Glaucoma Genetics in 2009
Patients' risk of developing disease depends on the genetic mutation.
Genes play an important role in glaucoma. Epidemiological studies, twins studies, and reports of families in which glaucoma is transmitted as a Mendelian trait show that genes are involved in the pathogenesis of this disease. Only during the past decade, however, have researchers identified specific glaucoma genes. This article reviews two important genes that confer risk for glaucoma in vastly different ways.
Mutations in one gene, myocilin (MYOC), confer a high likelihood for the development of glaucoma and almost never occur in subjects with healthy eyes. Conversely, mutations in the lysyl oxidase-like 1 gene (LOXL1) are common among both patients with exfoliation syndrome and normal subjects. Even so, LOXL1 mutations, also called risk alleles, are detected at a statistically higher frequency in patients with exfoliation syndrome than in normal subjects. Individuals who carry LOXL1 risk alleles are at a higher risk for developing exfoliation syndrome and secondary glaucoma than those who do not carry these alleles. Given the high frequency of LOXL1 risk alleles in the general population, however, most carriers never develop disease.
The previous examples illustrate the different ways that genes may contribute risk for disease. In some cases, mutations in a single gene, such as MYOC, may be the principal risk factor for disease. In other cases, genes such as LOXL1 confer risk that only leads to disease when combined with the action of other genetic and environmental factors.
Patients with glaucoma that is caused by defects in the myocilin gene generally have one of two distinct clinical presentations. One set of myocilin mutations is associated with juvenile open-angle glaucoma (JOAG) that is characterized by the early onset of disease, particularly high IOP, and a strong family history. Myocilin mutations have been associated with the autosomal dominant inheritance of JOAG in many large families and are responsible for 8% to 63% of the cases of JOAG overall.1-4
A second set of MYOC mutations is associated with more typical adult-onset primary open-angle glaucoma (POAG). In fact, the most commonly detected myocilin mutation in the United States, GLN368STOP, is associated with late-onset glaucoma that is clinically indistinguishable from POAG cases without myocilin mutations.5 Many mutations in myocilin have been discovered in populations of POAG patients from around the world. Overall, mutations in myocilin are associated with 3% to 4% of the cases of POAG.6
Elevated IOP appears to be a common feature of all myocilin-associated glaucoma, although the IOP is more markedly elevated in cases of JOAG.
Mechanism of Disease
The mechanism by which mutations in the myocilin gene lead to glaucoma is unclear. In fact, very little is known about the basic biology of myocilin, except that it is produced in the ocular tissues that are vital to the regulation of IOP (the trabecular meshwork7 and ciliary body8) and that, under normal circumstances, myocilin is secreted into the aqueous humor.
The normal function of myocilin is unknown, and studies of experimental strains of mice have shown that neither an excess nor an absence of myocilin activity leads to glaucoma.9-11 Instead, mutations in myocilin cause disease by altering the normal behavior of the encoded protein. Whereas normal myocilin protein is secreted from the trabecular meshwork cells, mutant myocilin protein is retained and accumulates intracellularly.12 Recent investigations have suggested that mutations may alter the protein structure of myocilin so that it binds to proteins that divert it from the secretory pathway to intracellular compartments, the peroxisomes.13 These studies suggest that the abnormal intracellular accumulation of myocilin protein may damage the tissues of the iridocorneal angle (especially the trabecular meshwork cells) and lead to reduced aqueous outflow, elevated IOP, and eventually damage to the optic nerve and glaucoma.
Testing for Myocilin Mutations
For many diseases, genetic testing has the potential to provide valuable information to patients and their physicians. Test results may be complex, however, and may affect other family members. Consequently, experienced physicians and genetic counselors should be involved in decisions about genetic testing and the interpretation of results.
Nonetheless, some general principles suggest which patients may benefit most from genetic testing for myocilin mutations, which account for approximately one in 25 cases of POAG. Large-scale population-based testing for myocilin mutations is not currently feasible given the relatively low prevalence of disease-causing mutations. Testing may be warranted, however, for a select subset of patients who have high-risk features of disease, such as individuals with a strong family history of glaucoma, an early onset of disease, and markedly elevated IOP. A high proportion of patients with these characteristics have a mutation in the myocilin gene. Genetic testing frequently may provide useful information to these individuals and their physicians. In particular, it would be helpful to screen young, unaffected at-risk myocilin family members to appropriately utilize resources and to follow closely those harboring disease-causing mutations.
EXFOLIATON SYNDROME AND THE LYSYL OXIDASE-LIKE 1 GENE
Recently, a genome-wide scan for risk alleles identified a pair of variations in the LOXL1 gene, Arg141Leu and Gly153Asp. Each was observed in patients with exfoliation syndrome at a significantly higher frequency than in normal control subjects.14 Initial studies with Icelandic and Swedish subjects14 were confirmed with studies of populations from the United States,15-18 Australia,19 Japan,20-24 India,25 and Germany and Italy.26 As mentioned earlier, although these "high-risk" LOXL1 alleles are more common among patients with exfoliation syndrome, they also occur in a majority of normal subjects. As a result, most carriers of high-risk alleles never develop disease. The high frequency of LOXL1 risk alleles in the general population suggests that other genes and possibly environmental factors determine which carriers of LOXL1 risk alleles go on to develop exfoliation syndrome.
Mechanisms of Disease
LOXL1 encodes an enzyme that has an important role in elastin synthesis27 and is expressed in many tissues of the eye, including the cornea, iris, ciliary body, lens capsule, and optic nerve.19 The risk alleles (Arg141Leu and Gly153Asp) are located within a segment of the encoded LOXL1 propeptide that is cleaved to form an active enzyme after binding to its substrates tropoelastin and fibulin-5.27-29 Although the mechanism by which these risk alleles contribute to the development of exfoliation syndrome is still under investigation, one hypothesis suggests that the risk alleles may alter cleavage of the LOXL1 propeptide, binding to substrates, or enzymatic activity.14 Such altered function may lead to the accumulation of fibrillar material in the anterior segment of the eye and the pathologic features of exfoliation syndrome.
Testing for High-Risk LOXL1 Alleles
The high prevalence of LOXL1 risk alleles limits the current utility of genetic testing. At present, the vast majority of test results would be false positives (carriers of LOXL1 risk alleles who do not have exfoliation syndrome) and would not provide useful information to patients and their physicians. When additional risk factors are identified, more comprehensive testing will be possible and will likely provide useful diagnostic and prognostic data.
Genes contribute to the development of glaucoma in multiple ways. In some cases, rare mutations in single genes can cause disease that is inherited as a Mendelian trait (eg, myocilin and autosomal dominant JOAG). In such instances, a mutation in a single gene contributes risk for disease that overwhelms other factors, and the vast majority of mutation carriers develop disease. Other cases of glaucoma are likely caused by the combined action of several common genetic risk alleles. In these instances, only the combined risk from multiple factors is sufficient to cause disease. Although individuals carrying any one risk allele (like a LOXL1 risk allele) are at higher risk for glaucoma, most do not have the disease.
John H. Fingert, MD, PhD, is an assistant professor of ophthalmology and genetics, Department of Ophthalmology & Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City. Dr. Fingert may be reached at (319) 467-5152; email@example.com.
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