Molecular analysis of myocilin and optineurin genes in Korean primary glaucoma patients
- Authors:
- Published online on: July 27, 2016 https://doi.org/10.3892/mmr.2016.5557
- Pages: 2439-2448
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Copyright: © Park et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Glaucoma is a complex, heterogeneous ocular disorder with multifactorial etiology characterized by structural damage to the optic nerve, visual field defects (1) and commonly relatively high intraocular pressure (IOP) (2). It is a leading cause of irreversible blindness worldwide (3,4) with ~20% of cases occurring secondary to other ocular or systemic diseases (1). Based on anatomical changes in the anterior chamber angle, primary glaucoma may be classified as primary angle closure glaucoma (PACG) or primary open-angle glaucoma (POAG), which may be further subdivided into juvenile open-angle glaucoma (JOAG) and adult onset POAG (1,5). Glaucoma is a treatable disease if detected early; however, many patients are diagnosed during routine examinations or only following advanced field loss, as glaucoma is typically asymptomatic in the early stages. Therefore, the development of an accurate test for the detection of presymptomatic carriers at risk is important for the management of glaucoma.
A family history of glaucoma is a well-known risk factor. Therefore genetic background is considered important for the development of the disease (6–8). The following genes have been reported to be associated with primary glaucoma: myocilin (MYOC) (9), optineurin (OPTN) (10), WD repeat domain 36 (11,12), neurotrophin 4 (13), optic atrophy 1 (14,15), cytochrome P450 family 1 subfamily B member 1 (16) and latent transforming growth factor β (17). To date, mutations in these genes account for only ~5% of patients with POAG (18), and the influence of mutations in these genes on patients with PACG remain controversial (19). The MYOC gene, located at the GLC1A locus on chromosome 1q24.3–q25.2, has been confirmed to be associated with JOAG and POAG, although mutation frequencies vary between ethnic groups (20). The altered protein product secreted into the extracellular matrix of the trabecular meshwork causes a severe form of autosomal dominant JOAG associated with very high IOP (9). Although up to 20% of JOAG may be associated with MYOC mutations, mutations in this gene have been identified in only 3 to 5% of POAG patients (7,21). Mutations in the OPTN gene, located at the GLC1E locus on chromosome 10p14–p15, result in normal tension glaucoma (NTG) without elevated IOP, a subtype of POAG (10).
To investigate the underlying genetic influences of primary glaucoma, molecular analysis of the MYOC and OPTN genes was performed in 112 Korean sporadic primary glaucoma patients, with the results compared to healthy controls.
Patients and methods
Patients
All 112 patients with primary glaucoma from unrelated Korean patients were recruited from the ophthalmology clinic of Seoul St. Mary's Hospital (Seoul, Korea), including 17 POAG, 19 JOAG and 76 NTG patients. Healthy, unrelated Korean individuals (n=100) served as the non-selected population control. All patients and healthy controls in the study provided written informed consent for clinical and molecular analyses, and the study protocol was approved by the institutional review board of The Catholic University of Korea (Seoul, Korea). The diagnostic criteria of POAG were an IOP >21 mmHg by Goldmann applanation tonometry (GAT), presence of glaucomatous visual field defect or glaucomatous optic neuropathy and open angle. Where onset occurred at 5–35 years of age, patients were diagnosed with JOAG (22). The diagnostic criteria of NTG were an IOP <22 mmHg by GAT, presence of glaucomatous visual field defect or glaucomatous optic neuropathy and open angle. Patients with secondary glaucoma resulting from trauma, uveitis, neovascular or steroid-induced glaucoma (SIG), and other associated ocular or systemic anomalies were excluded from the present study. Healthy controls had IOP <20 mmHg, a normal optic disc appearance without suspicious glaucomatous changes, and no family or personal history of primary glaucoma.
Molecular analysis of the MYOC and OPTN genes
Genomic DNA samples were extracted from the peripheral blood using the QIAamp DNA Mini kit (Qiagen GmbH, Hilden, Germany). Entire coding exons and flanking intronic sequences of MYOC and OPTN were amplified by polymerase chain reaction (PCR) using different combinations of forward and reverse primers designed by the authors (Table I). Briefly, the PCR reaction had a total volume of 15 μl, comprising 10 μl Taq PCR Master Mix kit (Qiagen GmbH) containing Taq DNA Polymerase, 2X Qiagen PCR Buffer, 3 mM MgCl2, and 400 μM of each deoxynucleotide, 2 μl 5X Q-Solution, 1 μl primer mix, and 2 μl genomic DNA (50 ng/μl). The PCR was amplified with a C1000 thermal cycler (Bio-Rad Laboratories, Inc., Hercules, CA, USA) under the following conditions: 5 min at 95°C, followed by 35 cycles of 95°C for 30 sec, 60°C for 30 sec and 72°C for 1 min, and a final step of 72°C for 5 min. Direct sequencing of PCR products was performed with the BigDye Terminator version 3.1 Cycle Sequencing kit (Applied Biosystems; Thermo Fisher Scientific, Inc., Waltham, MA, USA) and the products were resolved on ABI 3130XL Genetic Analyzer (Applied Biosystems; Thermo Fisher Scientific, Inc.). The resulting sequence electropherogram was analyzed using Sequencher software version 4.9 (Gene Codes Corporation, Ann Arbor, MI, USA). Sequence data were analyzed using reference sequences in GenBank (www.ncbi.nlm.nih.gov/genbank/). The RefSeq IDs NM_000261.1 for MYOC and NM_001008211.1 for OPTN were used for cDNA nucleotide numbering. All identified variants were confirmed by bidirectional resequencing.
Genetic variations were contrasted with Human Gene Mutation Database Public (www.hgmd.cf.ac.uk), 1,000 genomes project browser (browser.1000genomes.org) and the single nucleotide polymorphism database (www.ncbi.nlm.nih.gov/projects/SNP). Mutation pathogenicity was predicted through PolyPhen-2 version 2.2.2 (genetics.bwh.harvard.edu/pph2) (23) and PROVEAN version 1.1 (provean.jcvi.org) (24), the first predictor that includes in-frame insertions/deletions. To assess the extent of conservation of a novel variant of MYOC and OPTN hypothesized to be associated with disease, the amino acid sequence was aligned with protein sequences of various mammalian species using Clustal Omega software (www.ebi.ac.uk/Tools/msa/clustalo/) (25).
Haplotype analysis of the MYOC and OPTN genes
Haplotypes of each gene were constructed based on the genotype data of the MYOC and OPTN variants obtained from the 112 patients and 100 healthy controls. Haplotype reconstruction and frequency estimation were performed using haplo.em, an implementation of an Expectation-Maximization algorithm included in the R package haplo.stats, which computes maximum likelihood estimates of haplotype probabilities from unphased genotypes measured on unrelated individuals (R Foundation for Statistical Computing, Vienna, Austria; www.r-project.org). The frequencies of variant status between the patients and healthy controls were compared by χ2 or Fisher's exact test using MedCalc software version 12.7.2 (MedCalc Software bvba, Ostend, Belgium). P<0.05 was considered to indicate a statistically significant difference.
Results
A total of three MYOC and four OPTN variants potentially associated with primary glaucoma were identified in 4 and 18 patients, respectively (Table II).
Molecular analysis of MYOC
Missense variants of MYOC were identified in two JOAG patients (P107 and P044) with a family history of primary glaucoma (pedigree analysis of P107 is presented in Fig. 1A). One was determined to be a novel missense variant, p.Leu255Pro, (P107; Fig. 1B) which was predicted to be 'probably damaging' with a score of 0.970 by PolyPhen-2 and was expected to be 'deleterious' with a score of −2.887 by PROVEAN. The position of changed amino acid was conserved among other mammalian species (Fig. 1C). No healthy control exhibited the same variant. The other variant identified, p.Thr353Ile, has previously been reported in Korean POAG (26). In addition, combined heterozygous variants p.[Thr123=;Ile288=] were identified in 2 of 112 (2%) patients but not in healthy controls; p.Thr123=[rs75682756; minor allele frequency (MAF)/minor allele count (MAC) by 1000 Genomes=0.0014/7], p.Ile288=(rs181923440; MAF/MAC=0.0010/5). The MYOC promoter variant c.-83G>A (rs2075648; MAF/MAC=0.1380/691) was detected only as a heterozygous state in a JOAG patient with p.Leu255Pro and in five NTG patients, but not in the 100 healthy controls (Table III). Clinical manifestations of primary glaucoma with MYOC are summarized in Table IV.
Molecular analysis of OPTN
OPTN variants were identified in 18 patients with primary glaucoma. One patient (P086) harbored a novel variant, p.Arg271Cys as a heterozygous state (Fig. 2A). This variant was predicted to be 'benign' with a score of 0.047 by PolyPhen-2 and was expected to be 'neutral' with a score of −1.726 by PROVEAN. This protein sequence was not highly conserved across the compared species, and the sequence in chicken had a cysteine in that position (Fig. 2B). One novel synonymous variant, p.Leu568=; c.1704A>G was identified in heterozygosity. These two variants were not detected in healthy controls.
In addition, three reported variants associated with primary glaucoma (10,27), including p.Thr34=(rs2234968), p.Met98Lys (rs11258194) and p.Arg545Gln (rs75654767) were identified (Table V). The p.Thr34=, p.Met98Lys and p.Arg545Gln mutations were detected in 40 (36%), 19 (17%), and 10 (9%) patients with primary glaucoma as well as in 25 (25%), 18 (18%), and 2 (2%) healthy controls, respectively, in a heterozygous or homozygous state. The odds ratio (OR) was not statistically different for p.Thr34= and p.Met98Lys by the χ2 test (P=0.061 and P=0.492, respectively); however, it was significant for p.Arg545Gln by Fisher's exact test [OR=4.804, 95% confidence interval (CI)=1.026–22.482; relative risk=1.634, 95% CI=1.226–2.178; P=0.037]. The presence of one of homozygous p.[Thr34=;Thr34=] (4/112; 4%), homozygous p.[Met98Lys;Met98Lys] (4/112; 4%) or combined heterozygous p.[Thr34=;Arg545Gln] (9/112, 8%) was significantly associated with the development of primary glaucoma (OR=8.768, 95% CI=1.972–38.988; relative risk=1.818, 95% CI=1.473–2.244; P=0.001). Clinical manifestations of primary glaucoma with OPTN variants are summarized in Table VI.
Discussion
The present study reports a molecular analysis of MYOC and OPTN genes in 112 patients with primary glaucoma. One novel MYOC variant, p.Leu255Pro, in patient P107 with a family history of glaucoma was predicted to have a deleterious effect by in silico analysis. This variant is a possible pathogenic mutation associated with the development of primary glaucoma. The second MYOC variant, p.Thr353Ile, in patient P044 with a family history of glaucoma has been previously reported as a pathologic mutation for POAG and resides in the olfactomedin-homology region. It may be involved in the regulation of IOP in trabecular-meshwork cells (26). The presence of heterozygous p.Thr123= and p.Ile288= was observed only in patients with JOAG and NTG. Thus, p.[Thr123=;Ile288=] may be a part of the haplotype variant associated with the development of primary glaucoma. Further extended haplotype analysis is required to confirm the association of MYOC haplotype variants. The variant in the 5′-UTR region, c.-83G>A, which was initially reported in Western countries (20,28), and subsequently observed in Hong Kong (29) and the Philippines (30), was identified only in primary glaucoma patients in the present study. The association of c.-83G>A and the risk of primary glaucoma remains controversial due to the variable frequency and the non-significant differences between POAG patients and controls observed in previous studies (28,31,32).
Genetic analysis of the OPTN coding region was performed in all patients with primary glaucoma. Notably, OPTN variants (10/76, 13.2%) were identified more frequently than MYOC variants (1/76, 1.3%) in NTG patients, which is consistent with previous studies (33,34). The three OPTN variants p.Thr34=, p.Leu40= and p.Glu89His were identified in 7 of 53 Korean NTG patients (33), whereas only one patient with the MYOC variant p.Leu411= was reported from 32 separate Korean NTG patients (34). Supporting the findings of the present study, Rezaie et al (10) suggested that mutations in OPTN may be responsible for 16.7% of the hereditary forms of NTG and that there is an additional risk factor of 13.6% in familial and sporadic cases. Furthermore, Sohn et al (35) demonstrated that the MYOC gene itself was not associated with OAG, including POAG, NTG and SIG. Their results do not support the hypothesis that MYOC induction may be linked to IOP variation and that promoter variants of MYOC may be a risk factor for the pathogenesis of OAG.
A novel OPTN variant, p.Arg271Cys, of unknown significance was identified in patient P086 with NTG (1/112, 1%). This variant led to replacement of arginine with cysteine at codon 271, however, the protein sequence was not highly conserved across species. Although this variant was predicted to be 'benign' or 'neutral', it is potentially pathogenic as it was not present in the healthy controls. Segregation analysis and/or functional studies are required to verify the pathogenicity or neutrality of this variant.
Of the OPTN haplotype variants, p.Thr34=, p.Met98Lys and p.Arg545Gln have been previously reported as possible glaucoma-causing mutations (10,27). However, they were present at reduced frequencies as a heterozygous state in healthy controls.
The p.Thr34= variant was detected in 40 of 112 (36%) patients with primary glaucoma and in 25 of 100 (25%) healthy controls in a heterozygous or homozygous state in the present study. Homozygosity for p.Thr34= was observed only in four patients with primary glaucoma (P059, P060, P098 and P109). Funayama et al (27) reported that p.Thr34= was weakly associated with patients with OAG with elevated IOP, whereas p.Met98Lys was weakly associated with patients with OAG with normal IOP. In interaction analysis between olfactomedin 2 (OLFM2) and OPTN genes in patients with OAG, the c.317G>A; p.Arg106Gln of OLFM2 and c.412G>A; p.Thr34= of OPTN and the c.1281C>T; p.Arg427Arg of OLFM2 and c.412G>A; p.Thr34= of OPTN were significantly associated with OAG with elevated IOP. These results suggest that these variants in OLFM2 and OPTN contribute interactively to OAG, indicating a polygenic etiology with different properties for p.Thr34= and p.Met98Lys variants of OPTN.
The p.Met98Lys variant was identified in 19 of 112 (17%) patients with primary glaucoma as well as in 18 of 100 (18%) healthy controls as a heterozygous or homozygous state in the present study. Alward et al (36) and Fuse et al (37) reported a significant association between p.Met98Lys and glaucoma in Japanese patients. By contrast, Toda et al (38) identified similar frequencies of p.Met98Lys in Japanese glaucoma patients and controls. Notably, p.Met98Lys has been demonstrated to be a polymorphic variant in German, French and Moroccan patients (39,40). By contrast to previous studies (10,41,42), the frequency difference in the present study (4 vs. 0%) between the patients with homozygous p.Met98Lys (P014, P029, P054 and P058) and healthy controls was highly significant. p.Met98Lys is located within a putative basic leucine zipper domain and is conserved in macaques; it may represent a risk associated factor or a dominant susceptibility allele (10). Wild-type OPTN protein, operating through the tumor necrosis factor α pathway, may have a neuroprotective role in the eye and optic nerve; however when defective, it produces visual loss and optic neuropathy as typically observed in normal and high-pressure glaucoma (10).
The p.Arg545Gln variant was reported previously in POAG families with normal IOP (10). Although the p.Arg545Gln variant is not part of a known protein domain, it is situated near the only zinc finger motif within OPTN. This motif is typically observed in transcription factors. p.Arg545Gln has been detected in similar frequencies in Japanese glaucoma patients and healthy controls (38). Alward et al (36) suggested that p.Arg545Gln may not be a disease-causing polymorphism. Results concerning the effect of OPTN on glaucoma have been equivocal (10,32,43,44); however, the expression of MYOC may be regulated by OPTN (45). Notably, results from the present study support the view that the three variants of OPTN may be involved in the development of primary glaucoma, as the OR for the haplotype harboring homozygous p.Thr34= or p.Met98Lys as well as a simultaneous presence of heterozygous p.Thr34= and p.Arg545Gln was statistically significant by the Fisher's exact test (OR=8.768, 95%, CI=1.972–38.988; relative risk=1.818, 95% CI=1.473–2.244; P=0.001).
In conclusion, haplotype variants identified in the present study may be regarded as potential contributing factors for primary glaucoma in Korea. The present study provides insight into the genetic or haplotype variants contributing to primary glaucoma. Further studies, including on additional genes, are required to elucidate the underlying pathogenic mechanism using larger cohorts to provide additional statistical power.
Acknowledgments
The authors would like to thank The Catholic Genetic Laboratory Center (Seoul, Korea) for its assistance in conducting the present study and compiling this report. The present study was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea (Daejeon, Korea; grant no. NRF-2013R1A1A2006801) funded by the Ministry of Education (Sejong, Korea).
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