scientists who have discovered a new gene mutation that may be a root cause of severe cases of childhood glaucoma.

Through advanced genome-sequencing technology, the researchers found a mutation in the thrombospondin-1 (THBS1) gene in three ethnically and geographically diverse families with childhood glaucoma histories.

The researchers then confirmed their findings in a mouse model that possessed the genetic mutation and went on to develop symptoms of glaucoma driven by a previously unknown disease mechanism.

Led by Massachusetts Eye and Ear and Boston Children’s Hospital, co-authors of the study included Australians Dr Owen Siggs and Professor Jamie Craig (both from Flinders University), Dr Sandra Staffieri (Centre for Eye Research Australia), Jonathan Ruddle (consultant ophthalmologist) , and Lachlan Knight (orthoptist at Flinders Medical Centre).

The findings, published in the Journal of Clinical Investigationcould lead to improved screening for childhood glaucoma and earlier and more targeted treatments to prevent vision loss in children with the mutation, according to the study’s authors.

Siggs, associate professor at Flinders University and the Garvan Institute of Medical Research in Australia, said this work highlights the power of international collaborations.

“There’s such incredible genetic diversity across the globe, and comparing this information is becoming more and more critical for discoveries like this,” he said.

Dr Janey Wiggs, associate chief of ophthalmology clinical research at Mass Eye and Ear, who was also a guest speaker at RANZCO’s 53rd Congress in Brisbane last month, said it is a very exciting finding for families affected by childhood glaucoma.

“What was really striking about this finding is that these families all possessed this genetic variant, and it was not possible for them to be related because they were from such diverse backgrounds. That meant there was something really important about this mutation,” Wiggs said.

The researchers collaborated with Dr. Robert J. D’Amato, a professor of ophthalmology at Harvard Medical School, whose team developed a mouse model with the THBS1 mutation and found that the mouse also had features of glaucoma.

“Thrombospondin-1 is well known as a potent inhibitor of blood vessel growth, or angiogenesis,” D’Amato said.

“I assumed at first that THBS1 mutations were disrupting blood vessel formation in the eye, but our animal models showed normal angiogenesis. We realized that there must be another mechanism.”

Specifically, D’Amato’s lab showed that the mutation caused abnormal thrombospondin proteins to accumulate in the intraocular drainage structures of the eye involved with regulating IOP, which in turn, led to a build-up of pressure that damaged the optic nerve and led to the loss of retinal ganglion cells, thereby causing vision loss.

This was the first time that researchers identified this kind of disease mechanism for causing childhood glaucoma.

“With this new knowledge, we can offer genetic testing to identify children in a family who may be at risk for the disease and start disease surveillance and conventional treatments earlier to preserve their vision. In the future, we would look to develop new therapies to target this genetic mutation,” Wiggs, who is also vice chair for ophthalmology clinical research and Paul Austin Chandler Professor of Ophthalmology at Harvard Medical School, said.

Childhood, or congenital, glaucoma is a rare but serious disease that presents in children as early as birth and as late as three years of age. Despite its rarity, childhood glaucoma is responsible for 5% of cases of child blindness worldwide.

There is typically a strong hereditary component, often with multiple members of a family affected by the condition. According to Wiggs, by better understanding the genes involved, genetic testing can give affected families peace of mind to learn whether their child might be at risk for developing the disease.

The new finding has significant clinical implications, according to the researchers. While more work remains before comprehensive genetic testing can be offered, every gene that is found presents another opportunity to be able to identify causative mutations in these families through screening, according to the authors.

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