Myocilin Glaucoma

doi:10.1016/S0039-6257(02)00353-3

Survey of Ophthalmology

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

https://doi.org/10.1016/S0039-6257(02)00353-3 Get 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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Genetic rodent models are widely used in glaucoma related research. With vast amount of information revealed by human studies about genetic correlations with glaucoma, use of these models is relevant and required. In this review, we discuss the glaucoma endophenotypes and importance of their representation in an experimental animal model. Mice and rats are the most popular animal species used as genetic models due to ease of genetic manipulations in these animal species as well as the availability of their genomic information. With technological advances, induction of glaucoma related genetic mutations commonly observed in human is possible to achieve in rodents in a desirable manner. This approach helps to study the pathobiology of the disease process with the background of genetic abnormalities, reveals potential therapeutic targets and gives an opportunity to test newer therapeutic options. Various genetic manipulation leading to appearance of human relevant endophenotypes in rodents indicate their relevance in glaucoma pathology and the utility of these rodent models for exploring various aspects of the disease related to targeted mutation. The molecular pathways involved in the pathophysiology of glaucoma leading to elevated intraocular pressure and the disease hallmark, apoptosis of retinal ganglion cells and optic nerve degeneration, have been extensively explored in genetic rodent models. In this review, we discuss the consequences of various genetic manipulations based on the primary site of pathology in the anterior or the posterior segment. We discuss how these genetic manipulations produce features in rodents that can be considered a close representation of disease phenotype in human. We also highlight several molecular mechanisms revealed by using genetic rodent models of glaucoma including those involved in increased aqueous outflow resistance, loss of retinal ganglion cells and optic neuropathy. Lastly, we discuss the limitations of the use of genetic rodent models in glaucoma related research.
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Ocular hypertension is caused by dysregulated outflow resistance regulation by the conventional outflow (CO) pathway. The physiology of the CO pathway can be directly studied during ex vivo ocular perfusions. In addition to measuring outflow resistance generation by the CO tissues, perfusion media that is conditioned by CO pathway cells can be collected upon exiting the eye as effluent. Thus, contents of effluent include factors contributed by upstream cells that report on the (dys)functionality of the outflow tissues. Two methods have been used in the past to monitor effluent contents from perfused eyes, each with their limitations. To overcome these limitations, we designed and printed a metabolic chamber to accommodate eyes of different sizes during perfusions. To test this new chamber, human eyes were perfused for 4 h at constant flow rate of 2.5 μl/min, while pressure was continuously monitored and effluent was collected every hour. Facility was 0.28 ± 0.16 μl/min/mmHg for OD eyes and 0.33 ± 0.11 μl/min/mmHg for OS eyes (n = 3). Effluent samples were protein rich, with protein concentration ranging from 2700 to 10,000 μg/ml for all eyes and timepoints (N = 3). Effluent samples expressed proteins that were actively secreted by the TM and easily detectible including MYOC and MMP2. Taken together, our model provides a reliable method to collect effluent from ex vivo human eyes, while maintaining whole globe integrity.
Myocilin misfolding and glaucoma: A 20-year update
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Mutations in the gene MYOC account for approximately 5% of cases of primary open angle glaucoma (POAG). MYOC encodes for the protein myocilin, a multimeric secreted glycoprotein composed of N-terminal coiled-coil (CC) and leucine zipper (LZ) domains that are connected via a disordered linker to a 30 kDa olfactomedin (OLF) domain. More than 90% of glaucoma-causing mutations are localized to the OLF domain. While myocilin is expressed in numerous tissues, mutant myocilin is only associated with disease in the anterior segment of the eye, in the trabecular meshwork. The prevailing pathogenic mechanism involves a gain of toxic function whereby mutant myocilin aggregates intracellularly instead of being secreted, which causes cell stress and an early timeline for TM cell death, elevated intraocular pressure, and subsequent glaucoma-associated retinal degeneration. In this review, we focus on the work our lab has conducted over the past ∼15 years to enhance our molecular understanding of myocilin-associated glaucoma, which includes details of the molecular structure and the nature of the aggregates formed by mutant myocilin. We conclude by discussing open questions, such as predicting phenotype from genotype alone, the elusive native function of myocilin, and translational directions enabled by our work.
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Myocilin is a protein encoded by the MYOC in humans [133]. MYOC mutations are associated with high intraocular pressure in Primary Open Angle Glaucoma and account for up to 35% juvenile-onset and 4% adult-onset [134]. Myocilin consists of two domains; a leucine zipper domain at the N-terminal and an olfactomedin (OLF) domain at the C-terminal.
Trimethylamine N-oxide (TMAO) is a chemical chaperone found in various organisms including humans. Various studies unveiled that it is an excellent protein-stabilizing agent, and induces folding of unstructured proteins. It is also well established that it can counteract the deleterious effects of urea, salt, and hydrostatic pressure on macromolecular integrity. There is also existence of large body of data regarding its ability to restore functional deficiency of various mutant proteins or pathogenic variants by correcting misfolding defects and inhibiting the formation of high-order toxic protein oligomers. Since an important class of human disease called “protein conformational disorders” is due to protein misfolding and/or formation of high-order oligomers, TMAO stands as a promising molecule for the therapeutic intervention of such diseases. The present review has been designed to gather a comprehensive knowledge of the TMAO's effect on the functional restoration of various mutants, identify its shortcomings and explore its potentiality as a lead molecule. Future prospects have also been suitably incorporated.
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Juvenile-onset open-angle glaucoma (JOAG) is a subset of primary open-angle glaucoma that is diagnosed before 40 years of age. The disease may be familial or non-familial, with proportions varying among different populations. Myocilin mutations are the most commonly associated. JOAG is characterized by high intraocular pressures (IOP), with many patients needing surgery. The mean age at diagnosis is in the 3^rd decade, with a male preponderance. Myopia is a common association. The pathophysiology underlying the disease is immaturity of the conventional outflow pathways, which may or may not be observed on gonioscopy and anterior segment optical coherence tomography. The unique optic nerve head features include large discs with deep, steep cupping associated with high IOP-induced damage. Progression rates among JOAG patients are comparable to adult primary glaucomas, but as the disease affects younger patients, the projected disability from this disease is higher. Early diagnosis, prompt management, and life-long monitoring play an important role in preventing disease progression. Gene-based therapies currently under investigation offer future hope.
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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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Current researchMyocilin Glaucoma☆

Abstract

Section snippets

Heredity of POAG

Identification of the Myocilin Glaucoma Gene

Myocilin Gene Structure

Expression of Myocilin

Assessing the pathogenicity of myocilin mutations

Myocilin and steroid-induced ocular hypertension and glaucoma

Myocilin-Associated Glaucoma Vignettes

Models of Myocilin Pathogenesis

Benefits of Identifying Glaucoma Genes

Method of Literature Search

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntingtons disease chromosomes

The Huntingtons Disease Collaborative Research Group. Cell

Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma

Hum Mol Genet

Gln368Stop myocilin mutation in families with late-onset primary open-angle glaucoma

Invest Ophthal Vis Sci

Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A)

N Engl J Med

A novel mutation in the GLC1A gene causes juvenile open-angle glaucoma in 4 families from the Italian region of Puglia

Arch Ophthalmol

Myocilin Gln368stop mutation and advanced age as risk factors for late-onset primary open-angle glaucoma

Arch Ophthalmol

On some hereditary structural anomalies of the eye and on the inheritance of glaucoma

Notes on the question of hereditary glaucoma

Ophthalmologica

Notes on the heredity of glaucoma

Ophthalmologica

Genetic screening in a large family with juvenile onset primary open-angle glaucoma

Br J Ophthalmol

Founder effect in GLC1A-linked familial open-angle glaucoma in Northern France

Am J Med Genet

Altered secretion of a TIGR/MYOC mutant lacking the olfactomedin domain

Biochim Biophys Acta

Delayed secondary glucocorticoid response elements. Unusual nucleotide motifs specify glucocorticoid receptor binding to transcribed regions of alpha 2u-globulin DNA

J Biol Chem

Expression of the glaucoma gene myocilin (MYOC) in the human optic nerve head

FASEB J

Glucocorticoid-induced formation of cross-linked actin networks in cultured human trabecular meshwork cells

Invest Ophthalmol Vis Sci

The effect of dexamethasone on integrin and laminin expression in cultured human trabecular meshwork cells

Exp Eye Res

Doyne Memorial Lecture, 1975. Correlation of optic nerve and visual field defects in simple glaucoma

Trans Ophthalmol Soc U K

Recombinant TIGR/MYOC increases outflow resistance in the human anterior segment

Invest Ophthalmol Vis Sci

Evaluation of the myocilin (MYOC) glaucoma gene in monkey and human steroid-induced ocular hypertension

Invest Ophthalmol Vis Sci

Analysis of myocilin mutations in 1703 glaucoma patients from five different populations

Hum Mol Genet

Characterization and comparison of the human and mouse GLC1A glaucoma genes

Genome Res

Genetics and primary open-angle glaucoma

Am J Ophthalmol

The inheritance of glaucomaa pedigree of familial glaucoma

Am J Ophthalmol

Chronic simple glaucomahereditary aspects

Am J Ophthalmol

Non-secretion of mutant proteins of the glaucoma gene myocilin in cultured trabecular meshwork cells and in aqueous humor

Hum Mol Genet

Genetics and Glaucoma

Clinical features and linkage analysis of a family with autosomal dominant juvenile glaucoma

Ophthalmology

Revised Framingham eye study prevalence of glaucoma and diabetic retinopathy

Am J Epidemiol

Localization of myocilin/trabecular meshwork—inducible glucocorticoid response protein in the human eye

Invest Ophthalmol Vis Sci

TIGR gene in primary open-angle glaucoma and steroid-induced glaucoma

Korean J Ophthalmol

A novel Asp380Ala mutation in the GLC1A/myocilin gene in a family with juvenile onset primary open angle glaucoma

J Med Genet

Regulation of human myocilin/TIGR gene transcription in trabecular meshwork cells and astrocytesrole of upstream stimulatory factor

Genes Cells

Genomic organization of the human myocilin gene (MYOC) responsible for primary open angle glaucoma (GLC1A)

Biochem Biophys Res Commun

Novel mutations in the myocilin gene in japanese glaucoma patients

Hum Mutat

A novel myosin-like protein (myocilin) expressed in the connecting cilium of the photoreceptormolecular cloning, tissue expression, and chromosomal mapping

Current research
Myocilin Glaucoma☆