Molecular ophthalmologists at the University of Iowa aretraining their sights on the long arm of chromosome 1, wherethey hope to pinpoint the gene for familial glaucoma. They pintheir hopes on a five-generation extended Midwestern family,where half the members are at risk of the blindness-threatening eye disease.
Edwin Stone of the university hospital eye clinic on Mondayspoke to a gathering of science journalists, organized by theNew York-based Research to Prevent Blindness, which is one ofseveral institutions financing his group's gene-mapping project.
Stone's paper, titled "Genetic linkage of familial open angleglaucoma to chromosome 1q21-q31," will appear Saturday inthe May issue of Nature Genetics.
"What's new about this," Stone told BioWorld, "is that this is thefirst time a genetic cause for a type of open angle glaucoma hasever been mapped to a specific chromosomal region, andtherefore gives us a toehold that we'll actually get the gene."
That future discovery will, in turn, provide a toehold forfinding better ways to treat glaucoma, a disease, said TomFurlong, press officer of Research to Prevent Blindness, "that 3million Americans have, but 1 million don't know it."
He explained, "It's a sneaky disease, with no symptoms, nopain, that begins by robbing its victims of peripheral vision, anincrement at a time. About 120,000 people are presently blindfrom glaucoma, and their number increases by 5,500 a year,"Furlong told BioWorld. It's the prime cause of blindness inAfrican-Americans.
Glaucoma occurs when the aqueous humor, a liquid that fillsthe cavity between cornea and lens, undergoes increasedintraocular fluid pressure.
There are many types of glaucoma, caused by trauma ordisease. The Iowa group is focusing on a relatively uncommon,autosomal dominant form, juvenile-onset glaucoma, diagnosedin children and young adults. This enables the moleculargenealogists to map its allelic, polymorphic markers on thegenomes of living parents, grandparents and collateralrelatives. Once the gene is located, it will be possible to screensingle patients for mutations.
Stone's hunt began in 1987, he recalled, when a patient in hisearly 20s "showed up for his eye-clinic appointment. He hadhis whole family of 20 affected individuals drawn out on ayellow legal pad, complete with names, addresses, phonenumbers."
"Would this be helpful?" the young man asked theophthalmologists. Would it just! "It represented the largestidentified family with open angle glaucoma in the UnitedStates, if not the world," Stone exclaimed. All its presentkinfolks descended from a German woman who emigrated tothe American Midwest in the late 1800s.
Now that family numbers 37, of whom 22 were found to haveglaucoma. Eight DNA markers of nearly 100 examinednarrowed the gene search to a lengthy long-arm stretch ofchromosome 1. Next, the Iowa group intends to broaden itssearch, Stone said, "to find additional family members bycombing through earlier generations, including those no longerliving, but on whom we can obtain information," so as to honetheir linkage analysis closer to the actual disease gene.
Their search will spread to other states as well, "to identifybranches of the family that living members are unaware of."Once their augmented test population is large enough, they'llembark on the end-game gene hunt, involving such gambits asyeast artificial chromosome contigs and cDNA libraries madefrom relevant ocular and nerve tissue.
One provocative, though possibly illusory, clue concerns thereceptor for atrial natriuretic peptide (ANP), a substancesynthesized in heart tissue, which acts as a diuretic to helpcontrol blood pressure. ANP is also synthesized in the eye'sciliary body, which makes aqueous humor.
Its connection to glaucoma, said A. Tim Johnson, a co-author ofthe Stone paper, is that its receptor, localized by linkage in theIowa family, is in the same region of chromosome 1. "It seemsto be involved in pressure mechanism -- possibly," he toldBioWorld cautiously.
Stone is downright skeptical. Although his paper described theANP receptor as "an excellent candidate gene for involvementin glaucoma," he told BioWorld, "we have absolutely noevidence, other than the fact that this gene is in the samegeneral area of the genome, that ANP has anything to do withglaucoma." He added, "Obviously, we are suspicious enough of itso that we're going to pursue it, but in my experience, greatcandidate genes like this almost never pan out."
Buttressing that suspicion is an open-label clinical experimentthat Stone cited, conducted in Germany several years ago at theUniversity of Cologne Eye Hospital. Ten glaucoma patientsreceived 100 micrograms of human atrial natriuretic factor byintravenous injection. After eight hours, their intraocularpressure had diminished from an average 33 milligrams ofmercury to 26. But the study concluded the trial wasinconclusive because a truly therapeutic response would havebrought the pressure down to 22, and also it took no account ofpossible diurnal variations.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.