Newly identified gene increases glaucoma risk

Exfoliation syndrome (XFS) is a systemic disorder that manifests most clearly in the eye. It leads to accumulation of exfoliation material in the eye, impeding fluid drainage and leading to an increase in intraocular pressure. This increased pressure can lead to damage of the optic nerve and a gradual loss of vision. 

The resulting eye condition, glaucoma, is estimated to have affected 60.5 million people in 2010. This number is expected to almost double by 2040, disproportionately affecting people in Asia and Africa.

An international team of scientists, spanning six continents and 17 countries, has identified a new gene, CACNA1A, as a susceptibility gene for XFS. 

For many years, scientists believed that another gene, LOXL1, was the only gene responsible for the disease. But recent research has shown that LOXL1 causes protection from or risk for XFS depending on ethnic group and is not 100% consistent. Since 2007, many research groups around the world have tried to find a gene for XFS that is consistent across ethnic groups but to no avail. 

The work done by the international team, which included scientists from Saudi Arabia’s King Saud University and King Khaled Eye Specialist Hospital, suggests consistent association of CACNA1A with XFS across Asian, European and South African ancestry groups.

CACNA1A is involved in calcium channels, which play a key role in a cell’s ability to generate and transmit electrical signals. Scientists believe that malfunctioning calcium channels could cause alterations in calcium concentrations that might facilitate the formation of XFS aggregates. “[The new] finding points to a potential role of calcium ion signaling or transport in the disease formation of exfoliation syndrome,” says Chiea-Chuen Khor, senior research scientist at Genome Institute of Singapore.

Genes are formed of allele pairs that determine specific traits depending on whether one or both of the pairs is dominant or recessive for that trait.

Khor explains that each copy of the risk allele in CACNA1A increases susceptibility to XFS by 16%. 

The group’s gene analysis and tissue work suggest that LOXL1 and CACNA1A contribute to XFS independently from one another.

The results have some potential for XFS patients. Calcium channel blockers are readily available to treat heart conditions, so it is not impossible to develop blockers that can target them in the eye, says Khor. Further research is required. However, there is a potential that XFS patients may be treated in the future with calcium blocking drugs, he explains.

The team’s next steps will be twofold, says Khor. They will expand the study to involve more patients from existing and new participating countries to allow scientists to more precisely identify the signaling pathway responsible for the disease. They will also study CACNA1A in great detail to determine the exact mechanism in which changes in the gene’s function can lead to XFS. “It is only with this deep level of understanding that we can attempt to design new medications to treat XFS,” Khor says.

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