Current researchMyocilin Glaucoma☆
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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
References (90)
- et al.
Altered secretion of a TIGR/MYOC mutant lacking the olfactomedin domain
Biochim Biophys Acta
(2000) - et al.
Delayed secondary glucocorticoid response elements. Unusual nucleotide motifs specify glucocorticoid receptor binding to transcribed regions of alpha 2u-globulin DNA
J Biol Chem
(1991) Genetics and primary open-angle glaucoma
Am J Ophthalmol
(1966)Chronic simple glaucomahereditary aspects
Am J Ophthalmol
(1955)- et al.
Clinical features and linkage analysis of a family with autosomal dominant juvenile glaucoma
Ophthalmology
(1993) - et al.
Genomic organization of the human myocilin gene (MYOC) responsible for primary open angle glaucoma (GLC1A)
Biochem Biophys Res Commun
(1998) - et al.
A novel myosin-like protein (myocilin) expressed in the connecting cilium of the photoreceptormolecular cloning, tissue expression, and chromosomal mapping
Genomics
(1997) - et al.
National survey of the prevalence and risk factors of glaucoma in St. Lucia, West Indies. Part I. Prevalence findings
Ophthalmology
(1989) - et al.
Gene structure and properties of TIGR, an olfactomedin-related glycoprotein cloned from glucocorticoid-induced trabecular meshwork cells
J Biol Chem
(1998) - et al.
Cloning and characterization of subtracted cDNAs from a human ciliary body library encoding TIGR, a protein involved in juvenile open angle glaucoma with homology to myosin and olfactomedin
FEBS Lett
(1997)
Novel trabecular meshwork inducible glucocorticoid response mutation in an eight-generation juvenile-onset primary open-angle glaucoma pedigree
Ophthalmology
Localization of the fourth locus (GLC1E) for adult-onset primary open-angle glaucoma to the 10p15-p14 region
Am J Hum Genet
Age-dependent prevalence of mutations at the GLC1A locus in primary open-angle glaucoma
Am J Ophthalmol
Localization of a locus (GLC1B) for adult-onset primary open angle glaucoma to the 2cen-q13 region
Genomics
Mutations in the TIGR gene in familial primary open-angle glaucoma in Japan
Am J Hum Genet
The myocilin (MYOC) gene expression in the human trabecular meshwork
Curr Eye Res
Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region
Cell
A third locus (GLC1D) for adult-onset primary open-angle glaucoma maps to the 8q23 region
Am J Ophthalmol
Prevalence of mutations in TIGR/Myocilin in patients with adult and juvenile primary open-angle glaucoma
Am J Hum Genet
Genetic linkage of autosomal dominant juvenile glaucoma to 1q21-q31 in three affected pedigrees
Genomics
Detection of a new TIGR gene mutation in a Japanese family with primary open angle glaucoma
Jpn J Ophthalmol
Mutations of the TIGR/MYOC gene in primary open-angle glaucoma in Korea
Am J Hum Genet
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
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
The inheritance of glaucomaa pedigree of familial glaucoma
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
Revised Framingham eye study prevalence of glaucoma and diabetic retinopathy
Am J Epidemiol
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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.