Elsevier

Survey of Ophthalmology

Volume 47, Issue 6, November–December 2002, Pages 547-561
Survey of Ophthalmology

Current research
Myocilin Glaucoma

https://doi.org/10.1016/S0039-6257(02)00353-3Get rights and content

Abstract

Genetic factors have long been implicated in the pathophysiology of primary open-angle glaucoma (POAG). Recently, myocilin, a gene of unknown function, was associated with both juvenile open-angle glaucoma (JOAG) and POAG. Forty-three different myocilin mutations have been reported in open-angle glaucoma patients, and several large studies have suggested that as a group these mutations are associated with 3–4% of POAG in patient populations worldwide. Support for the pathogenicity of the individual myocilin mutations has been obtained from in vitro assays, statistical methods, and conservation of gene sequence arguments. Several of these myocilin mutations were observed in multiple patients allowing the identification of mutation-specific glaucoma phenotypes (maximum intraocular pressure and age at diagnosis). Associations between myocilin and other forms of open-angle glaucoma have been explored. At present there is no evidence to link myocilin mutations and steroid-induced ocular hypertension or normal-tension glaucoma. Clinical vignettes of POAG patients from four generations of a family harboring the TYR437HIS myocilin mutation are presented, highlighting the benefits of elucidating the genetics of glaucoma.

Section snippets

Heredity of POAG

The prevalence of POAG varies between ethnic populations, suggesting that there is a significant genetic component to the disease. POAG is five times more common in African Americans than in Caucasians.72 The prevalence of POAG in populations in predominantly black Barbados (12.8%) and St. Lucia (8.8%) is much higher than that of most other populations.15, 40

First-degree relatives of individuals affected with POAG have up to an eightfold increased risk of developing POAG when compared to the

Identification of the Myocilin Glaucoma Gene

Several methods have been used to identify genes that cause disease. Using a positional cloning approach, potential disease-causing genes are identified and evaluated based on their chromosomal location, without regard to their function or expression pattern. One way genes are identified by positional cloning is by mapping chromosomal rearrangements in rare patients with grossly abnormal karyotypes. If a patient has a recognized form of glaucoma in addition to a chromosomal translocation or

Myocilin Gene Structure

The organization of the myocilin gene is shown in Fig. 2.2, 19, 32, 45 The portion of the gene that encodes myocilin protein (coding sequence) is divided into three segments (exons). Upstream of the coding sequence is the promoter, which contains DNA sequences that regulate myocilin expression at the level of transcription.

Myocilin's promoter has been studied to gain insights into the regulation of its expression. Initial studies of the DNA sequence of myocilin's promoter have revealed the

Expression of Myocilin

Although every cell in the human body contains a complete library of all of the human genes, many genes are activated and expressed in only certain cells and tissues. Although it was first isolated from cultured TM cells, myocilin expression has been demonstrated in most tissues of the body, ranging from bone marrow to cardiac muscle.19 This global expression pattern suggests that myocilin does not have an eye-specific function.

Myocilin has a similar ubiquitous expression pattern in the eye.

Assessing the pathogenicity of myocilin mutations

Many myocilin mutations have been identified in glaucoma patients since the gene was first associated with the disease Table 1, Table 2.2, 3, 4, 5, 8a, 18, 28, 29, 33, 36, 38, 39, 42, 43, 54, 55, 61, 62, 68, 77, 78, 81, 86, 87 In addition to glaucoma-causing myocilin mutations, numerous sequence changes in the myocilin gene have also been discovered that are not associated with disease; these are called polymorphisms.18 Some criteria for judging which mutations are likely pathogenic have been

Myocilin and steroid-induced ocular hypertension and glaucoma

Although the current focus of myocilin research has centered on the gene's role in JOAG and POAG as described above, myocilin was identified by studies designed to select genes involved in steroid-induced ocular hypertension and the associated secondary glaucoma. Because it is quite clear that steroids (glucocorticoids) do greatly enhance myocilin protein production in human TM,48 it is a plausible hypothesis that this production might be an important step in the development of steroid-induced

Myocilin-Associated Glaucoma Vignettes

Following are clinical vignettes of four generations of family with a TYR437HIS mutation in the myocilin gene. This family was first described by Johnson et al in 1993,25 and it was studied by Sheffield et al when the linkage for JOAG on chromosome 1q was discovered.58 Three generations of the family are shown in Fig. 4.

G.D. was born in 1918 and by the age of 21 had developed glaucoma-associated visual field loss. After sustaining severe vision loss he underwent three surgeries. We have no

Models of Myocilin Pathogenesis

An early model of the pathogenesis of myocilin-associated glaucoma suggested that overproduction and secretion of myocilin protein by the TM might cause an abnormal accumulation in the trabecular meshwork. This collection of myocilin might then obstruct the outflow of the aqueous humor, thereby increasing IOP and causing glaucoma.48 In support of this theory, high levels of myocilin expression has been demonstrated in all of the subdivisions of the TM (corneoscleral, uveal, and the

Benefits of Identifying Glaucoma Genes

Every year, thousands of Americans are blinded by POAG. In most cases, the loss of vision caused by glaucoma could be limited or prevented by currently available therapies if the disease were identified in its early stages. Most cases of glaucoma are not discovered until vision has already been permanently lost, because clinical signs of early glaucoma are subtle to an ophthalmologist and silent to the patient.

The discovery of POAG disease genes provides a method for early detection of

Method of Literature Search

Reports of myocilin mutations from 1997 to 2001 were identified by querying the Pubmed database. The follow key words were used: myocilin, GLC1A, and TIGR. All myocilin mutation reports identified in this search were included in the tables and references of this article. Foreign literature with English translation was included in this manuscript. From this extensive literature search, aspects of myocilin glaucoma research of particular interest to the Survey of Ophthalmology readership were

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    Supported in part by the Carver Charitable Trust, The Grousbeck Family Foundation, NIH grants EY10564, EY08905, EY02477, and EY02162, and an unrestricted grant from Research to Prevent Blindness, New York, NY. The authors reported no proprietary or commerical interest in any product mentioned or concept discussed in this article.

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