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A new study published online in the journal Science has identified two key mutations in a single gene which account for nearly all cases of exfoliation glaucoma [Thorleifsson G et al. (2007) Science (Epub ahead of print)].

 

Glaucoma is a group of disorders that are characterized by damage to the optic nerve, resulting in progressive loss of vision and blindness. According to the World Health Organization (WHO), glaucoma is the second most common cause of visual impairment and blindness with around 60 million sufferers worldwide. A subtype known as exfoliation glaucoma is caused by exfoliation syndrome, which is characterized by the accumulation of abnormal fibrous deposits in the eye and has reported prevalence rates of 10-20% amongst the general population over age 60. Early diagnosis and treatment is severely hampered by the lack of symptoms in the early stages of the disease, so genetic testing could help identify individuals at risk.

 

The research to identify genetic variants that confer a risk of glaucoma was carried out by Icelandic gene-hunting company deCODE Genetics in collaboration with the National University Hospital in Reykjavik, Iceland and Uppsala University, Sweden. Nearly 16,000 patients and controls in Iceland and Sweden were involved in the study and over 300,000 SNPs were tested for association with glaucoma.

 

Two single nucleotide polymorphisms (SNPs) were identified within a single gene located on chromosome 15 coding for the lysyl oxidase protein 1 (LOXL1), an extracellular enzyme involved in elastic fiber homeostasis. Both SNPs identified are non-synonymous mutations located in the first exon of LOXL1, which encodes a pro-peptide that is cleaved off for catalytic activation of the enzyme following attachment to its substrate. The risk of exfoliation glaucoma is significantly increased by the presence of either of the high risk SNPs, whose effect appears to be to lower the expression of LOXL1. Together, the two variants account for over 99% of all exfoliation glaucoma cases.

 

This finding is in line with other recent research [Forsman E et al. (2007) Acta Opthalmol Scand.] suggesting that exfoliation syndrome is consistent with an autosomal dominant trait with incomplete penetrance. The discovery of a sub-group of a common disease where defects in a single gene are present in virtually all cases is highly unusual.