Eye (2011) 25, 587–595 & 2011 Macmillan Publishers Limited All rights reserved 0950-222X/11 www.nature.com/eye Primary open-angle JH Fingert REVIEW glaucoma genes Abstract of important biological pathways that once identified may help clarify the mechanisms that A substantial fraction of glaucoma has a lead to disease. The discovery of disease genes genetic basis. About 5% of primary open angle will also continue to provide insights into the glaucoma (POAG) is currently attributed to normal function of the eye. single-gene or Mendelian forms of glaucoma Discovery of the genes that cause eye disease (ie glaucoma caused by mutations in myocilin may also provide useful information for or optineurin). Mutations in these genes have a patients and their physicians. Identifying these high likelihood of leading to glaucoma and are genes will enable the design of DNA-based tests rarely seen in normal subjects. Other cases of that may help physicians assess their patient’s POAG have a more complex genetic basis and risk for disease and may also differentiate are caused by the combined effects of many between clinically similar disorders. Many genetic and environmental risk factors, each of such tests are already available on both a which do not act alone to cause glaucoma. fee-for-service and research basis (http:// These factors are more frequently detected in www.genetests.org). Identification of the patients with POAG, but are also commonly specific mutation or mutations that are observed in normal subjects. Additional genes responsible for a patient’s disease not only that may be important in glaucoma solidifies the diagnosis, but may also help pathogenesis have been investigated using predict its likely clinical course. Several quantitative traits approaches. Such studies mutation-specific phenotypes of hereditary eye have begun to identify genes that control the diseases have already been reported, including magnitude of important quantitative features glaucoma,10 retinitis pigmentosa,11 and Von of glaucoma that may also be important risk Hippel Lindau syndrome.12 Genetic variations factors for POAG, such as central corneal may also influence a patient’s response to thickness. Each of these different approaches therapeutic interventions and will help guide to study glaucoma genetics is providing new selection of their clinical and surgical care. insights into the pathogenesis of POAG. Discovery of the genes that cause disease is a Eye (2011) 25, 587–595; doi:10.1038/eye.2011.97 vital step in the development of new treatments for heritable eye conditions. The biological Keywords: glaucoma; genetics; POAG function of a disease-causing gene may in some cases suggest the application of currently available medical and surgical therapies. In Department of Ophthalmology and Visual other cases, new interventions may be Genes are important in eye disease Sciences, Carver College developed to compensate a genetic defect after of Medicine, University of Research breakthroughs have shown that genes it is identified. Such gene-directed therapies Iowa, Iowa City, IA, USA have key roles in the pathogenesis of common might include currently available or newly eye diseases, including age-related macular designed medications, gene therapy (replacing Correspondence: JH Fingert, degeneration,1–4 Fuchs corneal endothelial a mutant gene with a normal copy), and/or Department of 5 6 Ophthalmology, dystrophy, exfoliation syndrome, and primary other molecular genetic approaches such as The University of Iowa 7–9 13,14 open-angle glaucoma (POAG). The recent blocking mutant gene expression. College of Medicine, Iowa discovery of important risk factors for these Many eye diseases, including glaucoma, are City, IA 52242, USA common eye diseases underscores the utility both genetically and mechanistically Tel: þ 1 319 335 7508; of studying ophthalmic genetics. heterogeneous, meaning that it is unlikely that Fax: þ 1 887 434 9041. E-mail: john-fingert@ The identification of disease-causing genes one therapy will be effective for all forms of a uiowa.edu provides information about the pathogenesis disease. Genetic studies of complex diseases of heritable eye diseases at the most basic level. may also provide crucial information for future Received: 14 March 2011 For example, disease-causing genes may be part animal and clinical treatment trials. The most Accepted: 14 March 2011 Glaucoma genes JH Fingert 588 relevant animal models of eye disease will be those that mutations, ‘risk alleles’, may promote the development are designed to have the same genetic defects that are of POAG when combined with other glaucoma risk found in human disease. Such animal models would alleles and environmental factors but do not cause have great value for testing both the safety and efficacy of disease on their own (Table 1). These alleles or genetic new therapies. Additionally, researchers may use genetic risk factors are statistically more common in POAG tests to identify relatively homogeneous populations of patients, although they are very frequently detected in study patients for treatment trials or to study patients both patients and controls. In this report, the current state with the same molecular cause of disease. of our knowledge of the genetic basis for glaucoma is reviewed, including glaucoma causing genes, glaucoma genetic risk factors, and quantitative traits related to the Glaucoma is a heritable disease development of glaucoma. The idea that heredity has an important role in glaucoma pathogenesis is not new. Some of the earliest evidence came from reports of large pedigrees in which glaucoma POAG-causing genes (MendelianFsingle-gene was passed down from generation to generation in a disease) Mendelian pattern that demonstrated that at least some Myocilin (MYOC, OMIM #601652) cases of glaucoma have a genetic basis. Twin studies and familial clustering studies have also indicated that some Myocilin was the first gene to be associated with POAG, portion of glaucoma is caused by heredity.15–20 Finally, and mutations in this gene are the most common cause of several domesticated animal breeds, including the DBA/ glaucoma with a known molecularly defined basis. 2J mouse (pigmentary glaucoma), cats, and dogs, have Glaucoma-causing mutations in myocilin were first been documented to be afflicted by inherited detected in linkage-based studies of large pedigrees with glaucoma.21–25 Together these data provide strong juvenile open angle glaucoma (JOAG).7,27 Myocilin evidence that genes have an important role in the mutations have since been found in 3–4% of POAG pathogenesis of glaucoma and provide support for patients7,26 and a range of glaucoma-associated myocilin efforts to find these genes. mutations have now been cataloged in review articles28,29 In the last two decades significant progress has been and online at http://www.myocilin.com. In most cases, made in unraveling the genetic basis of POAG. myocilin-associated glaucoma appears to be transmitted Mutations that lead to POAG can be divided into two as an autosomal dominant trait and is associated with groups with very distinct characteristics (Table 1). One markedly elevated IOP. class of mutations are capable of ‘causing’ POAG on their own with little influence from other genes or the environment. These single-gene forms of glaucoma are Myocilin and JOAG. Glaucoma-causing mutations have responsible for disease that is transmitted as a Mendelian been identified in many JOAG pedigrees with glaucoma trait, often with an autosomal dominant inheritance that is inherited as an autosomal dominant trait. Myocilin pattern. Individuals that carry these types of mutations mutations are relatively common in patients with JOAG, almost always develop POAG and these mutations are and have been detected in 8–36% of patients in published rarely observed in subjects with normal eyes. Mutations case series.30–32 The likelihood of detecting myocilin in the myocilin (MYOC) and optineurin (OPTN) genes are mutations in subjects with JOAG appears to be greater in examples of mutations that ‘cause’ POAG and are patients with stronger family histories of glaucoma than discussed in more detail below. The other class of in patients with apparently sporadic glaucoma. Table 1 Two classes of POAG mutations Features of mutations Glaucoma-‘causing’ mutations Glaucoma risk alleles Generally Myocilin Generally Chromosome 7q31 risk (GLN368Stop) allele (rs4236601A) Frequency in POAG cohorts Low 1.6% Common 28.7% Frequency in normal cohorts Usually absent 0.13% Common 22.8% Likelihood of POAG in those with mutations High 98.6% Low Odds ratio 1.36 This table highlights the differences between mutations that primarily ‘cause disease’ on their own (such as the GLN368STOP mutation) and those that contribute to the overall risk for developing disease (such as the chromosome 7q31 risk allele). The data for the myocilin mutation (GLN368STOP) are from http://www.myocilin.com and Fingert et al.26 The data for the chromosome 7q31 risk allele are from Thorleifsson et al.8 Eye Glaucoma genes JH Fingert 589 Myocilin and POAG. Myocilin mutations are also decreased aqueous outflow, elevated IOP, and co-inherited with POAG in an autosomal dominant glaucoma.41,42 Animal models harboring myocilin pattern and have been detected in cohorts of POAG mutations have been developed and are beginning to patients from around the world. However, due to the reveal the specific molecular steps that lead from later onset of disease, the POAG pedigrees are smaller mutations in myocilin to the elevated IOP that is and the mode of inheritance is not as obvious as is characteristic of myocilin-related glaucoma.43–45 observed with JOAG families.26 Many mutations are only observed in specific geographic or ethnic populations, Optineurin (OPTN, OMIM #602432) but one myocilin mutation (GLN368STOP) has been detected in nearly all of the examined POAG populations, Optineurin was identified as a glaucoma-causing gene including African-Americans and Caucasians from the through investigations of a large normal tension United States, Canada, Australia, Europe, and South glaucoma (NTG) pedigree.