Alternative titles; symbols
HGNC Approved Gene Symbol: MYOC
Cytogenetic location: 1q24.3 Genomic coordinates (GRCh38): 1:171,635,417-171,652,688 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q24.3 | Glaucoma 1A, primary open angle | 137750 | Autosomal dominant | 3 |
Escribano et al. (1995) isolated and characterized cell-specific cDNA clones from a subtractive library of the ocular ciliary body, a tissue responsible for regulating aqueous humor secretion and intraocular pressure (IOP). Stone et al. (1997) demonstrated that one of these cDNAs encoding the trabecular meshwork-induced glucocorticoid response protein (TIGR) maps to 1q where the locus for the juvenile form of open angle glaucoma (GLC1A; 137750) had been mapped. By both STS content and radiation hybrid mapping, the TIGR gene was shown to map to the narrowest interval defined for GLC1A by linkage studies, and they identified mutations in the TIGR gene in glaucoma patients. The TIGR gene encodes a predicted 497-amino acid polypeptide.
By Northern blot analysis, Fingert et al. (1998) showed that MYOC was expressed as a 2.3-kb transcript not only in eye structures, but also in heart, skeletal muscle, stomach, thyroid, trachea, bone marrow, thymus, prostate, small intestine, and colon, with lower expression in lung, pancreas, testis, ovary, spinal cord, lymph node, and adrenal gland. MYOC was not expressed in brain, placenta, liver, kidney, spleen, or leukocytes. Sequence analysis predicted that GLC1A encodes an approximately 58-kD, 504-amino acid protein with a leucine zipper domain, 10 putative phosphorylation sites, and 4 potential glycosylation sites.
Nguyen et al. (1998) cloned TIGR from dexamethasone-treated trabecular meshwork cell RNA. TIGR contains 2 possible translation initiation sites. Use of the first initiation site produces a deduced 504-amino acid protein containing an N-terminal signal sequence, clusters of 2 and 7 leucine zippers, a C-terminal olfactomedin (see 605366) homology domain, and motifs for N- and O-glycosylation, glycosaminoglycan addition, and hyaluronic acid binding. A conserved cys433 residue may be involved in protein oligomerization via disulfide bond formation. The second translation initiation site corresponds to met15 in the 504-amino acid protein. Western blot analysis detected a TIGR doublet with an apparent molecular mass of 55 kD. Gel filtration analysis showed that TIGR formed dimers and higher order oligomers of over 200 kD.
By RT-PCR of human ocular tissues, Kong (2001) identified a variant of MYOC with a 338-bp internal deletion, removing the coding sequence for the entire leucine zipper region. Northern blot analysis of iris and ciliary body revealed transcripts of 2.1 and 1.8 kb. Each transcript was variably expressed in ocular tissue, and expression of the shorter form varied between individuals.
Abderrahim et al. (1998) characterized the mouse Tigr gene and compared it with the human gene.
Tomarev et al. (1998) independently cloned mouse Myoc. The deduced 490-amino acid mouse protein is translated from the second initiation codon compared with full-length human MYOC. Mouse Myoc lacks the first translation initiation codon in human MYOC. Mouse and human MYOC share 82% amino acid identity. Northern blot analysis of mouse tissues detected high Myoc expression in skeletal muscle, with weaker expression in heart, brain, and testis. Among ocular tissues, Myoc was expressed in ciliary body, iris, and retina, but not in lens or cornea.
By genomic sequence analysis, Fingert et al. (1998) determined that the GLC1A gene contains 3 exons of 604, 126, and 782 bp.
Independently, Kubota et al. (1998) determined that the MYOC gene contains 3 coding exons. They identified an imperfect palindromic glucacorticoid response element in the 5-prime UTR.
Tomarev et al. (1998) determined that the coding exons of the MYOC gene span 16 kb.
Nguyen et al. (1998) determined that the 5-prime UTR of the MYOC gene contains TATA and CAT boxes and has binding sites for multiple hormone and cell signaling response elements, but it lacks SP1 (189906)-binding sites. The 5-prime UTR contains MIR and Alu repeat sequences, and the 3-prime UTR contains 2 polyadenylation signal sequences.
Kong (2001) stated that the MYOC gene contains 3 polyadenylation signals.
By FISH, Kubota et al. (1997) localized the MYOC gene to chromosome 1q23-q24. Michels-Rautenstrauss et al. (1998) reported fine mapping of the MYOC gene to chromosome 1q24.3-q25.2.
By interspecific backcross analysis, Abderrahim et al. (1998) mapped the mouse Myoc gene to chromosome 1 in a region of syntenic homology to human chromosome 1q23-q24.
Stone et al. (1997) speculated that the TIGR gene product may cause increased intraocular pressure by obstruction of aqueous outflow. Its expression in trabecular meshwork (TM) and ciliary body (structures of the eye involved in the regulation of intraocular pressure) was consistent with this hypothesis. Obstruction of aqueous outflow is, however, not the only mechanism. Stone (1997) stated that because myocilin is expressed in large amounts in various types of muscle, ciliary body, papillary sphincter, skeletal muscle, heart, and other tissues, it is possible that some muscle-related ciliary body mechanism may be involved in the elevated intraocular pressure. Pilocarpine lowers pressure by constricting the ciliary body chronically; one might then expect a ciliary muscle abnormality to be associated with elevated intraocular pressure.
Nguyen et al. (1998) showed that recombinant human TIGR bound trabecular meshwork cells at a saturable site with high affinity and at a nonsaturable site with lower affinity.
Shepard et al. (2001) characterized the glucocorticoid responsiveness of the MYOC gene in cultured human trabecular meshwork cells. They found that application of the synthetic glucocorticoid dexamethasone to cultured TM cells resulted in a delayed (8 to 16 hours) induction of MYOC. The concentration dependence and reversal by the glucocorticoid antagonist, RU486, implicated the glucocorticoid receptor (GCCR; 138040). Treatment of TM cells with the protein synthesis inhibitor cycloheximide abolished the dexamethasone induction, suggesting an indirect effect of GCCR on MYOC expression. The RNA synthesis inhibitor actinomycin D also blocked dexamethasone induction, indicating that the dexamethasone effect was due to increased MYOC transcription. The authors concluded that MYOC is a delayed secondary glucocorticoid-responsive gene. They suggested that further investigation of the transcription factors that mediate the secondary response would shed light on the pathophysiology of steroid-induced ocular hypertension and glaucoma.
Lo et al. (2003) found that induction of TIGR by dexamethasone is specific to the human trabecular meshwork. However, the secretory and glycosylation characteristics of TIGR are ubiquitous. In addition, the authors found that a number of other genes were upregulated in the dexamethasone-induced trabecular meshwork, including a serine protease inhibitor (alpha-1-antichymotrypsin; 107280), a neuroprotective factor (pigment epithelium-derived factor; 172860), an antiangiogenesis factor (cornea-derived transcript-6), and a prostaglandin synthase (prostaglandin D2 synthase; 176803). They postulated that other trabecular meshwork/dexamethasone-specific genes might be good candidates for linkage to glaucoma.
Borras et al. (2002) investigated the effects of high intraocular pressure on MYOC expression, extracellular matrix deposition, and outflow facility in perfused human anterior segment cultures. High IOP appeared to cause a decrease in outflow pathway resistance at 1 to 4 days, and this effect seemed to disappear with further time. In contrast, induction of MYOC appeared to be strongest at 7 days. The authors speculated that this induction pattern might indicate a stress-related, rather than a possible homeostatic, role for the MYOC protein.
Torrado et al. (2002) isolated the gene for optimedin (607567), which shares 40% amino acid similarity and a comparable tissue expression pattern with MYOC. Cotransfection of COS-7 cells with constructs for optimedin and an MYOC mutation resulted in abnormal intracellular retention of both proteins. The authors suggested that the 2 proteins interact with one another, and that optimedin may represent another potential candidate gene for glaucoma.
Aroca-Aguilar et al. (2005) showed that wildtype human MYOC was proteolytically cleaved between arg226 and ile227, resulting in a 35-kD fragment containing the C-terminal olfactomedin-like domain and a 20-kD fragment containing the N-terminal leucine zipper-like domain. The 35-kD fragment was cosecreted with the nonprocessed protein. Western blot analysis showed that human aqueous humor and some ocular tissues contained the processed 35-kD form.
By yeast 2-hybrid screening of a human skeletal muscle cDNA library, Joe et al. (2005) showed that MYOC interacted with the lipid raft protein flotillin-1 (FLOT1; 606998). Protein pull-down and coimmunoprecipitation studies confirmed the interaction. MYOC proteins with glaucoma-associated mutations failed to interact with flotillin-1 in yeast 2-hybrid assays.
Yam et al. (2007) evaluated the effect of chemical chaperones on the trafficking of secretion-incompetent primary open angle glaucoma-associated mutant myocilin. Treatment with 4-phenylbutyrate, but not with glycerol or dimethylsulfoxide, reduced the amount of detergent-insoluble myocilin aggregates, diminished myocilin interaction with calreticulin (109091), and restored the secretion of mutant myocilin. Sodium 4-phenylbutyrate treatment of cells coexpressing mutant and wildtype myocilin relieved endoplasmic reticulum (ER) stress and significantly reduced the rate of apoptosis.
Park et al. (2007) studied the relationship between 2 glaucoma-related genes, OPTN (602432) and MYOC. MYOC overexpression had no effect on OPTN expression, but OPTN overexpression upregulated endogenous MYOC in human trabecular meshwork cells. This induction was also observed in other ocular and nonocular cell types, including rat PC12 pheochromocytoma cells. Endogenous levels of both Optn and Myoc were increased in PC12 cells following NGF (see 162030)-induced neuronal differentiation. Overexpressed OPTN, which localized to the cytoplasm, prolonged the turnover rate of MYOC mRNA, but it had little effect on MYOC promoter activity. Park et al. (2007) concluded that OPTN has a role in stabilizing MYOC mRNA.
Stone et al. (1997) found 1 of 3 mutations in the TIGR gene (601652.0003) in 13 of 330 unrelated glaucoma patients (3.9%) and in 1 of 471 controls (0.2%).
Adam et al. (1997) described 5 novel mutations in the TIGR gene in 8 French families with primary open angle glaucoma (e.g., 601652.0004). They pointed out that all mutations known to that time were concentrated in the evolutionarily conserved C-terminal domain of TIGR, which bears homology to frog olfactomedin, an extracellular matrix glycoprotein of the olfactory epithelium, as well as to rat and human neuronal olfactomedin-related proteins and to F11C3.2, a protein from Caenorhabditis elegans. This conserved domain of TIGR is encoded by a single exon to which mutation screening can be limited. Adam et al. (1997) stated that the TIGR message, which is abundantly transcribed in the trabecular meshwork and also in the ciliary body and sclera, is not expressed in the optic nerve, whose degeneration is the primary lesion of primary open angle glaucoma. They granted that the high expression in the trabecular meshwork and ciliary body accounts for the major elevation of intraocular pressure 'often observed in GLC1A-linked POAG' (primary open-angle glaucoma).
Mansergh et al. (1998) analyzed the TIGR gene in 2 families: a Spanish family segregating autosomal dominant juvenile-onset open angle glaucoma and an Irish family with a later-onset form of autosomal dominant POAG. In the Spanish family, they found a G-to-T transversion in the first base of codon 426 in all affected members of the Spanish family, which resulted in a valine-to-phenylalanine amino acid substitution. In the Irish family, they found a G-to-A transition at the first base of codon 367 that segregated through all but one branch and of the family and resulted in a glycine-to-arginine amino acid substitution. Members of the family that carried the gly367-to-arg change (601652.0008) also shared a common haplotype that was not present in any of the unaffected members of the family or in the branch that did not segregate the mutation.
In screening 2 families with juvenile open angle glaucoma, Michels-Rautenstrauss et al. (1998) found 2 previously reported mutations, pro370 to leu (601652.0004) and gly367 to arg (601652.0008). No mutations were found in screening 100 unselected sporadic cases of primary open angle glaucoma.
Morissette et al. (1998) described a French Canadian family in which both parents had glaucoma due to heterozygosity for a lys423-to-glu (K423E) mutation of the TIGR gene (601652.0010). Among their 10 children, only 2 had glaucoma, and both of these were heterozygous for the K423E mutation. Three others were homozygous for the mutation and did not have glaucoma when last examined at the ages of 50, 49, 47, and 43. The findings were considered consistent with a dominant-negative effect of the K423E mutation when present in single dosage, and may represent the first example of autosomal dominant 'metabolic interference,' as suggested by Johnson (1980).
Wiggs et al. (1998) could demonstrate mutations in the MYOC gene in only 8% of the juvenile-onset POAG pedigrees studied. Their results in the 127 families affected by adult-onset POAG confirmed earlier reports that mutations in the MYOC gene are an uncommon cause of the disorder.
Fingert et al. (1999) screened a total of 1,703 patients with primary open angle glaucoma from 5 different populations representing 3 racial groups. There were 1,284 patients from primarily Caucasian populations in Iowa (727), Australia (390), and Canada (167); 312 African American patients from New York City; and 107 Asian patients from Japan. Overall, 61 different myocilin sequence variations were identified, 21 of which were judged to be probable disease-causing mutations. Fifty-eight of the 1,703 (3.4%) patients carried such mutations. Of the 21 mutations, 16 (76%) were found in only 1 population. The most common mutation observed, gln368 to ter (601652.0003), was found in 27 of the 1,703 (1.6%) glaucoma probands, and at least once in all groups except the Japanese. Studies of genetic markers flanking the myocilin gene suggested that most cases of gln368-to-ter mutations are descended from a common founder. Although the specific mutations found in each of the 5 populations were different, the overall frequency of myocilin mutations was similar (approximately 2 to 4%) in all populations, suggesting that the increased rate of glaucoma in African Americans is not due to a higher prevalence of myocilin mutations.
Wiggs and Vollrath (2001) examined a patient with a complex deletion of the maternal copy of chromosome 1 that included the entire TIGR/MYOC gene. Neither the patient nor her family showed evidence of glaucoma. The authors concluded that haploinsufficiency of the TIGR/MYOC protein is not the cause of early-onset glaucoma associated with mutations in TIGR/MYOC even though missense and nonsense mutations in the gene have been associated with juvenile- and adult-onset primary open-angle glaucoma.
In a retrospective study of 142 POAG patients, Colomb et al. (2001) evaluated the influence on glaucoma phenotype of a novel biallelic polymorphism (-1000C/G) located in the upstream region of the MYOC gene. Allele frequencies were similar among patients and controls. However, the G allele (frequency 17.6%) was associated with increased intraocular pressure (IOP) and a more damaged visual field. Both effects were predominant in females. Moreover, whereas IOP in -1000G noncarriers decreased very markedly to the normal range between diagnosis and inclusion in the study, reflecting successful therapy, it decreased less noticeably in the -1000G-positive male patients and not at all in the -1000G-positive female patients. This polymorphism appears, therefore, to be an indicator of poor IOP control and greater visual field damage in diagnosed POAG patients, potentially due to a lack of response to therapeutic intervention.
Ming and Muenke (2002) stated that mutations in CYP1B1 (601771), at the GLC3A locus, are present in a substantial proportion of patients with congenital glaucoma (231300), a recessive disorder. The gene encodes a member of the P450 superfamily. Both CYP1B1 and the MYOC gene are expressed in the iris, trabecular meshwork, and ciliary body of the eye.
Vincent et al. (2002) described a Canadian family segregating both autosomal dominant primary adult-onset (137760) and juvenile (137750) open angle glaucoma, which were caused by mutations in both the MYOC (601652.0013) and the CYP1B1 (601771.0012) genes. All affected family members carried the MYOC mutation; those who also had the CYP1B1 mutation had juvenile glaucoma, whereas those with only the MYOC mutation had the adult-onset form. The mean age at onset of disease among carriers of the MYOC mutation alone was 51 years, whereas carriers of both MYOC and CYP1B1 mutations had an average age at onset of only 27 years. Individuals carrying only the CYP1B1 mutation were not clinically affected. Thus, in this family, CYP1B1 appeared to be acting as a modifier of MYOC.
Faucher et al. (2002) determined the prevalence of MYOC mutations in 440 French Canadian patients with either glaucoma or ocular hypertension, including 18 affected families and 180 patients. Four families segregated distinct mutations (including gly367 to arg, 601652.0008; gln368 to ter, 601652.0003; and lys423 to glu, 601652.0010), while 14 unrelated glaucoma patients harbored 6 known mutations (including gly367 to arg, 601652.0008; gln368 to ter, 601652.0003; and lys423 to glu, 601652.0010) and 2 novel mutations. The frequencies of these mutations were 3.8% and 22.2% in the unrelated and family studies. The gly367-to-arg and lys423-to-glu variants caused the earliest ages at onset. Evidence for specific founder effects were observed for 5 of the 6 mutations conveyed by at least 2 patients. Recombination probability estimates suggested that the French Canadian population had most probably inherited these 6 mutations from 7 to 10 Quebec settlers.
Polansky et al. (2003) found that a major variant in the promoter region of the MYOC gene, TIGR/MYOC mt.1(+), is associated with more rapid progression of the glaucoma disease state. Time-to-event analyses using the Cox proportional hazards model produced substantial statistical evidence that this variant accelerates worsening for both optic disc and visual field measures of disease progression. The analyses were based on evaluations of 147 patients with primary open-angle glaucoma (POAG) over 35 years of age with an average follow-up of approximately 15 years. Their findings were consistent with those of Colomb et al. (2001). The observation indicated that the mt.1(+) genotypes associated with a marked increased risk of progression, without noticeable association with intraocular pressure.
In 5 of 79 patients suffering from glaucoma, Saura et al. (2005) found sequence variants in the consensus region of the MYOC promoter. They hypothesized that these sequence variants might be involved in the altered association between the consensus region and the corresponding transcription factor.
Pathogenic Effects of MYOC Mutations
To provide a functional assay to distinguish TIGR/MYOC mutations from polymorphisms, Zhou and Vollrath (1999) transfected mammalian cells with TIGR/MYOC constructs containing sequence changes seen in glaucoma patients. The authors found that 100% of 12 putative mutations rendered the expressed protein insoluble in the detergent Triton X-100. They hypothesized that this altered biochemical property may represent the ability of mutant TIGR/MYOC to interfere with secretion, dimerization, or interaction of TIGR/myocilin with other extracellular matrix components of the trabecular meshwork.
Liu and Vollrath (2004) found that disease-causing myocilin mutants were misfolded, highly aggregation-prone, and accumulated in large aggregates in the endoplasmic reticulum of human embryonic kidney cells and differentiated primary human trabecular meshwork (HTM) cells. In HTM cells, P370L (601652.0004) mutant myocilin was not secreted under normal culture conditions, and prolonged expression resulted in abnormal cell morphology and cell killing. Culturing HTM cells at 30 degrees C to facilitate protein folding, promoted secretion of mutant myocilin, normalized cell morphology, and reversed cell lethality. The authors concluded that myocilin-associated glaucoma is an ER storage disease, and suggested a progression of events in which chronic expression of misfolded, nonsecreted myocilin may lead to HTM cell death, trabecular meshwork dysfunction, and, ultimately, a dominant glaucoma phenotype.
Aroca-Aguilar et al. (2005) found that several glaucoma-associated MYOC mutations inhibited endoproteolytic processing of full-length MYOC into the 35- and 20-kD forms, resulting in accumulation of insoluble mutant MYOC aggregates in the ER. Of the 4 mutations examined, P370L, which causes the most severe glaucoma phenotype, elicited the most potent inhibition of MYOC processing.
Shepard et al. (2007) identified peroxisomal targeting signal type 1 receptor (PTSR1), encoded by the PEX5 gene (600414), as a binding partner for misfolded myocilin and demonstrated that glaucoma-causing mutations in human MYOC induce exposure of a cryptic peroxisomal targeting sequence, which must interact with PTS1R to elevate intraocular pressure. Coimmunoprecipation assays in transfected trabecular meshwork cells showed that wildtype myocilin and a nondisease-causing polymorphic variant did not appreciably interact with PTSR1, whereas mutant myocilin interacted with PTSR1 either directly or indirectly, and the more severe myocilin mutants, Y437H (601652.0001) and G364V (601652.0002), showed the strongest levels of interaction. In addition, Y437H and G364V showed the greatest colocalization with peroxisomes, whereas a less severe mutation (Q368X; 601652.0003) showed modest colocalization and wildtype myocilin did not colocalize with peroxisomes. Shepard et al. (2007) concluded that these data support a unique gain-of-function role for MYOC in glaucoma, contingent upon the interaction of mutant myocilin with PTSR1, and they noted that this was the first demonstration of a disease resulting from mutation-induced exposure of a cryptic signaling site that causes mislocalization of mutant protein to peroxisomes.
Reclassified Variants
The R46X variant in the MYOC gene (601652.0011) identified in a patient with juvenile-onset primary open angle glaucoma (137750) by Yoon et al. (1999) has been reclassified as a polymorphism.
Kim et al. (2001) found that Myoc -/- mice were viable and fertile, lacked any discernible phenotype, and showed normal intraocular pressure. They concluded that primary open angle glaucoma is not due to MYOC haploinsufficiency, but may be due to MYOC gain of function.
Gould et al. (2004) found that mice overexpressing Myoc to a level similar to that induced by corticosteroids did not develop elevated intraocular pressure or glaucoma. They hypothesized that disease pathogenesis in primary open-angle glaucoma patients may depend upon expression of abnormal mutant MYOC protein.
Zillig et al. (2005) used the chicken beta-B1-crystallin promoter to overexpress human wildtype and mutated Y437H (601652.0001) myocilin in the lenses of transgenic mice. They found that increasing amounts of myocilin were not secreted in vivo but remained in the rough endoplasmic reticulum, causing severe alterations of cellular structure and function. Lenses expressing mutated Y437H myocilin developed nuclear cataracts, completely lost transparency, and eventually ruptured.
Shepard et al. (2007) demonstrated that mutations in human MYOC induce exposure of a cryptic peroxisomal targeting sequence which must interact with PTS1R to elevate intraocular pressure (IOP). They noted that the lack of a PTS1 signal on mouse myocilin explains why IOP was unchanged in mice overexpressing mouse wildtype myocilin (Gould et al., 2004) and in knock-in mice expressing the mouse ortholog of human Y437H myocilin (Gould et al., 2006). In contrast, expression of human MYOC glaucomatous mutations in mouse eyes did cause elevation of IOP. Shepard et al. (2007) stated that this was the first disease-gene-based animal model of human primary open-angle glaucoma.
In all 22 affected members of the original family in which Sheffield et al. (1993) demonstrated linkage of open angle glaucoma to 1q (137750), Stone et al. (1997) demonstrated a tyr430-to-his mutation (TYR430HIS) in the TIGR gene.
Alward et al. (1998) referred to this mutation as tyr437 to his (Y437H), noting that the numbering used by Stone et al. (1997) resulted from an error in the cDNA sequence originally submitted to GenBank. Alward et al. (1998) found 27 patients in 2 families with primary open angle glaucoma due to the Y437H mutation in the MYOC gene.
In 2 families, including a previously unreported adult-onset open angle glaucoma (137750) family with 15 affected members, Stone et al. (1997) detected a gly357-to-val mutation in the TIGR gene.
In 2 families with 1q-linked glaucoma (137750) included in an initial survey, Stone et al. (1997) found a nonsense mutation (glutamine to stop) in codon 368 of the TIGR gene (Q168X). The mutation would be expected to result in a 136-amino acid truncation of the gene product. Eight additional individuals harboring the gln368-to-ter mutation were identified by screening 4 different populations: glaucoma patients with a family history of the disease; unselected primary open angle glaucoma (POAG) probands seen in a single clinic; the general population; and unrelated volunteers over the age of 40 with normal intraocular pressures and no personal or family history of glaucoma. The gln368-to-ter mutation was found in 3 of 103 consecutive unrelated open angle glaucoma patients seen in a glaucoma clinic; it was found in 1 of 471 control subjects. Based on a cDNA sequence that contained a 7-codon error, this common mutation was originally referred to by Stone et al. (1997) as GLN361TER (Stone, 1999).
Craig et al. (2001) studied the phenotype and age-related penetrance of primary open angle glaucoma in families with Q368X, the most common myocilin mutation in Australia. They found that the Q368X mutation was associated with primary open angle glaucoma with younger onset and higher peak intraocular pressure than nonmutation glaucoma cases. In addition, Q368X mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. They did not observe simple autosomal dominant inheritance patterns for primary open angle glaucoma in the 8 pedigrees studied. They concluded that other factors were involved in expression of the primary open angle glaucoma phenotype in Q368X pedigrees.
To identify a possible founder, Baird et al. (2003) studied 15 'unrelated' POAG families from southeastern Australia who carried the Q368X mutation. In 1 large family, 9 affected and 10 unaffected individuals were identified with the mutation. Closely linked polymorphic microsatellite markers were used to establish a disease haplotype in this family. Additional genotyping of markers in the other 14 families revealed the presence of the same disease haplotype. These findings indicated that the mutation in all 15 families shared a common origin before the European settlement of Australia in the early 1800s.
Baird et al. (2001) found that the use of the Taa1 restriction enzyme offered a relatively simple, rapid, and reproducible technique for detection of the Q368X mutation.
In a French family with 4 members and a second French family with 10 members affected with primary open angle glaucoma (137750), Adam et al. (1997) found a C-to-T transition at nucleotide 1109 of the MYOC gene, causing a pro370-to-leu (P370L) amino acid substitution.
In Japan, Suzuki et al. (1997) performed mutation analysis of the MYOC gene in 52 patients with primary open angle glaucoma and with a family history (50 pedigrees). Two patients in 1 family, a father and daughter, carried a heterozygous C-to-T transition at the second nucleotide in the codon corresponding to the 370 amino acid residue of the TIGR protein, resulting in a P370L amino acid substitution. The father was diagnosed with POAG at age 26 years, the daughter at age 16 years.
In a French family in which 20 individuals had primary open angle glaucoma (137750) with a median age at diagnosis of 33 years (range, 11 to 51 years), Adam et al. (1997) demonstrated a T-to-G transversion of nucleotide 1430 in the MYOC gene, leading to an ile477-to-ser (I477S) amino acid substitution. The family also contained 10 healthy carriers of median age 29 years (range, 6 to 68 years).
In 3 French families containing a total of 52 patients with primary open angle glaucoma (137750), Adam et al. (1997) identified a C-to-A transversion at nucleotide 1440 of the MYOC gene, resulting in an asn480-to-lys (N480K) amino acid substitution in the protein product.
Brezin et al. (1998) linked 6 French families with 71 living patients affected with juvenile-onset and middle-age POAG (age at diagnosis ranging from 10 to 65 years) to the GLC1A locus. All patients carried the N480K mutation in the olfactomedin-homology domain, which is encoded by the third exon of the MYOC gene. The N480K mutation was also identified in 14 unaffected carriers. Although 4 of the families had ancestors identified in northern France, the pedigrees could not be interconnected by genealogic investigation. However, haplotype analysis indicated that all the carriers had inherited the N480K mutation from the same founder. In a screening of a selected set of 67 POAG patients who originated from Northern France and underwent trabeculectomy before the age of 50, Brezin et al. (1998) detected 1 patient with the N480K mutation associated with the same disease phenotype found in the 6 families. This collection of 72 living POAG patients with the same mutation is the largest one having the GLC1A mutation in common and should provide a useful tool for investigating the factors influencing the variable expressivity of the gene.
In a Japanese patient with primary open angle glaucoma (137750), Suzuki et al. (1997) found a gly367-to-arg (G367R) mutation in the MYOC gene. POAG was diagnosed at the age of 45 years. Two aunts and 5 cousins had POAG but blood samples were not available.
Stoilova et al. (1997) found an A-to-G transition in the TIGR gene that caused a gln337-to-arg amino acid substitution. It was found in members of a well-documented Edinburgh family with juvenile-onset open angle glaucoma (137750) through 6 generations (Crombie and Cullen, 1964, Fleck and Cullen, 1986).
In a French Canadian family with primary open angle glaucoma (POAG; 137750), Morissette et al. (1998) identified an A-to-G transition at nucleotide 1332 of the MYOC gene, resulting in a change of glutamic acid for lysine at codon 423 (K423E). Four adult homozygotes were asymptomatic, with POAG affecting only the heterozygotes. Morissette et al. (1998) stated that the K423E mutation appeared to be the first mutation that caused an autosomal dominant heterozygote-specific disease phenotype in humans. This may be an example of the situation hypothesized by Johnson (1980) and termed metabolic interference or negative complementation.
This variant, formerly titled GLAUCOMA 1, OPEN ANGLE, A, AUTOSOMAL RECESSIVE, has been reclassified as a polymorphism based on the report of Scelsi et al. (2021).
In a Korean family, Yoon et al. (1999) found evidence suggesting autosomal recessive inheritance of the juvenile-onset type of primary open angle glaucoma (JOAG; 137750). At age 15 years, the proband showed severe visual-field loss and optic-nerve damage; her parents were 42 and 40 years old. Because the disorder progressed aggressively and medical treatment was not effective, surgery was required in both eyes. Yoon et al. (1999) found that the proband was homozygous for an arg46-to-ter mutation in the MYOC gene. The father, mother, and a sister were heterozygous for the mutation, apparently without detectable symptoms. The proband's brother had 2 normal copies and did not have any symptoms of OAG. Yoon et al. (1999) suggested that the heterozygotes may develop OAG later in life. Another possibility they considered was that, because of consanguinity, the proband was homozygous at other loci that modified the glaucoma phenotype.
Vasconcellos et al. (2000) reported mutation analysis of 25 unrelated Brazilian patients with juvenile open angle glaucoma (137750). Seven of them had a T-to-C transition at nucleotide 1374 of the MYOC gene leading to a cysteine-to-arginine substitution at position 433 (cys433 to arg). This mutation was associated with a common haplotype, suggesting that it was inherited from a common ancestor. The mutation is located in the most conserved region of a highly conserved olfactomedin-like domain.
In a patient with early-onset glaucoma (137750) and a strong family history of autosomal dominant glaucoma with variable age of onset, Vincent et al. (2002) found 2 mutations: gly399 to val (G399V) in the MYOC gene and arg368 to his in the CYP1B1 gene (R368H; 601771.0012). All individuals with glaucoma carried the G399V mutation, which was the result of a 1218G-T transversion. Individuals with both the MYOC and CYP1B1 mutations had early-onset glaucoma with a mean age at onset of 27 years (range, 23 to 38 years). Those with only the MYOC mutation had a mean age at onset of 51 years (range, 48 to 64 years) (137760). The CYP1B1 mutation appeared to function as a modifier of MYOC expression, suggesting that the 2 genes may interact through a common pathway.
In 2 of 100 unrelated Indian patients with glaucoma, Sripriya et al. (2004) identified a heterozygous 144G-A transition in the MYOC gene, resulting in a gln48-to-his (Q48H) substitution. One patient was from northern India and had juvenile-onset open angle glaucoma (JOAG; 137750); 4 other members with JOAG in this family had the same mutation. The second patient was from southern India and had primary open angle glaucoma with no family history of the disorder.
In a patient with primary congenital glaucoma (231300), Kaur et al. (2005) identified 2 mutations: a heterozygous 144G-T transversion in the MYOC gene, resulting in a gln48-to-his (Q48H) substitution, and an arg368-to-his (R368H; 601771.0012) substitution in the CYP1B1 gene. Each of the parents was heterozygous for 1 of the mutations. The heterozygous Q48H mutation was also identified in 3 additional probands with primary congenital glaucoma, without mutations in the CYP1B1 gene. In 1 family, both the proband and his unaffected mother had the mutation. All 4 probands had onset of glaucoma by 4 months of age. Although all 4 families were from India, haplotype analysis indicated independent origins. Neither mutation was identified in 200 control chromosomes. Kaur et al. (2005) suggested a role for the MYOC gene in primary congenital glaucoma via digenic interactions with other genes.
In a Chinese mother and 3 offspring with JOAG or ocular hypertension (137750), Fan et al. (2006) identified heterozygosity for a 734G-A transition in exon 3 of the MYOC gene, resulting in a cys245-to-tyr (C245Y) substitution. The mutation was not found in 200 unrelated Chinese individuals.
In a Caucasian patient with juvenile primary open angle glaucoma (137750) diagnosed at age 26 years, Shimizu et al. (2000) identified a gly252-to-arg (G252R) substitution in the MYOC gene. Booth et al. (2000) found the G252R mutation in affected members of a large Scottish family segregating JOAG. The mean age at diagnosis was approximately 30.8 +/- 7.3 years. Hewitt et al. (2007) identified the same mutation in all affected members with JOAG from a large Australian family. Mean age at diagnosis was 46.3 years (range, 31-60 years). Hewitt et al. (2007) identified a common founding haplotype between MY5 and D2S218 in all Caucasian individuals tested with this mutation. The phenotype in the Australian family was less severe than that in previously described families with this mutation.
In 7 affected members of a US family segregating primary open angle glaucoma (137750), Wirtz et al. (2007) identified heterozygosity for an asp380-to-his (D380H) mutation in the MYOC gene. Another member of the family with this mutation had high intraocular pressure. The disease presented in this family with extremely high IOPs requiring trabeculectomies to control the pressure. The age at diagnosis ranged from 30 to 45 years. Wirtz et al. (2007) concluded that this family had an intermediate phenotype between juvenile- and adult-onset glaucoma. The asp380 residue appeared to be important in myocilin function because substitution at this position with 4 different amino acids (his and 3 previously described substitutions of ala, asn, and gly) all resulted in an intermediate presentation of POAG.
In affected members of an 8-generation family with juvenile-onset primary open-angle glaucoma (137750), originally reported by Stokes (1940), Richards et al. (1998) found a substitution of asparagine for isoleucine at codon 477 near the C-terminal end of the protein. Mean age of diagnosis of glaucoma for the whole family was 26.2 years.
Abderrahim, H., Jaramillo-Babb, V. L., Zhou, Z., Vollrath, D. Characterization of the murine TIGR/myocilin gene. Mammalian Genome 9: 673-675, 1998. [PubMed: 9680392] [Full Text: https://doi.org/10.1007/s003359900844]
Adam, M. F., Belmouden, A., Binisti, P., Brezin, A. P., Valtot, F., Bechetoille, A., Dascotte, J.-C., Copin, B., Gomez, L., Chaventre, A., Bach, J.-F., Garchon, H.-J. Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma. Hum. Molec. Genet. 6: 2091-2097, 1997. [PubMed: 9328473] [Full Text: https://doi.org/10.1093/hmg/6.12.2091]
Alward, W. L. M., Fingert, J. H., Coote, M. A., Johnson, A. T., Lerner, S. F., Junqua, D., Durcan, F. J., McCartney, P. J., Mackey, D. A., Sheffield, V. C., Stone, E. M. Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A). New Eng. J. Med. 338: 1022-1027, 1998. [PubMed: 9535666] [Full Text: https://doi.org/10.1056/NEJM199804093381503]
Aroca-Aguilar, J. D., Sanchez-Sanchez, F., Ghosh, S., Coca-Prados, M., Escribano, J. Myocilin mutations causing glaucoma inhibit the intracellular endoproteolytic cleavage of myocilin between amino acids arg226 and ile227. J. Biol. Chem. 280: 21043-21051, 2005. [PubMed: 15795224] [Full Text: https://doi.org/10.1074/jbc.M501340200]
Baird, P. N., Craig, J. E., Richardson, A. J., Ring, M. A., Sim, P., Stanwix, S., Foote, S. J., Mackey, D. A. Analysis of 15 primary open-angle glaucoma families from Australia identifies a founder effect for the Q368STOP mutation of myocilin. Hum. Genet. 112: 110-116, 2003. [PubMed: 12522550] [Full Text: https://doi.org/10.1007/s00439-002-0865-5]
Baird, P. N., Dickinson, J., Craig, J. E., Mackey, D. A. The Taa1 restriction enzyme provides a simple means to identify the Q368STOP mutation of the myocilin gene in primary open angle glaucoma. Am. J. Ophthal. 131: 510-511, 2001. [PubMed: 11292420] [Full Text: https://doi.org/10.1016/s0002-9394(00)00812-6]
Booth, A. P., Anwar, R., Chen, H., Churchill, A. J., Jay, J., Polansky, J., Nguyen, T., Markham, A. F. Genetic screening in a large family with juvenile onset primary open angle glaucoma. Brit. J. Ophthal. 84: 722-726, 2000. [PubMed: 10873982] [Full Text: https://doi.org/10.1136/bjo.84.7.722]
Borras, T., Rowlette, L. L. S., Tamm, E. R., Gottanka, J., Epstein, D. L. Effects of elevated intraocular pressure on outflow facility and TIGR/MYOC expression in perfused human anterior segments. Invest. Ophthal. Vis. Sci. 43: 33-40, 2002. [PubMed: 11773009]
Brezin, A. P., Adam, M. F., Belmouden, A., Lureau, M.-A., Chaventre, A., Copin, B., Gomez, L., Dupont de Dinechin, S., Berkani, M., Valtot, F., Rouland, J.-F., Dascotte, J.-C., Bach, J.-F., Garchon, H.-J. Founder effect in GLC1A-linked familial open-angle glaucoma in northern France. Am. J. Med. Genet. 76: 438-445, 1998. [PubMed: 9556305]
Colomb, E., Nguyen, T. D., Bechetoille, A., Dascotte, J.-C., Valtot, F., Brezin, A. P., Berkani, M., Copin, B., Gomez, L., Polansky, J. R., Garchon, H.-J. Association of a single nucleotide polymorphism in the TIGR/MYOCILIN gene promoter with the severity of primary open-angle glaucoma. Clin. Genet. 60: 220-225, 2001. [PubMed: 11595024] [Full Text: https://doi.org/10.1034/j.1399-0004.2001.600308.x]
Craig, J. E., Baird, P. N., Healey, D. L., McNaught, A. I., McCartney, P. J., Rait, J. L., Dickinson, J. L., Roe, L., Fingert, J. H., Stone, E. M., Mackey, D. A. Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier. Ophthalmology 108: 1607-1620, 2001. [PubMed: 11535458] [Full Text: https://doi.org/10.1016/s0161-6420(01)00654-6]
Crombie, A. L., Cullen, J. F. Hereditary glaucoma: occurrence in five generations of an Edinburgh family. Brit. J. Ophthal. 48: 143-147, 1964. [PubMed: 14193667] [Full Text: https://doi.org/10.1136/bjo.48.3.143]
Escribano, J., Ortego, J., Coca-Prados, M. Isolation and characterization of cell-specific cDNA clones from a subtractive library of the ocular ciliary body of a single normal human donor: transcription and synthesis of plasma proteins. J. Biochem. 118: 921-931, 1995. [PubMed: 8749308] [Full Text: https://doi.org/10.1093/jb/118.5.921]
Fan, B. J., Leung, D. Y. L., Wang, D. Y., Gobeil, S., Raymond, V., Tam, P. O. S., Lam, D. S. C., Pang, C. P. Novel myocilin mutation in a Chinese family with juvenile-onset open-angle glaucoma. Arch. Ophthal. 124: 102-106, 2006. [PubMed: 16401791] [Full Text: https://doi.org/10.1001/archopht.124.1.102]
Faucher, M., Anctil, J.-L., Rodrigue, M.-A., Duchesne, A., Bergeron, D., Blondeau, P., Cote, G., Dubois, S., Bergeron, J., Arseneault, R., The Quebec Glaucoma Network, Morissette, J., Raymond, V. Founder TIGR/myocilin mutations for glaucoma in the Quebec population. Hum. Molec. Genet. 11: 2077-2090, 2002. [PubMed: 12189160] [Full Text: https://doi.org/10.1093/hmg/11.18.2077]
Fingert, J. H., Heon, E., Liebmann, J. M., Yamamoto, T., Craig, J. E., Rait, J., Kawase, K., Hoh, S.-T., Buys, Y. M., Dickinson, J., Hockey, R. R., Williams-Lyn, D., Trope, G., Kitazawa, Y., Ritch, R., Mackey, D. A., Alward, W. L. M., Sheffield, V. C., Stone, E. M. Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum. Molec. Genet. 8: 899-905, 1999. [PubMed: 10196380] [Full Text: https://doi.org/10.1093/hmg/8.5.899]
Fingert, J. H., Ying, L., Swiderski, R. E., Nystuen, A. M., Arbour, N. C., Alward, W. L. M., Sheffield, V. C., Stone, E. M. Characterization and comparison of the human and mouse GLC1A glaucoma genes. Genome Res. 8: 377-384, 1998. [PubMed: 9548973] [Full Text: https://doi.org/10.1101/gr.8.4.377]
Fleck, B. W., Cullen, J. F. Autosomal dominant juvenile onset glaucoma affecting six generations in an Edinburgh family. (Letter) Brit. J. Ophthal. 70: 715 only, 1986. [PubMed: 3756132] [Full Text: https://doi.org/10.1136/bjo.70.9.715]
Gould, D. B., Miceli-Libby, L., Savinova, O. V., Torrado, M., Tomarev, S. I., Smith, R. S., John, S. W. M. Genetically increasing Myoc expression supports a necessary pathologic role of abnormal proteins in glaucoma. Molec. Cell. Biol. 24: 9019-9025, 2004. [PubMed: 15456875] [Full Text: https://doi.org/10.1128/MCB.24.20.9019-9025.2004]
Gould, D. B., Reedy, M., Wilson, L. A., Smith, R. S., Johnson, R. L., John, S. W. Mutant myocilin nonsecretion in vivo is not sufficient to cause glaucoma. Molec. Cell Biol. 26: 8427-8436, 2006. [PubMed: 16954374] [Full Text: https://doi.org/10.1128/MCB.01127-06]
Hewitt, A. W., Bennett, S. L., Richards, J. E., Dimasi, D. P., Booth, A. P., Inglehearn, C., Anwar, R., Yamamoto, T., Fingert, J. H., Heon, E., Craig, J. E., Mackey, D. A. Myocilin gly252-to-arg mutation and glaucoma of intermediate severity in Caucasian individuals. Arch. Ophthal. 125: 98-104, 2007. [PubMed: 17210859] [Full Text: https://doi.org/10.1001/archopht.125.1.98]
Joe, M. K., Sohn, S., Choi, Y. R., Park, H., Kee, C. Identification of flotillin-1 as a protein interacting with myocilin: implications for the pathogenesis of primary open-angle glaucoma. Biochem. Biophys. Res. Commun. 336: 1201-1206, 2005. [PubMed: 16198165] [Full Text: https://doi.org/10.1016/j.bbrc.2005.09.006]
Johnson, W. G. Metabolic interference and the +/- heterozygote: a hypothetical form of simple inheritance which is neither dominant nor recessive. Am. J. Hum. Genet. 32: 374-386, 1980. [PubMed: 6770678]
Kaur, K., Reddy, A. B. M., Mukhopadhyay, A., Mandal, A. K., Hasnain, S. E., Ray, K., Thomas, R., Balasubramanian, D., Chakrabarti, S. Myocilin gene implicated in primary congenital glaucoma. Clin. Genet. 67: 335-340, 2005. [PubMed: 15733270] [Full Text: https://doi.org/10.1111/j.1399-0004.2005.00411.x]
Kim, B. S., Savinova, O. V., Reedy, M. V., Martin, J., Lun, Y., Gan, L., Smith, R. S., Tomarev, S. I., John, S. W. M., Johnson, R. L. Targeted disruption of the myocilin gene (Myoc) suggests that human glaucoma-causing mutations are gain of function. Molec. Cell. Biol. 21: 7707-7713, 2001. [PubMed: 11604506] [Full Text: https://doi.org/10.1128/MCB.21.22.7707-7713.2001]
Kong, T. H. Post-transcriptional modification of the gene genetically linked to juvenile open-angle glaucoma: novel transcripts in human ocular tissues. Gene 280: 115-122, 2001. [PubMed: 11738824] [Full Text: https://doi.org/10.1016/s0378-1119(01)00777-6]
Kubota, R., Kudoh, J., Mashima, Y., Asakawa, S., Minoshima, S., Hejtmancik, J. F., Oguchi, Y., Shimizu, N. Genomic organization of the human myocilin gene (MYOC) responsible for primary open angle glaucoma (GLC1A). Biochem. Biophys. Res. Commun. 242: 396-400, 1998. [PubMed: 9446806] [Full Text: https://doi.org/10.1006/bbrc.1997.7972]
Kubota, R., Noda, S., Wang, Y., Minoshima, S., Asakawa, S., Kudoh, J., Mashima, Y., Oguchi, Y., Shimizu, N. A novel myosin-like protein (myocilin) expressed in the connecting cilium of the photoreceptor: molecular cloning, tissue expression, and chromosomal mapping. Genomics 41: 360-369, 1997. [PubMed: 9169133] [Full Text: https://doi.org/10.1006/geno.1997.4682]
Liu, Y., Vollrath, D. Reversal of mutant myocilin non-secretion and cell killing: implications for glaucoma. Hum. Molec. Genet. 13: 1193-1204, 2004. [PubMed: 15069026] [Full Text: https://doi.org/10.1093/hmg/ddh128]
Lo, W. R., Rowlette, L. L., Caballero, M., Yang, P., Hernandez, M. R., Borras, T. Tissue differential microarray analysis of dexamethasone induction reveals potential mechanisms of steroid glaucoma. Invest. Ophthal. Vis. Sci. 44: 473-485, 2003. [PubMed: 12556371] [Full Text: https://doi.org/10.1167/iovs.02-0444]
Mansergh, F. C., Kenna, P. F., Ayuso, C., Kiang, A.-S., Humphries, P., Farrar, G. J. Novel mutations in the TIGR gene in early and late onset open angle glaucoma. Hum. Mutat. 11: 244-251, 1998. [PubMed: 9521427] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)11:3<244::AID-HUMU10>3.0.CO;2-Z]
Michels-Rautenstrauss, K. G., Mardin, C. Y., Budde, W. M., Liehr, T., Polansky, J., Nguyen, T., Timmerman, V., Van Broeckhoven, C., Naumann, G. O. H., Pfeiffer, R. A., Rautenstrauss, B. W. Juvenile open angle glaucoma: fine mapping of the TIGR gene to 1q24.3-q25.2 and mutation analysis. Hum. Genet. 102: 103-106, 1998. [PubMed: 9490287] [Full Text: https://doi.org/10.1007/s004390050661]
Ming, J. E., Muenke, M. Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am. J. Hum. Genet. 71: 1017-1032, 2002. [PubMed: 12395298] [Full Text: https://doi.org/10.1086/344412]
Morissette, J., Clepet, C., Moisan, S., Dubois, S., Winstall, E., Vermeeren, D., Nguyen, T. D., Polansky, J. R., Cote, G., Anctil, J.-L., Amyot, M., Plante, M., Falardeau, P., Raymond, V. Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma. (Letter) Nature Genet. 19: 319-321, 1998. [PubMed: 9697688] [Full Text: https://doi.org/10.1038/1203]
Nguyen, T. D., Chen, P., Huang, W. D., Chen, H., Johnson, D., Polansky, J. R. Gene structure and properties of TIGR, an olfactomedin-related glycoprotein cloned from glucocorticoid-induced trabecular meshwork cells. J. Biol. Chem. 273: 6341-6350, 1998. [PubMed: 9497363] [Full Text: https://doi.org/10.1074/jbc.273.11.6341]
Park, B.-C., Tibudan, M., Samaraweera, M., Shen, X., Yue, B. Y. J. T. Interaction between two glaucoma genes, optineurin and myocilin. Genes Cells 12: 969-979, 2007. [PubMed: 17663725] [Full Text: https://doi.org/10.1111/j.1365-2443.2007.01102.x]
Polansky, J. R., Juster, R. P., Spaeth, G. L. Association of the myocilin mt.1 promoter variant with the worsening of glaucomatous disease over time. Clin. Genet. 64: 18-27, 2003. [PubMed: 12791035] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00099.x]
Richards, J. E., Ritch, R., Lichter, P. R., Rozsa, F. W., Stringham, H. M., Caronia, R. M., Johnson, D., Abundo, G. P., Willcockson, J., Downs, C. A., Thmopson, D. A., Musarella, M. A., Gupta, N., Othman, M. I., Torrez, D. M., Herman, S. B., Wong, D. J., Higashi, M., Boehnke, M. Novel trabecular meshwork inducible glucocorticoid response mutation in an eight-generation juvenile-onset primary open-angle glaucoma pedigree. Ophthalmology 105: 1698-1707, 1998. [PubMed: 9754180] [Full Text: https://doi.org/10.1016/S0161-6420(98)99041-8]
Saura, M., Cabana, M., Ayuso, C., Valverde, D. Mutations including the promoter region of myocilin/TIGR gene. Europ. J. Hum. Genet. 13: 384-387, 2005. [PubMed: 15483649] [Full Text: https://doi.org/10.1038/sj.ejhg.5201299]
Scelsi, H. F., Barlow, B. M., Saccuzzo, E. G., Lieberman, R. L. Common and rare myocilin variants: predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data. Hum. Mutat. 42: 903-946, 2021. [PubMed: 34082484] [Full Text: https://doi.org/10.1002/humu.24238]
Sheffield, V. C., Stone, E. M., Alward, W. L. M., Drack, A. V., Johnson, A. T., Streb, L. M., Nichols, B. E. Genetic linkage of familial open angle glaucoma to chromosome 1q21-q31. Nature Genet. 4: 47-50, 1993. [PubMed: 8513321] [Full Text: https://doi.org/10.1038/ng0593-47]
Shepard, A. R., Jacobson, N., Fingert, J. H., Stone, E. M., Sheffield, V. C., Clark, A. F. Delayed secondary glucocorticoid responsiveness of MYOC in human trabecular meshwork cells. Invest. Ophthal. Vis. Sci. 42: 3173-3181, 2001. [PubMed: 11726619]
Shepard, A. R., Jacobson, N., Millar, J. C., Pang, I.-H., Steely, H. T., Searby, C. C., Sheffield, V. C., Stone, E. M., Clark, A. F. Glaucoma-causing myocilin mutants require the peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure. Hum. Molec. Genet. 16: 609-617, 2007. [PubMed: 17317787] [Full Text: https://doi.org/10.1093/hmg/ddm001]
Shimizu, S., Lichter, P. R., Johnson, A. T., Zhou, Z., Higashi, M., Gottfredsdottir, M., Othman, M., Moroi, S. E., Rozsa, F. W., Schertzer, R. M., Clarke, M. S., Schwartz, A. L., Downs, C. A., Vollrath, D., Richards, J. E. Age-dependent prevalence of mutations at the GLC1A locus in primary open-angle glaucoma. Am. J. Ophthal. 130: 165-177, 2000. [PubMed: 11004290] [Full Text: https://doi.org/10.1016/s0002-9394(00)00536-5]
Sripriya, S., Uthra, S., Sangeetha, R., George, R. J., Hemamalini, A., Paul, P. G., Amali, J., Vijaya, L., Kumaramanickavel, G. Low frequency of myocilin mutations in Indian primary open-angle glaucoma patients. Clin. Genet. 65: 333-337, 2004. [PubMed: 15025728] [Full Text: https://doi.org/10.1111/j.1399-0004.2004.00232.x]
Stoilova, D., Child, A., Brice, G., Crick, R. P., Fleck, B. W., Sarfarazi, M. Identification of a new 'TIGR' mutation in a family with juvenile-onset primary open angle glaucoma. Ophthalmic Genet. 18: 109-118, 1997. [PubMed: 9361308] [Full Text: https://doi.org/10.3109/13816819709057124]
Stokes, W. H. Hereditary primary glaucoma. Arch. Ophthal. 24: 885-909, 1940.
Stone, E. M., Fingert, J. H., Alward, W. L. M., Nguyen, T. D., Polansky, J. R., Sunden, S. L. F., Nishimura, D., Clark, A. F., Nystuen, A., Nichols, B. E., Mackey, D. A., Ritch, R., Kalenak, J. W., Craven, E. R., Sheffield, V. C. Identification of a gene that causes primary open angle glaucoma. Science 275: 668-670, 1997. [PubMed: 9005853] [Full Text: https://doi.org/10.1126/science.275.5300.668]
Stone, E. M. Personal Communication. Iowa City, Iowa 11/20/1997.
Stone, E. M. Personal Communication. Iowa City, Iowa 6/16/1999.
Suzuki, Y., Shirato, S., Taniguchi, F., Ohara, K., Nishimaki, K., Ohta, S. Mutations in the TIGR gene in familial primary open-angle glaucoma in Japan. (Letter) Am. J. Hum. Genet. 61: 1202-1204, 1997. [PubMed: 9345106] [Full Text: https://doi.org/10.1086/301612]
Tomarev, S. I., Tamm, E. R., Chang, B. Characterization of the mouse Myoc/Tigr gene. Biochem. Biophys. Res. Commun. 245: 887-893, 1998. [PubMed: 9588210] [Full Text: https://doi.org/10.1006/bbrc.1998.8541]
Torrado, M., Trivedi, R., Zinovieva, R., Karavanova, I., Tomarev, S. I. Optimedin: a novel olfactomedin-related protein that interacts with myocilin. Hum. Molec. Genet. 11: 1291-1301, 2002. [PubMed: 12019210] [Full Text: https://doi.org/10.1093/hmg/11.11.1291]
Vasconcellos, J. P. C., Melo, M. B., Costa, V. P., Tsukumo, D. M. L., Basseres, D. S., Bordin, S., Saad, S. T. O., Costa, F. F. Novel mutation in the MYOC gene in primary open angle glaucoma patients. J. Med. Genet. 37: 301-303, 2000. [PubMed: 10819638] [Full Text: https://doi.org/10.1136/jmg.37.4.301]
Vincent, A. L., Billingsley, G., Buys, Y., Levin, A. V., Priston, M., Trope, G., Williams-Lyn, D., Heon, E. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am. J. Hum. Genet. 70: 448-460, 2002. [PubMed: 11774072] [Full Text: https://doi.org/10.1086/338709]
Wiggs, J. L., Allingham, R. R., Vollrath, D., Jones, K. H., De La Paz, M., Kern, J., Patterson, K., Babb, V. L., Del Bono, E. A., Broomer, B. W., Pericak-Vance, M. A., Haines, J. L. Prevalence of mutations in TIGR/myocilin in patients with adult and juvenile primary open-angle glaucoma. (Letter) Am. J. Hum. Genet. 63: 1549-1552, 1998. [PubMed: 9792882] [Full Text: https://doi.org/10.1086/302098]
Wiggs, J. L., Vollrath, D. Molecular and clinical evaluation of a patient hemizygous for TIGR/MYOC. Arch. Ophthal. 119: 1674-1678, 2001. [PubMed: 11709019] [Full Text: https://doi.org/10.1001/archopht.119.11.1674]
Wirtz, M. K., Samples, J. R., Choi, D., Gaudette, N. D. Clinical features associated with an asp380-to-his myocilin mutation in a US family with primary open-angle glaucoma. Am. J. Ophthal. 144: 75-80, 2007. [PubMed: 17499207] [Full Text: https://doi.org/10.1016/j.ajo.2007.03.037]
Yam, G. H.-F., Gaplovska-Kysela, K., Zuber, C., Roth, J. Sodium 4-phenylbutyrate acts as a chemical chaperone on misfolded myocilin to rescue cells from endoplasmic reticulum stress and apoptosis. Invest. Ophthal. Vis. Sci. 48: 1683-1690, 2007. [PubMed: 17389500] [Full Text: https://doi.org/10.1167/iovs.06-0943]
Yoon, S.-J. K., Kim, H.-S., Moon, J.-I., Lim, J. M., Joo, C.-K. Mutations of the TIGR/MYOC gene in primary open-angle glaucoma in Korea. (Letter) Am. J. Hum. Genet. 64: 1775-1778, 1999. [PubMed: 10330365] [Full Text: https://doi.org/10.1086/302407]
Zhou, Z., Vollrath, D. A cellular assay distinguishes normal and mutant TIGR/myocilin protein. Hum. Molec. Genet. 8: 2221-2228, 1999. [PubMed: 10545602] [Full Text: https://doi.org/10.1093/hmg/8.12.2221]
Zillig, M., Wurm, A., Grehn, F. J., Russell, P., Tamm, E. R. Overexpression and properties of wild-type and tyr437his mutated myocilin in the eyes of transgenic mice. Invest. Ophthal. Vis. Sci. 46: 223-234, 2005. [PubMed: 15623777] [Full Text: https://doi.org/10.1167/iovs.04-0988]