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EW INTERNATIONAL 52 December 2014 by Matt Young and Gloria D. Gamat EyeWorld Contributing Writers S ince the first genetic linkage for open-angle glaucoma was described by researchers at the University of Iowa in 1997, Wallace L.M. Alward, MD, has focused his research on the molecular genetics of the disease. Speaking at the National Healthcare Group Eye Institute 7th International Ophthalmology Congress in Singapore, Dr. Alward, director of the glaucoma service, and professor of ophthalmology and visual sciences, University of Iowa, took Congress attendees through a journey of the first gene discovered for glaucoma, and elaborated on how this is important for ophthal- mologists in their clinical practice. Myocilin glaucoma gene: The beginning "Our beginning was in 1987 when a man came in and asked if he [could] have surgery," Dr. Alward said. "He recognized that everyone in his fam- ily with glaucoma who was treated medically had gone blind, and those who were operated on had done well. With his help we figured out his pedigree, which is quite exten- sive: Of the 60 people in the family that we looked at, half were affected, had very striking glaucoma, with very high IOPs, and very early age of onset [as early as 8 years old]— a dominant heritage pattern." Based on the man's glaucoma heritage pattern, the research team was able to link findings to chromo- some 1, a locus called GLC1A, and then subsequently, in 1997, pub- lished a paper in Science describing myocilin as the gene that caused the family's glaucoma. The paper, titled "Identification of a gene that causes primary open angle glaucoma" by Stone et al., described how the analyses of se- quence tagged site (STS) content and haplotype sharing between families affected with chromosome 1q-linked open-angle glaucoma (GLC1A) were used to prioritize candidate genes for mutation screening. The myocilin gene (formerly known as TIGR) was mapped to the narrowest disease in- terval by STS content and radiation hybrid mapping. Among the population studied, 13 glaucoma patients were found to have 1 of 3 mutations in this gene (3.9%). One of these mutations was also found in a control individual (0.2%). The identification of these mutations helped in early diagnosis, which was essential for optimal ap- plication of existing therapies then. The glaucoma gene, myocilin (MYOC), is responsible for juvenile open-angle glaucoma and a subset of adult-onset primary open-angle glaucoma. Since it was first identi- fied, numerous studies have shown that MYOC is expressed in the trabecular meshwork, which is in- volved in the development of ocular hypertension and often associated with the development of glaucoma. "Myocilin usually causes this type of glaucoma [very early onset, very high pressures] but can also cause glaucoma that looks just like what we see every day in the clinic: people in their late 50s with not very high IOPs," Dr. Alward said. As reported in the 1997 Science paper, the mutations in the myoci- lin gene at the GLC1A locus caused juvenile glaucoma in 3–5% of adult- onset open-angle glaucoma—a figure, according to Dr. Alward, that has been replicated by clinics in every continent around the world. "To put that in perspective, in the United States that means there are 110,000 people who have myo- cilin glaucoma, which is more than all of the retinitis pigmentosa in the U.S. put together," he said. Understanding molecular genetic pathways Glaucoma is a family of diseases, and family history of glaucoma is a major risk factor for many glaucoma types. Molecular genetics in glaucoma: Hope for better management "I am optimistic that we are in a quest of developing designer drugs that will help specific forms of glaucoma, rather than treating all glaucomas like they are the same—drugs that might treat the underlying molecular defect, not just the pressure problem." –Wallace L.M. Alward, MD