Researchers in the U.S. have identified a new genetic candidate for primary open angle glaucoma (POAG). The mutation, identified in the only natural animal model of POAG, alters a gene known as ADMTS10, which codes for an extracellular matrix protein that is highly expressed in the trabecular meshwork through which the eye’s aqueous humor flows.
The scientists are now investigating whether the ADMTS10 gene is also mutated in human POAG. If so, they hope it will provide a promising new target for therapeutic intervention.
The beagle studies, led by a team headed by Rachel Kuchtey, M.D., and John Kuchtey, Ph.D., at Vanderbilt Eye Institute and Vanderbilt University Medical Center in Nashville, were published yesterday in PLoS Genetics, in a paper titled, “Mapping of the Disease Locus and Identification of ADAMTS10 as a Candidate Gene in a Canine Model of Primary Open Angle Glaucoma.”
POAG is characterized by an increase in resistance to the outflow of aqueous humor through the trabecular meshwork, which causes elevated intraocular pressure, the authors report. However, the underlying mechanisms that lead to this resistance remain unknown. Moreover, while three genes have previously been linked with POAG, these candidates only appear to account for a small fraction of POAG cases, and none have shed much light on the disease process.
“It seems kind of simple – there’s a decrease in the rate of aqueous humor flowing out of the eye,” points out John Kuchtey. “But the basic mechanisms of aqueous humor outflow at the cellular and molecular level, and how they are disrupted in glaucoma, are not understood. It’s a long-standing puzzle in ophthalmology.”
In order to try and identify a more likely genetic candidates for POAG, the Vanderbilt team’s sequencing approach centered on a well-established colony of beagle dogs that represents the only naturally occurring animal model of POAG. In these animals POAG is inherited as an autosomal recessive trait. Affected dogs start to display increases in intraocular pressure at 8 to 16 months of age, due to increased resistance to outflow of aqueous humor. As with POAG in humans, optic nerve cupping, loss of optic nerve axons, and vision loss occur in affected beagles following the slowly progressing and sustained elevations of intraocular pressure.
To hunt for a candidate gene in these dogs, the researchers homed in on a region of canine chromosome 20 that harbored SNPS for which all 19 studied POAG-affected dogs were homozygous, and all 10 carrier dogs were heterozygous. Encouragingly, this region matched a section of human chromosome 19 that previous studies had linked with the regulation of intraocular pressure.
In order to narrow the search down further to a single gene, the team then sequenced the entire 4 Mb POAG locus in an affected beagle, a carrier dog, and a normal dog from the colony. This found a single base pair change in the affected dogs that results in a nonconservative amino acid substitution in a region of the ADAMTS10 gene that is highly conserved in vertebrate species. The gene is part of the family of secreted metalloproteinases, and the Gly661Arg variant found in POAG-affected beagles is predicted to disrupt protein function, the authors point out.
“Unlike the three POAG genes identified thus far in humans, the ADAMTS10 variant identified in this study has obvious functional implications, supporting ADAMTS10 as a strong candidate gene”, the Vanderbilt team states. Moreover, they add, a role for metalloproteinases in ocular hypertension has long been suggested by in vitro studies, and changes in the amount or composition of extracellular matrix within the trabecular meshwork have been hypothesized to contribute to ocular hypertension by increasing resistance to outflow of aqueous humor. “Although the specific substrate for ADAMTS10 is unknown, other ADAMTS family members are known to participate in collagen processing and proteoglycan degradation. ADAMTS10 is likely to function in some capacity in regulation of extracellular matrix and therefore disruption of its function could lead to POAG by increasing resistance to aqueous humor outflow through the trabecular meshwork”.