Open Access

Research progress on human genes involved in the pathogenesis of glaucoma (Review)

  • Authors:
    • Hong‑Wei Wang
    • Peng Sun
    • Yao Chen
    • Li‑Ping Jiang
    • Hui‑Ping Wu
    • Wen Zhang
    • Feng Gao
  • View Affiliations

  • Published online on: May 23, 2018     https://doi.org/10.3892/mmr.2018.9071
  • Pages: 656-674
  • Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Glaucoma is the leading cause of irreversible blindness globally. It is known that the incidence of glaucoma is closely associated with inheritance. A large number of studies have suggested that genetic factors are involved in the occurrence and development of glaucoma, and even affect the drug sensitivity and prognosis of glaucoma. In the present review, 22 loci of glaucoma are presented, including the relevant genes (myocilin, interleukin 20 receptor subunit B, optineurin, ankyrin repeat‑ and SOCS box‑containing protein 10, WD repeat‑containing protein 36, EGF‑containing fibulin‑like extracellular matrix protein 1, neurotrophin 4, TANK‑binding kinase 1, cytochrome P450 subfamily I polypeptide 1, latent transforming growth factor β binding protein 2 and TEK tyrosine kinase endothelial) and 74 other genes (including toll‑like receptor 4, sine oculis homeobox Drosophila homolog of 1, doublecortin‑like kinase 1, RE repeats‑encoding gene, retinitis pigmentosa GTPase regulator‑interacting protein, lysyl oxidase‑like protein 1, heat‑shock 70‑kDa protein 1A, baculoviral IAP repeat‑containing protein 6, 5,10‑methylenetetrahydrofolate reductase and nitric oxide synthase 3 and nanophthalmos 1) that are more closely associated with glaucoma. The pathogenesis of these glaucoma‑associated genes, glaucomatous genetics and genetic approaches, as well as glaucomatous risk factors, including increasing age, glaucoma family history, high myopia, diabetes, ocular trauma, smoking, intraocular pressure increase and/or fluctuation were also discussed.

Introduction

Glaucoma, a neurodegenerative eye disease, may lead to damage to the optic nerve and consequent vision loss, and is the leading cause of irreversible blindness globally (1). Vision loss results from damage to the optic nerve, which is caused by increased intraocular pressure (IOP) in glaucoma. If untreated, once vision loss from glaucoma has occurred, it is life long. There are an estimated 57.5 million people worldwide with glaucoma (2); for every 1,000 people, approximately eight are affected with glaucoma. It has been reported recently that there will be ~79.6 million people with glaucoma by 2020 (3) and an expected 111.8 million glaucoma cases by 2040 (4). Glaucoma has numerous subtypes; however, the different types have a number of common clinical manifestations, including nausea, mid-dilated pupils, serious eye pain, redness and blurred vision (5). Glaucoma has a number of classifications, according to anatomy, etiology, onset age and pathogenesis, and the clinical classifications (6) are presented in Fig. 1.

Besides genetics, there are numerous other risk factors for glaucoma, including increasing age (79), estrogen (10), frailty (11), myopia (12), diabetes (1317), high myopia (18), hyperopia (19), hypertension (20), vasospasm (13), low ocular perfusion pressure (21), family history of glaucoma (7), sex (22), race (23), migraine (24), pigmentary dispersion syndrome (25), pseudoexfoliation syndrome (PEX) (7,9), oral microbiome (26), butanoate metabolism (27), unstable oxygen supply (28), infection (29,30), hematopoietic cell lineage (27), the p38-mitogen activated protein kinase pathway (31), retinitis pigmentosa (32), mitochondrial dysfunction (33), obstructive sleep apnea syndrome (34), basal transcription factors (27), calcium channel medication, α-blocker medication (7), treatment for systemic hypertension or Raynaud's disease (35), adrenergic agents (36), γ-aminobutyric acid and acetyl-coenzyme A metabolism (27), sulfa-based drug (36), corticosteroids (37), smoking (17), lysine degradation (27), IOP fluctuation (38), IOP increase (39) and caffeine (40). Of those risk factors for glaucoma mentioned, increased IOP is the strongest risk factor in the majority of subtypes of glaucoma (41); however, its pathogenesis remains unclear. Increased IOP may subsequently lead to posterior displacement and thinning of the lamina cribrosa (LC), which causes axonal damage and disrupted axonal transport to and from the lateral geniculate nucleus (LGN). Disruption of axonal transport interrupts retrograde delivery of nutrients from relay neurons of the LGN to retinal ganglion cells (RGCs) (42), possibly leading to the death of RGCs.

In addition to the afore-mentioned pathogenic factors for glaucoma, heredity additionally serves an important role in the pathogenesis of glaucoma. A previous study suggested that glaucoma maybe inherited from one generation to the next (43), indicating that specific types of glaucoma may have a genetic basis. Furthermore, familial clustering and twin studies demonstrate that specific types of glaucoma arise from heredity (44,45). The present review focuses on the current understanding and newest breakthroughs in pathogenic genes for glaucoma with the purpose of providing a comprehensive analysis of how reported gene mutations involved in glaucoma lead to the clinical phenotypes expressed in glaucoma. An overview of glaucoma-associated genes is presented.

Genetics of glaucoma

It is well known that there is a genetic basis for glaucoma in specific populations due to sex, ethnicity and positive family history predisposition to glaucoma. There has been strong evidence suggesting that glaucoma is markedly affected by genetic factors and is a complex, multi-factorial disease (46). Glaucoma has numerous types, of which the two most common are primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) (47). POAG is associated with high heritability and complex genetic factors. POAG is responsible for 74% of all glaucoma cases, of which 47% of POAG cases are of Asian descent and ~24% are European (1). In contrast to Asian and European descent, the prevalence of severe and rapid POAG progression is increased in Hispanic and African-Caribbean populations (48,49). A previous study additionally suggested that American Caucasians have a lower prevalence of severe and rapid POAG compared with African Americans, who have the highest severe and rapid POAG prevalence (5.2% at 60 years and 12.2% at 80 years) (50). The increase in POAG prevalence per decade of age is highest among Hispanic and Caucasian populations, with the lowest in East and South Asian populations (50). There has been strong evidence that the POAG incidence in populations of African descent is two to five times higher compared with those of European descent (50,51). All the data suggests that POAG is affected via ancestral factors associated with genetics. Furthermore, certain articles indicate that men are more susceptible to POAG compared with women in Australia (52) and the Netherlands (53). Abu-Amero et al (50) demonstrated that a positive family history is a risk factor for POAG. A previous study demonstrated that the prevalence among individuals with a positive family history of POAG is five to 10 times greater compared with individuals without a positive family history (54).

For PACG, a positive family history is one of the principal risk factors. There is a lot of evidence to support the hypothesis. From previous studies it is known that there is high prevalence among siblings of patients affected with PACG (55), and that the risk of having PACG is increased by 3.7 times in Greenland Eskimos (56,57), 3.5 times in Eskimos (58), and six times in the Chinese (59) for siblings with a positive family history. Furthermore, high IOP (60,61) and the depth of the anterior chamber (56,57) are associated with genetic factors involved in the pathogenesis of PACG. The association between the depth of the anterior chamber and PACG reveals that a predisposition of morphological features to PACG is additionally heritable. It is recognized that high IOP and the size of the anterior chamber are markedly affected in PACG. Besides genetic risk factors, PACG is additionally associated with sex. There is evidence that the sex ratio of PACG prevalence is ~3.25 female to 1 male (62).

Genetic approaches for glaucoma study

Research on glaucoma inheritance has benefited from the development of genetic approaches to identify loci that are involved in a specific glaucomatous phenotype or mutations that account for glaucoma. Traditional linkage analysis based on one or more families with multiple members affected with glaucoma have been widely used to establish the linkage of different phenotypes of glaucoma to particular loci [GLC1A to GLC1N (63), GLC1P (63), GLC3A Online Mendelian Inheritance in Man (OMIM) no. 231300], GLC3B (OMIM no. 600975) and has been less frequently applied to glaucomatous gene mutations, except myocilin (MYOC) (64,65), optineurin (OPTN) (65,66), glutathione S-transferase mu-1 (65), WD repeat-containing protein 36 (WDR36) (65,6769), cytochrome P450 subfamily I polypeptide 1 (CYP1B1) (65), neurotrophin 4 (NTF4) (70), ankyrin repeat- and SOCS box-containing protein 10 (ASB10) (71) and TANK-binding kinase 1 (TBK1) (63). The aforementioned studies demonstrated that this approach is useful to identify glaucomatous loci. However, linkage analysis is largely limited by its reliance on prior knowledge of disease pathophysiology. This traditional candidate gene approach appears to have been powerless to examine an unclear pathophysiology of complex diseases, such as glaucoma (72,73).

Glaucoma is a complex disease, which may be a polygenic disease rather than a monogenic disease. Glaucoma-causing genes have small variations, including single nucleotide polymorphisms (SNPs), and larger variations, including copy number variations (CNVs). Furthermore, the pathogenic levels of these variations differ, from highly to medium to weakly pathogenic, possibly pathogenic, or even protective. Therefore, traditional linkage analysis has not been applicable to study these variations in glaucoma, which is more complex and with unknown pathophysiology (72). A suggested alternative to linkage analysis, genome-wide association studies (GWAS), based on SNPs arrays (73), was proposed. GWAS, additionally known as whole genome association studies, is a genome-wide approach that compares the genetic profile of SNPs throughout the genome, among affected cases and unaffected controls to see if any genomic regions are associated with a certain trait or disease (73). In the examination of the glaucomatous pathology, the most common approach of GWAS to glaucoma is the case-control setup; one control group and the other case group affected with glaucoma. GWAS primarily focuses on the associations between SNPs and traits of glaucoma. There is strong evidence that GWAS is more powerful than linkage analysis in identifying causal variations in genes of weak effect, which may account for the development of glaucoma (73,74).

It was thought that SNPs were the most prevalent genetic variations. However, recently, certain studies revealed CNVs area principal source of variations (73) that may be pathogenic in POAG (75). CNVs manifest primarily as submicroscopic deletions and duplications. Numerous CNVs in POAG have been reported. It is worth mentioning that CNVs contain more nucleotide content compared with SNPs per genome, and that suggests the importance of CNVs in the evolution and diversity of genes (76).

Pathogenic genes associated with glaucoma

Pathogenic genes located in the GLC1A-GLC1Q and GLC3A-GLC3E loci

To date, 22 loci of glaucoma (Table I) have been identified and designated as GLC1A-Q and GLC3A-E. POAG is linked to 17 loci; GLC1A, 1C, 1E-H, 1O-P, for which the responsible genes are MYOC, interleukin 20 receptor subunit β (IL20RB), OPTN, ASB10, WDR36, EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1), NTF4 and TBK1, respectively; and GLC1B, 1D, 1I-N, and 1Q, for which the responsible genes remain unidentified. There are five loci linking to primary congenital glaucoma (PCG), GLC3A and 3D-E, for which the responsible genes are CYP1B1, latent transforming growth factor-β-binding-protein 2 (LTBP2) and TEK tyrosine kinase endothelial (TEK), respectively; the responsible genes of GLC3B-C remain unidentified. GLC1A-Q, except GLC1A, 1J, 1K, 1M and 1N, which contribute only to juvenile open angle glaucoma (JOAG), contribute to adult-onset POAG. All of GLC3A-E have been implicated in PCG. Glaucoma-causing mutations may be classified into two groups. One is autosomal dominant, including POAG-causing genes (MYOC, IL20RB, OPTN, EFEMP1 and TBK1) and a PCG-causing gene (TEK). The other is autosomal recessive, including a PCG-causing gene (CYP1B1). Of the 22 loci, GLC1A (MYOC) and GLC3A (CYP1B1) are the most important for glaucoma; they have correspondingly been the most investigated in research.

Table I.

Candidate genes and 22 loci associated with glaucoma.

Table I.

Candidate genes and 22 loci associated with glaucoma.

Authors, yearLocus nameCandidate geneLocationGlaucoma subtypeAssociation with glaucoma(Refs.)/OMIM no.
Faiq et al, 2013GLC3ACYP1B1 (P4501B1)8q24.3PCG, POAGThe most common pathogenesis of PCG; digenic pathogenic mechanism of CYP1B1 with MYOC and TEK, respectively; conferring increased susceptibility to PCG(6)
Stone et al, 1997; Kumar et al, 2016GLC1A (JOAG1)MYOC (TIGR)1q24.3POAG, NTG, HTG, JOAG1Decreasing AH outflow; increasing IOP; obstructing neurite outgrowth; accumulation of abnormal MYOC protein that is harmful to TM cells(64,65)
GLC1B2cen-q13APOAGFinding the disorder to GLC1B in adult-onset POAGOMIM no.606689
GLC1CIL20RB3q21-q24POAGExpressed in human TM, possibly pathogenicOMIM no.605621
GLC1D8q23POAGIncreased IOP preceded by optic neuropathy and visual field lossOMIM no.602429
Kumar et al, 2016; Pasutto et al, 2009GLC1ONTF419q13.33POAGSignificantly involved in POAG; possibly deriving from multiple ancestors(65,70)
Kumar et al, 2016; Rezaie et al, 2002G LC1EOPTN10p13POAG, NTGImpairing autophagy and trafficking leading to death of retinal cells(65,77)
GLC1FASB107q36.1POAGInfluencing AH outflow; in TM cells, involved in the ubiquitin-mediated degradation pathwaysOMIM no.615054
Kumar et al, 2016; Monemi et al, 2005; Rangachari et al, 2011GLC1GWDR365q22.1POAG, HTGWidely expressed in many ocular tissues; a risk factor for POAG(65,78,79)
GLC1HEFEMP12p16-p15POAGInvolved in decreasing the optic disc areaOMIM no.601548
GLC1I15q11-q13POAGRequires investigationOMIM no.609745
GLC1J (JOAG2)9q22JPOAGRequires investigationOMIM no.608695
GLC1K (JOAG3)20p12JPOAGRequires investigationOMIM no.608696
GLC1L3p22-p21Adult-onsetRequires investigationOMIM no.137760
GLC1M5q22.1-q32JOAGLocation between NRG2 and D5S2051; excluding NRG2 as the causative gene for GLC1MOMIM no.610535
GLC1N15q22-q24JOAGRequires investigationOMIM no.611274
Fingert et al, 2011GLC1PTBK112q14POAGRequires investigation as a causative gene for GLC1P(80)
Porter et al, 2011GLC1Q4q35.1-q35.2POAGRequires investigation(81)
GLC3B1p36.2-p36.1PCGRequires investigationOMIM no.600975
GLC3C14q24.3PCGRequires investigationOMIM no.613085
Ali et al, 2009GLC3DLTBP214q24PCG, SGMaintaining ciliary muscle tone; development of the anterior chamber of human eye(82)
GLC3ETEK9p21.2PCGObstructing AH outflow and causing increased IOPOMIM no.600221

[i] EFEMP1 is unclear as a GLC1H gene. TIGR, trabecular meshwork-induced glucocorticoid response protein; POAG, primary open-angle glaucoma; NTG, normal tension glaucoma; HTG, high-tension glaucoma; JOAG, juvenile open angle glaucoma; AH, aqueous humor; IOP, intraocular pressure; TM, trabecular meshwork; JPOAG, juvenile POAG; PCG, primary congenital glaucoma; MYOC, myocilin; IL20RB, interleukin 20 receptor β; OPTN, optineurin; ASB10, ankyrin repeat- and SOCS box-containing protein 10; WDR36, WD repeat-containing protein 36; EFEMP1, EGF-containing fibulin-like extracellular matrix protein 1; NTF4, neurotrophin 4; TBK1, TANK-binding kinase 1; CYP1B1, cytochrome P450 subfamily I polypeptide 1; LTBP2, latent transforming growth factor-β-binding protein 2; TEK, TEK tyrosine kinase endothelial; SG, secondary glaucoma.

Only four pathogenic genes, MYOC (64,65), NTF4 (65,70), OPTN (65,77) and WDR36 (65,78), have been definitively linked to POAG. Furthermore, it was reported that mutations in OPTN, MYOC or WDR36 account for ~4% of all glaucoma (79). The link between ASB10, IL20RB and EFEMP1, and POAG, is less certain. TBK1 is controversial, since GLC1P covers three other genes, n-acetylglucosamine-6-sulfatase, ras association domain family protein 3 and exportin-t (80); however, TBK1 has been suggested to be the most possible glaucoma-causing gene for GLC1P (80).

Only one pathogenic gene for PCG, CYP1B1 (6), has been clearly identified in the locus GLC3A. Numerous genes have been observed in 1p36 that contain GLC3B, however, none have been demonstrated to be associated with PCG (6). To date, it remains to be investigated whether LTBP2 is associated with the GLC3C or GLC3D loci. LTBP2 is ~1.3 Mb proximal to GLC3C (82), thus there is a hypothesis that LTBP2 may be the GLC3C gene; however, the possibility that it may be an adjacent gene associated with PCG may not be ruled out. Another study suggested that GLC3D is distal to GLC3C without overlapping (83). Furthermore, there is evidence that LTBP2 is a candidate for GLC3D (82); therefore, in the present review LTBP2 is presented as the GLC3D gene. There is strong evidence (OMIM) that mutations of TEK may result in GLC3E, and the locus of TEK is GLC3E.

Other genes associated with glaucoma

To the best of the authors' knowledge, besides the 22 loci of glaucoma mentioned, there are 74 genes that are more closely associated with glaucoma presented in Table II. Of those 74, 48 (64%) are associated with POAG, followed by PACG (16%), PCG (4%) and pseudoexfoliation glaucoma (PEXG; 4%). Toll-like receptor 4, sine oculis homeobox Drosophila homolog of 1, doublecortin-like kinase 1, RE repeats-encoding gene, retinitis pigmentosa GTPase regulator-interacting protein, lysyl oxidase-like protein 1 (LOXL1), heat-shock 70-kD protein 1A (HSP70-1), baculoviral IAP repeat-containing protein 6, 5,10-methylenetetrahydrofolate reductase (MTHFR) and nitric oxide synthase 3 (ENOS) are human genes involved in more than one phenotype of glaucoma. Nanophthalmos 1 is identified to be the only human gene known to cause PACG (140). For other genes (ATP-binding cassette subfamily C member 5, SPARC-related modular calcium-binding protein 2, matrix metalloproteinase 9, membrane-type frizzled-related protein, hepatocyte growth factor, HSP70-1, pleckstrin homology domain-containing protein family A member 7, collagen type XI α-1, MTHFR and ENOS) identified to be associated with PACG in Table II, it remains unclear whether they are pathogenic genes for PACG; however, they may be a risk factor for the development of PACG. Among genes associated with PEXG and PEX, the majority of research has been conducted on LOXL1 to determine whether it is pathogenic and how it contributes to the two diseases. PEX, characterized by the accumulation of protein fibers in the eyes, may have a genetic basis. The accumulation of protein obstructs aqueous humor (AH) outflow, and that results in PEXG. Previously, two studies (111,141) have confirmed that LOXL1 is significantly associated with PEXG and PEX. A decrease in LOXL1 expressionmay cause degenerative tissue alterations in LC, and consequently results in patients with PEX being more vulnerable to optic nerve damage caused by pressure (141), a risk factor for PEXG development.

Table II.

Possible pathogenic or risk genes associated with glaucoma.

Table II.

Possible pathogenic or risk genes associated with glaucoma.

Authors, yearGene symbol (name)Location/locusGlaucoma subtypeAssociation with glaucoma(Refs.)
Fuchshofer et al, 2012TGF-β1 (Transforming growth factor, β-1)19q13.2POAGAccelerating degeneration of the optic nerve axons(84)
Millá et al, 2007LMX1B (LIM homeobox transcription factor 1, β)9q33.3OAGPossibly pathogenic(85)
Vishal et al, 2016MPP7 (Membrane protein, palmitoylated 7)10p12.1POAGAffecting AH dynamics, highly expressed in human TM(86)
Al-Dabbagh et al, 2017SMOC2 (SPARC-related modular calcium-binding protein 2)6q27PACGRegulation of ECM and MMPs(87)
Chakrabarti et al, 2009FOXC1/FKHL7 (Forkhead box C1)6p25.3PCGLimited role in glaucoma pathogenesis; regulation of MYOC secretion;(88)
Moazzeni et al, 2016PITX2 (Paired-like homeodomain transcription factor 2)4q25PCGAffecting IOP(89)
Othman et al, 1998NNO1 (Nanophthalmos1)11pPACGPossibly pathogenic(90)
Nongpiur et al, 2014ABCC5 (ATP-binding cassette, subfamily C, member 5)3q27.1PACGAffecting anterior chamber depth(91)
Simpson et al, 2017TP63 (Tumor protein p63)3q28OAGPossibly pathogenic(92)
Wu et al, 2017MMP-9 (Matrix metalloproteinase 9)20q13.12PACGPossibly protective and susceptibility to acute PACG(93)
Micheal et al, 2018TP53BP2 (Tumor protein p53-binding protein 2)1q41POAGRegulating RGC apoptosis, possibly pathogenic(94)
Liao et al, 2016B4GALT3 (UDP-Gal: βGlcNAc β-1,4-galactosyltransferase polypeptide 3)1q23.3POAGPossibly pathogenic(95)
Vithana et al, 2011COL5A1 (Collagen, type V, α-1)9q34.3Affecting central corneal thickness, possible pathogenic(96)
Vithana et al, 2011; Janssen et al, 2013COL8A2 (Collagen, type VIII, α-2)1p34.3POAGAffecting central corneal thickness, pathogenic(96,97)
Janssen et al, 2013EDNRA (Endothelin receptor, type A)4q31.22-q31.23POAGPossibly pathogenic, highly expressed in the aorta(97)
FBN1 (Fibrillin 1)15q21.1POAGPossibly pathogenic, highly expressed in CBE(97)
TLR4 (Toll-like receptor 4)9q33.1POAG, NTGPossibly pathogenic, highly expressed in CBE PEXG(97)
Tezel et al, 2008TNF-α (Tumour necrosis factor α)6p21.33POAGApoptotic death of RGC, possible pathogenic(98)
Fujikawa et al, 2010VAV2 (Vav2 oncogene)9q34.2POAGElevated IOP caused by VAV2 deficiency(99)
VAV3 (Vav 3 oncogene)1p13.3POAGAdditive effect with VAV2 on glaucomatous phenotype
Cao et al, 2009CALCRL (Calcitonin receptor-like gene)2q32.1Acute PACGPossibly pathogenic in acute; however, not chronic PACG(100)
Awadalla et al, 2012MFRP (Membrane-type frizzled-related protein)11q23.3PACGTendency to be pathogenic(101)
Mabuchi et al, 2012CDKN2B (Cyclin-dependent kinase inhibitor 2B)9p21.3NTGPossibly affecting VCDR, related to glaucoma(102)
SIX1 (Sine oculis homeobox, Drosophila, homolog of, 1)14q23.1POAG, NTG HTGOptic nerve degeneration in glaucoma
CHEK2 (Checkpoint kinase 2, S. pombe, homolog of)22q12.1HTGA genetic risk factor for glaucoma
ATOH7 (Atonal, Drosophila, homolog of, 7)10q21.3NTGPossibly relevant, higher frequency in glaucoma
DCLK1 (Doublecortin-like kinase 1)13q13.3POAG, NTG HTGPossibly pathogenic; however, not up to development of glaucoma
RERE (RE repeats-encoding gene)1p36.23POAG, NTG HTGPossibly pathogenic; however, not up to development of glaucoma
Junglas et al, 2012TGF-β2/TGFB2 (Transforming growth factor, β-2)1q41POAGHigher amounts in AH of glaucoma(103)
CTGF (Connective tissue growth factor)6q23.2POAGModification of TM actin cytoskeleton, increasing IOP
Wang et al, 2012TNF-α/TNFA/TNF (Tumor necrosis factor α)6p21.33POAGPossibly protective factor in the development of glaucoma(104)
Dursun et al, 2012MBL-2 (Lectin, mannose-binding, soluble, 2)10q21.1POAGHigher MBL-2 serum levels in glaucoma(105)
Kang et al, 2011NOS3 (Nitric oxide synthase 3)7q36.1POAGInteractions of reproductive factors with glaucomatous pathogenesis(106)
Awadalla et al, 2011HGF (Hepatocyte growth factor)7q21.11PACGSignificantly associated with glaucoma(107)
Wittström et al, 2011BEST1 (Bestrophin 1)11q12.3ACGAnterior segment abnormality, shallow anterior chambers and reduced axial lengths(108)
Fernández-Martínez et al,RPGRIP1 (Retinitis pigmentosa14q11.2POAG,Increasing the susceptibility to various(109)
2011GTPase regulator-interacting protein) NTG JOAGtypes of glaucoma and possible pathogenic
Mookherjee et al, 2010IL-1β (Interleukin 1-β)2q14.1HTGA risk to glaucoma(110)
IL-1α (Interleukin 1-α)2q14.1HTGLittle association with glaucoma
Zhou et al, 2016CARD10 (Caspase recruitment domain-containing protein 10)22q13.1POAGPossibly pathogenic(111)
Álvarez et al, 2015LOXL1 (Lysyl oxidase-like 1)15q24.1PEXG, PCGPossibly pathogenic(112)
Khawaja et al, 2016Mitochondrial gene mutationsPOAG, NTG, HTG, PACGPathogenic(113)
Bailey et al, 2016TXNRD2 (Thioredoxin reductase 2)22q11.21POAGCausing RGC apoptosis and mitochondrial dysfunction(114)
ATXN2 (Ataxin 2)12q24.12POAGNeurodegeneration, pathogenic(114)
Lascaratos et al, 2012MFN1 (Mitofusin 1)POAGSusceptibility to glaucoma(115)
MFN2 (Mitofusin 2)1p36.22POAGSusceptibility to glaucoma
PARL (Presenilin-associated rhomboid-like protein)3q27.1POAGSusceptibility to glaucoma
GST/SLCO6A1 (Gonad-specific transporter)5q21.1POAGSusceptibility to glaucoma
SOD2 (Superoxide dismutase 2)6q25.3POAGDevelopment of glaucoma
Liu et al, 2016MIR182 (MicroRNA 182)7q32.2POAG (HTG)Possibly pathogenic(116)
Chandra et al, 2016CYP46A1 (Cytochrome P450, family 46, subfamily A, polypeptide 1)14q32.2POAGRisk prediction(117)
Shah et al, 2017; Skowronska-Krawczyk et al, 2015SIX6 (Sine oculis homeobox, Drosophila, homolog of, 6)14q23.1POAGSusceptibility to glaucoma; increasing VCDR; enhanced risk by p16INK4a to glaucoma(118,119)
Skowronska-Krawczyk et al, 2015CDKN2A/p16(INK4a) (Cyclin-dependent kinase inhibitor 2A)9p21.3POAGPossibly pathogenic; leading to RGC senescence(119)
Shin et al, 2016GALC (Galactosylceramidase)14q31.3POAGPossibly pathogenic(120)
Nowak et al, 2015BDNF (Brain-derived neurotrophic factor)11p14.1POAGPossibly pathogenic(121)
Janssen et al, 2013; Nowak et al, 2015APOE (Apolipoprotein E)19q13.32POAG, NTGPossibly pathogenic; decreasing NTG risk(97,121)
Chen et al, 2014ABCA1 (ATP-binding cassette, subfamily A, member 1)9q31.1POAGDevelopment of glaucoma(122)
Ayub et al, 2010ENOS (Nitric oxide synthase 3)7q36.1PACG, POAGSignificantly associated with glaucoma(123)
Nowak et al, 2015; Ayub et al, 2010HSP70-1 (Heat-shock 70-kD protein 1A)6p21.33POAG, PACG NTGPossibly pathogenic(121,123)
Carbone et al, 2011PDIA5 (Protein disulfide isomerase, family A, member 5)3q21.1POAGPossibly pathogenic(124)
Carbone et al, 2011; Ayub et al, 2014BIRC6 (Baculoviral IAP repeat-containing protein 6)2p22.3POAG, PEXGPossibly protective(124,125)
Chen et al, 2014PLEKHA7 (Pleckstrin homology domain-containing protein, family A, member 7)11p15.2-p15.1PACGConferring significant risk for acute glaucoma(126)
COL11A1 (Collagen, type XI, α-1)1p21.1PACGConferring significant risk for acute glaucoma(126)
Cuchra et al, 2013APE1/APEX1 (Apex nuclease 1)14q11.2POAGExpressed in RGC, TM; possibly decreasing the risk of POAG progression(127)
Janssen et al, 2013; Surgucheva et al, 2011CAV1 (Caveolin 1)7q31.2POAGGlaucomatous alterations in TM(97,128)
Surgucheva et al, 2011; Thorleifsson et al, 2010CAV2 (Caveolin 2)7q31.2POAGExpressed in TM and RGC(128,129)
Lascaratos et al, 2012; Yu-Wai-Man et al, 2010OPA1 (Optic atrophy 1)3q29NTGA strong risk for glaucoma and causing optic atrophy(115,130)
Mossböck et al, 2008PAI-1 [Serpin peptidase inhibitor, clade E (NEXIN plasminogen activator inhibitor type 1, member 1]7q22.1POAGDecreasing proteolysis of ECM in TM and possibly increasing IOP(131)
Wang et al, 2008SAA2 (Serum amyloid A2)11p15.1Increasing IOP and possibly causing pathogenic alterations to TM in glaucoma.(132)
Micheal et al, 2017PRPF8 (Precursor mRNA-processing factor 8, S. cerevisiae, homolog of)17p13.3POAGPathogenic(133)
Woo et al, 2009; Clement et al, 2009MTHFR (5,10-methylenetetrahydrofolate reductase)1p36.22NTG, POAGA genetic risk to glaucoma(134,135)
Bhattacharya et al, 2005COCH (Cochlin)14q12POAGIncreasing IOP, causing TM cell aggregation, impeding AH outflow(136)
Bhattacharya et al, 2006PADI2 (peptidyl arginine deiminase, type II)1p36.13POAGIncreasing in glaucomatous optic nerve(137)
Vishal et al, 2016MMP-7 (membrane protein palmitoylated 7)11q22.2POAGInfluencing the aqueous humor dynamics; highly expressed in the human TM cells(138)
Lu et al, 2013FNDC3B (Fibronectin type III domain-containing protein 3B)3q26.31POAGSignificantly associated with POAG risk(139)

a International Radiation Hybrid Mapping Consortium. POAG, primary open-angle glaucoma; PACG, primary angle-closure glaucoma; PCG, primary congenital glaucoma; AH, aqueous humor; TM, trabecular meshwork; ECM, extracellular matrix; MMP, matrix metalloproteinase; IOP, intraocular pressure; RGC, retinal ganglion cell; NTG, normal tension glaucoma; PEXG, pseudoexfoliation glaucoma; HTG, high-tension glaucoma; VCDR, vertical cup/disc ratio; JOAG, juvenile open angle glaucoma.

MYOC in the GLC1A locus

To date, the majority of research efforts have been on MYOC among all the glaucoma-causing genes. There is a consensus that 2–4% of POAG cases harbor MYOC mutations (142) and MYOC mutations have been reported to be the most frequent in POAG. In the present review, the research findings on MYOC are detailed and summarized. In 1993, Sheffield et al (143) discovered the first genetic locus, GLC1A, for POAG, and in 1997, a glaucoma-causing gene, MYOC, was identified by Stone et al (64). MYOC is a gene associated with POAG, JOAG, normal tension glaucoma (NTG), high-tension glaucoma (HTG) and steroid-induced glaucoma (144). In 1997, the location of MYOC was linked to chromosome 1q23-q24 by Kubota et al (145), and there was a report on fine mapping to chromosome 1q24.3-q25.2 (146). In 1998, cells treated with steroids secreted the same MYOC protein, which was termed TIGR (trabecular meshwork-induced glucocorticoid response protein) (147). Under stress, eyes may produce the MYOC protein in increased amounts, suggesting that MYOC may serve a protective role similar to a molecular chaperone (148). The MYOC protein is produced by numerous ocular tissues (43,73,149), including the ciliary body, trabecular meshwork (TM), optic nerve, LC, cornea, iris, sclera, retina and lens, and is usually visualized in muscles, including the ciliary muscle, iris and smooth muscle. MYOC is additionally secreted into the vitreous humor for undetermined reasons. Stone et al (64) suggested that there is a possible association of the muscle-associated ciliary body with increased IOP. MYOC expression does not exhibit a significant difference in the blood of patients with POAG compared with blood from individuals without POAG; however, there is a significant difference in the TM (150). Therefore MYOC expression may account for a genetic susceptibility to POAG in specific tissues, including the ciliary body and TM.

Pathogenesis of MYOC

The pathogenesis of MYOC mutations is unclear; however, the three most possible causes for glaucoma are as follows. In the unhealthy state, there is poor normal MYOC protein secretion. MYOC mutations may lead to accumulation of mutated MYOC proteins within the TM (151154). Retention of abnormal MYOC protein may be harmful to TM cells and result in their dysfunction or death, which may obstruct AH outflow, and consequently increase IOP (43,64,147,155,156). In addition, accumulation of mutated MYOC proteins in the endoplasmic reticulum activates the unfolded protein response (UPR) in TM cells (157), subsequently leading to apoptosis that may cause high IOP. Over activated UPR may lead to certain neurodegenerative diseases, and inhibiting UPR is a possible therapy for these diseases (158). Thus, this method may additionally be applicable to glaucoma. Normal MYOC is involved in exosome shedding into the aqueous humor, and exosomes are associated with paracrine and autocrine signaling (74), that therefore may serve as vehicles of MYOC protein trafficking. Notably, normal MYOC protein is absent in the aqueous humor of glaucomatous patients with pathogenic MYOC mutations (151). Thus, another prevalent hypothesis on the pathogenesis of MYOC mutations is that they interfere with MYOC protein trafficking and lead to the intracellular aggregation of the misfolded MYOC protein (74). Accumulation of misfolded MYOC proteins decreases AH out flow, and that influences IOP regulation; however, its mechanism is unclear (74). The third hypothesis is regarding specific interactions between MYOC mutations and mitochondria in the TM (159,160). A subsequent study indicated that MYOC mutations lead to dysregulation of calcium channels resulting in mitochondrial depolarization in the TM, consequently resulting in TM contraction, which decreases AH outflow and further causes increased IOP (161).

Digenic and polygenic mechanism of MYOC

There is strong evidence that only ~5% of POAG (65) is caused by a single gene, and other cases of POAG are caused by digenic or polygenic cooperation mechanisms, none of which may alone cause glaucoma. Usually, cooperation of MYOC mutations with one or more genes contributes to glaucoma. Mutations in MYOC, OPTN and CYP1B1 are identified to coexist in ~3.59% of POAG cases (162). This demonstrates that mutations in the three genes together may be involved in the pathogenesis of POAG. There are other studies investigating the association between MYOC and OPTN. OPTN and MYOC are observed in POAG (69,162166), exfoliative glaucoma (164) and exfoliation syndrome (164). Overexpression of OPTN may upregulate MYOC in TM and stabilize MYOC mRNA (167). There is a possible polygenic interaction among MYOC, OPTN and apolipoprotein E (APOE). Disease-causing mutations in MYOC and OPTN contribute to only a small number of Chinese POAG cases (163). However, common polymorphisms in MYOC, OPTN (69,163,166), APOE (69,163) and WDR36 (69) may together account for POAG. Common polymorphisms of these genes are not associated with POAG alone; however, they may cooperatively contribute to the disease, which indicates a polygenic pathogenesis. A study reported that the mean onset age of carriers with only MYOC mutations is 51 years; however, the mean onset age of carriers with MYOC and CYP1B1 mutations is 27 years (168). This indicates that mutations in the two genes may interact to advance the onset age of glaucoma. Notably, in a study (169) Gln48His, a MYOC mutation, was observed in POAG and PCG; however, one patient with PCG had a CYP1B1 mutation (Arg368His), and the other patient with PCG had none of the CYP1B1 mutations. These results demonstrate that there is a possible digenic interaction between MYOC and CYP1B1, without excluding the possibility that there has been an unidentified gene associated with glaucoma. However, another study reported that none of the CYP1B1 mutations was observed in all five POAG cases with MYOC mutations (170). Forkhead box C1 (FOXC1) may regulate MYOC secretion through modulation of RAB3 GTPase-activating protein catalytic subunit 1 RAB, synaptosomal-associated protein 25-kD and RAB3 GTPase-activating protein noncatalytic subunit (144). A different study (171) suggested that MYOC and FOXC1 mutations are not associated with the pathogenesis of PCG. The mutations Leu486Phe in MYOC and Val108Ile in UDP-Gal: β GlcNAc β-1,4-galactosyltransferase polypeptide 3 may cooperatively contribute to the pathogenesis of POAG (94).

Pathogenic genes in the GLC1B-GLC1Q loci

OPTN

OPTN, widely expressed in retinal ganglion cells (172), the nonpigmented ciliary epithelium, human TM and the retina (77), is an autophagy receptor. Autophagy may remove damaged organelles and proteins via lysosomal degradation (172). Autophagy and membrane vesicle trafficking serve an important role in the regulation of OPTN functions (172). Furthermore, the level of autophagy mediated through OPTN is very important for the survival of retinal cells (172). Mutations in OPTN are involved in POAG (172). Another conclusion contradicted this result, reporting that OPTN is not associated with POAG in Spain (173). Of these disease-causing mutations, two are noteworthy, Glu50Lys and Met98Lys.

The frequency of Glu50Lys in POAG is 13.5% (77). Notably, 81.6% of POAG cases with recurrent Glu50Lys have normal IOP; whereas only 18.4% of those have increased IOP (77). However, another study suggested that OPTN mutations are involved in POAG rather than glaucoma with normal IOP in Japanese patients (174). Glu50Lys impairs autophagy (172) and trafficking (172,175), resulting in the death of retinal cells through apoptosis (172) and disrupting the endocytic recycling that is very important for maintaining homeostasis (175).

Rezaie et al (77) first reported that Met98Lys is a risk-causing mutation for POAG, and the frequency of Met98Lys in POAG (13.6%) is significantly higher compared with controls (2.1%). In another study by Sripriya et al (176), Met98Lys was not identified in controls; however, it was identified in POAG (4.1%) and NTG (6%) (162). Mukhopadhyay et al (177) did not detect Met98Lys in NTG, and the frequency of Met98Lys was 11% in POAG and 5.5% in controls. An alternative study (162) presented the contrary conclusion that Met98Lys may not be a risk-causing factor for POAG on account of a very similar frequency in POAG (7.97%) and controls (7.29%). Met98Lys is usually known as a disease-causing mutation and the majority of POAG cases with Met98Lys additionally have normal IOP, similar to Glu50Lys (77). The possible pathogenesis of Met98Lys is that it may impair autophagy, which consequently leads to the death of retinal cells through apoptosis and transferrin receptor degradation (172). However, the pathogenic mechanism of glaucoma-causing Met98Lys requires further research and examination.

WDR36

WDR36, located within the POAG linkage locus GLC1G and first identified by Monemi et al (78), is widely expressed in numerous ocular tissues, including the optic nerve, ciliary body, retina, TM, ciliary muscles, iris, lens and sclera. Monemi et al (78) formerly suggested that the frequency of WDR36 mutations in POAG is 1.6–17%. There is a possible association of WDR36 with the pathogenic mechanism of HTG (67,68). WDR36 mutations may alter the cell phenotype supporting the theory that WDR36 is associated with the polygenic pathogenesis of glaucoma (178). To date, WDR36 importance remains unclear; furthermore, its pathogenicity is controversial. As subsequent studies did not demonstrate WDR36 mutations to be POAG-causing mutations, it was demonstrated that WDR36 mutations may only be a risk factor for POAG (6769). In addition, Fingert et al (179) were not able to confirm the association of WDR36 with pathogenesis of POAG.

NTF4, ASB10, EFEMP1 and IL20RB

NTF4, located within the POAG linkage locus GLC1O, is localized to RGCs (70). Pasutto et al (70) suggested that the frequency of NTF4 mutations in POAG is 1.7% and there is strong genetic evidence that NTF4 mutations are involved in POAG of European origin. Liu et al (180) additionally identified coding alterations in five POAG cases and 12 controls of European origin from Southeastern USA, of which two mutations were previously detected by Pasutto et al (70). Therefore, Liu et al concluded that these NTF4 coding alterations are not significantly associated with the pathogenesis of POAG. In addition, another study by Chen et al (181) suggested that NTF4 does not mainly contribute to the molecular genetics of POAG. From the above, the association of NTF4 mutations with POAG pathogenesis remains to be investigated. In addition, besides the European origin, NTF4 mutations have been identified in Chinese populations (182). This indicates that NTF4 mutations may derive from multiple ancestors.

ASB10, located within the POAG linkage locus GLC1F (183), influences AH outflow (71). ASB10 is most highly expressed in the iris, followed by human TM, RGCs, the ciliary body, choroid, optic nerve, retina, lamina and a little in the lens (71). Among patients with POAG and controls, the frequency of ASB10 mutations is 6 and 2.8%, respectively (71). To test whether ASB10 influences AH drainage, Pasutto et al (71) applied RNA interference silencing for knockdown of ASB10 mRNA expression in perfused human anterior segment cultures. The results revealed that the decrease in AH outflow facility was ~50%. In addition, ASB10 may be involved in the ubiquitin-mediated degradation pathways through interactions of ASB10 with the α4 subunit of the 20s proteasome and with HSP70 in TM (184).

EFEMP1, located within the POAG linkage locus GLC1H, is a plausible candidate for POAG (185). Although there have been a few efforts to confirm the linkage to GLC1H, it remains uncertain. Mutations in EFEMP1 are involved in decreasing the optic disc area (186). Another mutation, c.418C>T in EFEMP1 may be predictive for POAG (185). Expression of EFEMP1 may be influenced by transforming growth factor (TGF)-β2. A study by Junglas et al (187) reported that TGF-β2 is more highly expressed in AH of POAG and maybe associated with the increase in AH outflow resistance in POAG. Higher amounts of TGF-β2 inhibit the expression of EFEMP1 (188).

IL20RB, located within the POAG linkage locus GLC1C, has a role in POAG pathogenesis (189). An IL20RB mutation, Thr104 Met, lying in an active binding site of IL20RB (190), has been observed in a large POAG family (189); therefore, this additionally demonstrates that IL20RB may be implicated in the pathogenesis of POAG. According to OMIM (no. 605621), IL20RB is highly expressed in human skin and testes, and less expressed in the muscle, placenta, heart, ovary and lung. Recently, IL20RB was detected to be additionally expressed in human TM (191). To the best of the authors' knowledge, thus far, little research effort has been made to investigate IL20RB as a POAG-causing gene.

Pathogenic genes in the GLC3A-GLC3E loci

CYP1B1

In humans, the CYP1B1 gene encodes cytochrome P450 1B1, and is regulated via the aryl hydrocarbon receptor. CYP1B1 was the first gene identified in PCG-associated loci (GLC3A-3E) (192), and its role has been clearly understood (65). CYP1B1 is widely expressed in the eyes, including the retina, iris, ciliary body and TM (193). However, certain previous studies suggested that CYP1B1 is not expressed in TM at any stage of eye development (194). CYP1B1 has been thought to be significantly associated with human fetal eye development (194). To date, at least 147 CYP1B1 mutations have been identified globally in 542 patients with PCG in various countries, including Brazil, China, India, Iran, Morocco, Russia, Saudi Arabia, Slovak Gypsy populations, Turkey, USA, Spain, Pakistan, Oman, the Netherlands, Mexico, Kuwait, Japan, Israel, Indonesia, Germany, Ecuador, Canada, Britain and Algeria (6,195). Among CYP1B1 mutations, Glu387Lys has been traced to a common genetic origin for PCG (196). CYP1B1 mutations, which have been reportedly associated with a wider range of glaucomatous phenotypes, including PCG (6,169,195197), POAG (198200), JOAG (201) and PEXG (199), appear in patients with glaucoma at a higher frequency compared with other glaucoma-associated genes (199). CYP1B1 mutations may confer increased susceptibility to PCG and are the most common pathogenic factors of PCG (6). However, the frequency of PCG-causing mutations in CYP1B1 varies significantly in different populations, including Mexican (<10%) (202), Vietnamese (16.7%) (197), Chinese, Japanese and Indonesian (all 20%) (202), Indian (40%) (169). Furthermore, PCG-causing mutations in CYP1B1 occur with extremely high incidence in Slovak Gypsy and Saudi Arabian populations (202), which supports an additional study reporting that consanguinity is a fundamental mechanism for high PCG incidence in Slovak Gypsy and Saudi Arabian populations (203) Available data demonstrate that CYP1B1 may not be the primary disease-causing gene for glaucoma in East Asians and South East Asians, unlike in Gypsy and Saudi Arabian populations. Furthermore, PCG in Mexicans may not be caused by CYP1B1 mutations. In addition, only ~10% of cases of POAG in Mexico harbor CYP1B1 mutations (198), demonstrating that CYP1B1 mutations may not be the cause of the pathogenesis of POAG; however, dysfunction of CYP1B1 may increase the risk of POAG. A low percentage of JOAG cases (~5%) harbor CYP1B1 mutations (168), and CYP1B1 possibly contributes to JOAG in a monogenic model (201).

An increasing amount of research attention is focusing on the interactions of CYP1B1 with other genes. There is growing evidence that interactions of CYP1B1 with MYOC occur in patients with PCG (169,204). In the process of interactions, MYOC is a potential modifier gene (205). In addition, TEK mutations co-occur with CYP1B1 mutations in patients with PCG; notably, the parents of these patients with PCG harbor either heterozygous CYP1B1 or TEK alleles and are asymptomatic (206). Furthermore, there is strong evidence suggesting that the interaction between CYP1B1 and TEK accounts for the pathogenesis of PCG (206); however, the mode of interaction remains unclear regarding whether an overlapping or independent mode is involved in the pathogenic mechanism of PCG. The interaction of CYP1B1 with MYOC and TEK, respectively, in the pathogenesis of PCG further lends support to the digenic inheritance of PCG.

Although CYP1B1 mutations are the most common cause of PCG, these mutations only contribute to a very small proportion of the total amount of PCG (6). Besides CYP1B1, there are a number of genes demonstrated to be associated with PCG, including LTBP2, FOXC1 and MYOC. Therefore, it is reasonable to speculate that other genes may participate in the pathogenesis of PCG; however, there still remain a large number of unknown genes requiring identification.

LTBP2

LTBP2, located within the PCG linkage locus GLC3D, is the largest member of the latent TGF-β family whose signaling failure in the anterior and posterior eye may cause pathogenic alterations in POAG (84). LTBP2 is most highly expressed in the lens capsule (192), secondly in the TM and ciliary processes (82,192) that are thought to be associated with PCG pathogenesis, with a very small amount in the sclera, corneal stroma and iris (192). LTBP2 mutations are identified in different populations, including Pakistani (82), Indian (207), Gypsy (82), Iranian, Moroccan, and Saudi Arabian populations (OMIM). From the aforementioned data, LTBP2 mutations appear to derive from West Asia and South Asia. Although Morocco is located in Africa, 75% of Moroccans are of Arabic descent; furthermore, the origin of the Gypsy ethnicity is thought to be in Ancient India. To the best of our knowledge, LTBP2 mutations have been not observed in other populations. Therefore, it is reasonable to hypothesize that LTBP2 mutations may have the same ancestor.

LTBP2 is a disease-causing gene for PCG (192) and is very important in the development of the anterior chamber of the human eye, where LTBP2 possibly serves a role in maintaining ciliary muscle tone (82). Besides PCG, LTBP2 mutations maybe associated with PACG and POAG (208). Therefore, there may be an overlap in the pathogenic mechanism among various types of glaucoma. It is this overlap that may account for the common characteristics among these various types of glaucoma, including optic nerve impairment and decreased vision, and for the common clinical presentation at onset, including eye pain, red-eye, blurred vision, nausea and mid-dilated pupils. However, another study (207) had contrary conclusions that LTBP2 mutations are not implicated in the pathogenesis of PCG. In addition, LTBP2 is not thought to be a disease-causing gene for PCG in the Han Chinese population (209).

TEK

TEK, located within the PCG linkage locus GLC3E, is an angiopoietin receptor, additionally termed cluster of differentiation 202B and tyrosine kinase with immunoglobulin-like and EGF-like domains 2, and may regulate vascular homeostasis (210). Although TEK and other vascular growth factors are important for AH outflow and Schlemm's canal development, their association with glaucoma remains unclear (211). A 50% decrease in TEK adequately demonstrated defective Schlemm's canal development and impaired AH outflow (210), and this demonstrates that TEK concentration is important for the AH drainage pathways. Variable expression of TEK is possibly produced by oligogenic or digenic inheritance, in line with other ocular disorders of developmental origin produced by mutations in optic atrophy 1, FOXC1, paired box gene 6 and MYOC (210). In addition, another recent study demonstrated that TEK mutations co-occur with CYP1B1 mutations in PCG (206), and demonstrated that interactions between TEK and CYP1B1 account for digenic inheritance in PCG pathogenesis.

Potential pathogenic mechanism and recent advances in treatments

Potential pathological mechanism

Among the 96 genes, mutations of MYOC (GLC1A) and CYP1B1 (GLC3A) have the closest associations with potential pathological mechanisms in glaucoma. Besides the aforementioned glaucomatous pathogenesis, a novel pathogenic mechanism for MYOC-associated glaucoma is proposed. Extracellular matrix (ECM) proteins of TM are synthesized in the endoplasmic reticulum (ER) and finally secreted into the ECM. Malfunction of the ER during ER stress caused by mutant myocilin accumulation in the ER may affect ECM protein processing and secretion, which results in aberrant intracellular accumulation of ECM proteins in TM (212). The accumulation of ECM proteins may deteriorate ER stress, leading to TM cell dysfunction and obstructing AH outflow, thereby increasing IOP (212).

CYP1B1 defects cause angle abnormalities involving TM and Schlemm's canal (213). CYP1B1 mutations lower activity or stability of the enzyme in the mitochondria (214,215) and reduce expression levels of ECM proteins in TM (215). These may impact the development or filtering function of TM. In addition, abnormal mitochondria caused by CYP1B1 mutations [the same case as with MYOC mutations (161)] may cause dysregulation of calcium channels resulting in mitochondrial depolarization in TM, consequent TM contraction, reduction of AH outflow and an increase in IOP.

Recent advances in treatment

Based on previous studies on the potential pathogenic mechanism of MYOC mutation, at present, there have been three novel approaches to treatment for MYOC-associated POAG: i) Using chemical chaperones (based on molecular mechanisms) to decrease misfolding or unfolding of proteins and increase MYOC secretion (216); ii) given the gain-of-function nature of MYOC mutations, another novel approach is targeting MYOC mRNA or the myocilin protein (216); and iii) targeting MYOC by gene editing with clustered regularly interspaced short palindromic repeats-Cas9 technology to reduce ER stress and lower IOP (216).

According to previous studies on potential pathogenic mechanisms of CYP1B1 mutation, researchers developed two novel therapies: One is the approach based on the gene, directly attempting to correct or replace abnormal CYP1B1 (217); the more novel approach differentiates into a specific lineage and transfers stem cells containing wild-type CYP1B1 to stimulate the normal development of TM cells (217).

Conclusion and prospects

As mentioned, the pathogenic mechanism of MYOC- or CYP1B1-associated glaucoma is associated with aberrant ECM proteins in TM. The accumulation of deposits of ECM proteins may lead to ER stress as described, resulting in the misfolding or unfolding of MYOC proteins. If ER stress is too severe or if UPR (an adaptive response to ER stress) fails to compensate for the ER stress, dysfunction and apoptosis occurs (218221), which may cause increased IOP. At present, the novel protein-remodeling factors as potential therapeutics are highly promising to correct the misfolding or unfolding of proteins in neurodegenerative diseases or disorders (221). Therefore, as glaucoma is a neurodegenerative disease, the highly promising protein-remodeling factors (including engineered Hsp104 mutations) may be useful in the development of novel glaucoma therapies, and to better understand the glaucomatous mechanism.

Additionally, combined with the prospect for glaucoma healthcare, certain important problems require addressing in future studies. More in vivo animal models (monkey, pig and cow, whose eyes are similar to human), with stem cell-based studies on glaucoma-associated genes, including MYOC and CYP1B1, are required. In addition, using autologous stem cells, including bone marrow derived stem cells (217), that have been genetically modified to serve an important role in the pathogenic mechanism of glaucoma may be a promising future therapy for MYOC- or CYP1B1-associated glaucoma.

In conclusion, strong evidence indicates that genes are significantly associated with the pathogenesis of glaucoma, and additionally provides a stimulus for the identification of these pathogenic genes. Further efforts to research clinical trials on potential feasible therapeutic targets are necessary, which may construct future therapeutic paradigms for glaucoma. Presently, although a number of genes have been identified to be associated with glaucoma, their pathogenic mechanisms remain unclear, with the exception of MYOC and CYP1B1. Furthermore, certain studies are controversial, even contradictory. Therefore, further research is required to better comprehend the association between pathogenic genes and glaucoma.

Acknowledgements

The authors would like to acknowledge the Laboratory of Qiqihar Medical University (Heilongjiang, China) for provision of the relevant literature.

Funding

The present study was supported by a grant from Taizhou Science and Technology Support Projects for Social Development (2016) of Taizhou Science and Technology Bureau (grant no. SSF20160112).

Availability of data and materials

Not applicable.

Authors' contributions

H-WW produced the manuscript. H-WW, PS and FG conceived and designed framework of this article. YC, L-PJ, WZ and H-PW collected and analyzed the literature.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Quigley HA and Broman AT: The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmo. 190:262–267. 2006. View Article : Google Scholar

2 

Foris LA and Gossman WG: Glaucoma, open angle. StatPearls Publishing Internet; Nov 21–2018

3 

Kumar S, Malik MAKS, Sihota R and Kaur J: Genetic variants associated with primary open angle glaucoma in Indian population. Genomic. 109:27–35. 2017. View Article : Google Scholar

4 

Tham YC, Li X, Wong TY, Quigley HA, Aung T and Cheng CY: Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis. Ophthalmology. 121:2081–2090. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Mantravadi AV and Vadhar N: Glaucoma. Prim Care. 42:437–449. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Faiq M, Sharma R, Dada R, Mohanty K, Saluja D and Dada T: Genetic biochemical and clinical insights into primary congenital glaucoma. J Curr Glaucoma Pract. 7:66–84. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Le A, Mukesh BN, McCarty CA and Taylor HR: Risk factors associated with the incidence of open-angle glaucoma: The visual impairment project. Invest Ophthalmol Vis Sci. 44:3783–3789. 2003. View Article : Google Scholar : PubMed/NCBI

8 

Suzuki Y, Iwase A, Araie M, Yamamoto T, Abe H, Shirato S, Kuwayama Y, Mishima HK, Shimizu H, Tomita G, et al: Risk factors for open-angle glaucoma in a Japanese population: The Tajimi Study. Ophthalmology. 113:1613–1617. 2006. View Article : Google Scholar : PubMed/NCBI

9 

European Glaucoma Prevention Study (EGPS) Group, . Miglior S, Pfeiffer N, Torri V, Zeyen T, Cunha-Vaz J and Adamsons I: Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma. Prevention study Ophthalmology. 114:3–9. 2007. View Article : Google Scholar : PubMed/NCBI

10 

Dewundara SS, Wiggs JL, Sullivan DA and Pasquale LR: Is estrogen a therapeutic target for glaucoma? Semin Ophthalmol. 31:140–146. 2016. View Article : Google Scholar : PubMed/NCBI

11 

McMonnies CW: Glaucoma history and risk factors. J Optom. 10:71–78. 2017. View Article : Google Scholar : PubMed/NCBI

12 

Cho HK and Kee C: Population-based glaucoma studies in Asians. Surv Ophthalmol. 59:434–447. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Flammer J, Pache M and Resink T: Vasospasm, its role in the pathogenesis of diseases with particular reference to the eye. Prog Ret Eye Res. 20:319–349. 2001. View Article : Google Scholar

14 

Mitchell P, Lee AJ, Wang JJ and Rochtchina E: Intraocular pressure over the clinical range of blood pressure: Blue mountains eye study findings. Am J Ophthalmol. 140:131–132. 2005. View Article : Google Scholar : PubMed/NCBI

15 

Zhou M, Wang W, Huang W and Zhang X: Diabetes mellitus as a risk factor for open-angle glaucoma: A systematic review and meta-analysis. PLoS One. 9:e1029722014. View Article : Google Scholar : PubMed/NCBI

16 

Congdon N, Wang F and Tielsch JM: Issues in the epidemiology and population-based screening of primary angle-closure glaucoma. Surv Ophthalmol. 36:411–423. 1992. View Article : Google Scholar : PubMed/NCBI

17 

Doucette LP, Rasnitsyn A, Seifi M and Walter MA: The interactions of genes, age, and environment in glaucoma pathogenesis. Surv Ophthalmol. 60:310–326. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Ma F, Dai J and Sun X: Progress in understanding the association between high myopia and primary open-angle glaucoma. Clin Exp Ophthalmol. 42:190–197. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Xu L, Fang WF, Wang YX, Chen CX and Jonas JB: Anterior chamber depth and chamber angle and their associations with ocular and general parameters: The Beijing eye study. Am J Ophthalmol. 145:929–936. 2008. View Article : Google Scholar : PubMed/NCBI

20 

Topouzis F, Coleman AL, Harris A, Jonescu-Cuypers C, Yu F, Mavroudis L, Anastasopoulos E, Pappas T, Koskosas A and Wilson MR: Association of blood pressure status with the optic disk structure in non-glaucoma subjects: The Thessaloniki eye study. Am J Ophthalmol. 142:60–67. 2006. View Article : Google Scholar : PubMed/NCBI

21 

Leske MC, Wu S-Y, Hennis A, Honkanen R and Nemesure B: BESs Study Group: Risk factors for incident open-angle glaucoma: The Barbados eye studies. Ophthalmology. 115:85–93. 2008. View Article : Google Scholar : PubMed/NCBI

22 

Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK II, Wilson MR and Kass MA: The ocular hypertension treatment study: Baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 120:714–720; discussion 829–830. 2002. View Article : Google Scholar : PubMed/NCBI

23 

Racette L, Wilson MR, Zangwill LM, Weinreb RN and Sample PA: Primary open-angle glaucoma in blacks: A review. Surv Ophthalmol. 48:295–313. 2003. View Article : Google Scholar : PubMed/NCBI

24 

Cursiefen C, Wisse M, Cursiefen S, Jünemann A, Martus P and Korth M: Migraine and tension headache in high-pressure and normal-pressure glaucoma. Am J Ophthalmol. 129:102–104. 2000. View Article : Google Scholar : PubMed/NCBI

25 

Farrar SM, Shields MB, Miller KN and Stoup CM: Risk factors for the development and severity of glaucoma in the pigment dispersion syndrome. Am J Ophthalmol. 108:223–229. 1989. View Article : Google Scholar : PubMed/NCBI

26 

Astafurov K, Elhawy E, Ren L, Dong CQ, Igboin C, Hyman L, Griffen A, Mittag T and Danias J: Oral microbiome link to neurodegeneration in glaucoma. PLoS One. 9:e1044162014. View Article : Google Scholar : PubMed/NCBI

27 

Bailey JN, Yaspan BL, Pasquale LR, Hauser MA, Kang JH, Loomis SJ, Brilliant M, Budenz DL, Christen WG, Fingert J, et al: Hypothesis-independent pathway analysis implicates GABA and acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma. Hum Genet. 133:1319–1330. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Konieczka K, Todorova MG, Chackathayil TN and Henrich PB: Cilioretinal artery occlusion in a young patient with flammer syndrome and increased retinal venous pressure. Klin Monbl Augenheilkd. 232:576–578. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Liao Q, Sun XY, Guo H and Li C: Exploring the potential mechanism and screening small molecule drugs for glaucoma by using bioinformatics approach. Eur Rev Med Pharmacol Sci. 18:132–140. 2014.PubMed/NCBI

30 

Kurtz S, Regenbogen M, Goldiner I, Horowitz N and Moshkowitz M: No association between Helicobacter pylori infection or CagA-bearing strains and glaucoma. J Glaucoma. 17:223–226. 2008. View Article : Google Scholar : PubMed/NCBI

31 

Jindal V: Glaucoma: An extension of various chronic neurodegenerative disorders. Mol Neurobiol. 48:186–189. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Wang M, Lin HT, Bai YJ, Ge J and Zhuo YH: Clinical evidence in concurrence of retinitis pigmentosa and glaucoma. Chin Med J Engl. 124:1270–1274. 2011.PubMed/NCBI

33 

Lee S, Van Bergen NJ, Kong GY, Chrysostomou V, Waugh HS, O'Neill EC, Crowston JG and Trounce IA: Mitochondrial dysfunction in glaucoma and emerging bioenergetic therapies. Exp Eye Res. 93:204–212. 2011. View Article : Google Scholar : PubMed/NCBI

34 

Lin CC, Hu CC, Ho JD, Chiu HW and Lin HC: Obstructive sleep apnea and increased risk of glaucoma: A population-based matched-cohort study. Ophthalmology. 120:1559–1564. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Leske MC: The epidemiology of open-angle glaucoma: A review. Am J Epidemiol. 118:166–186. 1983. View Article : Google Scholar : PubMed/NCBI

36 

Lachkar Y and Bouassida W: Drug-induced acute angle closure glaucoma. Curr Opin Ophthalmol. 18:129–133. 2007. View Article : Google Scholar : PubMed/NCBI

37 

Jones R III and Rhee DJ: Corticosteroid-induced ocular hypertension and glaucoma: A brief review and update of the literature. Curr Opin Ophthalmol. 17:163–167. 2006.PubMed/NCBI

38 

McMonnies CW: An examination of the hypothesis that intraocular pressure elevation episodes can have prognostic significance in glaucoma suspects. J Optom. 8:223–231. 2014. View Article : Google Scholar : PubMed/NCBI

39 

McMonnies CW: Intraocular pressure spikes in keratectasia axial myopia and glaucoma. Optom Vis Sc. 85:1018–1026. 2008. View Article : Google Scholar

40 

Li M, Wang M, Guo W, Wang J and Sun X: The effect of caffeine on intraocular pressure: A systematic review and meta-analysis. Graefes Arch Clin Exp Ophthalmol. 249:435–442. 2011. View Article : Google Scholar : PubMed/NCBI

41 

Sommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt J and Singh K: Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 109:1090–1095. 1991. View Article : Google Scholar : PubMed/NCBI

42 

Weinreb RN, Aung T and Medeiros FA: The pathophysiology and treatment of glaucoma: A review. JAMA. 311:1901–1911. 2014. View Article : Google Scholar : PubMed/NCBI

43 

Fingert JH: Primary open-angle glaucoma genes. Eye Lond. 25:587–595. 2011. View Article : Google Scholar : PubMed/NCBI

44 

Teikari JM, Airaksinen PJ, Kaprio J and Koskenvuo M: Primary open-angle glaucoma in 2 monozygotic twin pairs. Acta Ophthalmol Copenh. 65:607–611. 1987. View Article : Google Scholar : PubMed/NCBI

45 

Biró I: Notes on the heredity of glaucoma. Ophthalmologica. 98:43–50. 1939. View Article : Google Scholar

46 

Ahram DF, Alward WL and Kuehn MH: The genetic mechanisms of primary angle closure glaucoma. Eye Lond. 29:1251–1259. 2015. View Article : Google Scholar : PubMed/NCBI

47 

King A, Azuara-Blanco A and Tuulonen A: Glaucoma. BMJ. 346:f35182013. View Article : Google Scholar : PubMed/NCBI

48 

Friedman DS, Wolfs RC, O'Colmain BJ, Klein BE, Taylor HR, West S, Leske MC, Mitchell P, Congdon N and Kempen J: Eye Diseases Prevalence Research Group: Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol. 122:532–538. 2004. View Article : Google Scholar : PubMed/NCBI

49 

He M, Foster PJ, Ge J, Huang W, Zheng Y, Friedman DS, Lee PS and Khaw PT: Prevalence and clinical characteristics of glaucoma in adult Chinese: A population-based study in Liwan District, Guangzhou. Invest Ophthalmol Vis Sci. 47:2782–2788. 2006. View Article : Google Scholar : PubMed/NCBI

50 

Abu-Amero K, Kondkar AA and Chalam KV: An updated review on the genetics of primary open angle glaucoma. Int J Mol Sci. 16:28886–28911. 2015. View Article : Google Scholar : PubMed/NCBI

51 

Friedman DS, Jampel HD, Muñoz B and West SK: The prevalence of open-angle glaucoma among blacks and whites 73 years and older: The salisbury eye evaluation glaucoma study. Arch Ophthalmol. 124:1625–1630. 2006. View Article : Google Scholar : PubMed/NCBI

52 

Mukesh BN, McCarty CA, Rait JL and Taylor HR: Five-year incidence of open-angle glaucoma: The visual impairment project. Ophthalmology. 109:1047–1051. 2002. View Article : Google Scholar : PubMed/NCBI

53 

de Voogd S, Ikram MK, Wolfs RC, Jansonius NM, Hofman A and de Jong PT: Incidence of open-angle glaucoma in a general elderly population: The rotterdam study. Ophthalmology. 112:1487–1493. 2005. View Article : Google Scholar : PubMed/NCBI

54 

Wang X, Harmon J, Zabrieskie N, Chen Y, Grob S, Williams B, Lee C, Kasuga D, Shaw PX, Buehler J, et al: Using the utah population database to assess familial risk of primary open angle glaucoma. Vis Res. 50:2391–2395. 2010. View Article : Google Scholar : PubMed/NCBI

55 

Lowe RF: Primary angle-closure glaucoma. Inheritance and environment. Br J Ophthalmol. 56:13–20. 1972. View Article : Google Scholar : PubMed/NCBI

56 

Alsbirk PH: Anterior chamber depth and primary angle-closure glaucoma. II. A genetic study. Acta Ophthalmol Copenh. 53:436–449. 1975. View Article : Google Scholar : PubMed/NCBI

57 

Alsbirk PH: Anterior chamber depth and primary angle-closure glaucoma. I. An epidemiologic study in Greenland Eskimos. Acta Ophthalmol Copenh. 53:89–104. 1975. View Article : Google Scholar : PubMed/NCBI

58 

Alsbirk PH: Primary angle-closure glaucoma. Oculometry, epidemiology, and genetics in a high risk population. Acta Ophthalmol Suppl. 5–31. 1976.PubMed/NCBI

59 

Hu CN: An epidemiologic study of glaucoma in Shunyi County Beijing. Zhonghua Yan Ke Za Zhi. 25:115–119. 1989.(In Chinese). PubMed/NCBI

60 

He M, Wang D, Zheng Y, Zhang J, Yin Q, Huang W, Mackey DA and Foster PJ: Heritability of anterior chamber depth as an intermediate phenotype of angle-closure in Chinese: The Guangzhou twin eye study. Invest Ophthalmol Vis Sci. 49:81–86. 2008. View Article : Google Scholar : PubMed/NCBI

61 

van Koolwijk LM, Despriet DD, van Duijn CM, Cortes Pardo LM, Vingerling JR, Aulchenko YS, Oostra BA, Klaver CC and Lemij HG: Genetic contributions to glaucoma: Heritability of intraocular pressure, retinal nerve fiber layer thickness, and optic disc morphology. Invest Ophthalmol Vis Sci. 48:3669–3676. 2007. View Article : Google Scholar : PubMed/NCBI

62 

Day AC, Baio G, Gazzard G, Bunce C, Azuara-Blanco A, Munoz B, Friedman DS and Foster PJ: The prevalence of primary angle closure glaucoma in European derived populations: A systematic review. Br J Ophthalmol. 96:1162–1167. 2012. View Article : Google Scholar : PubMed/NCBI

63 

Liu Y and Allingham RR: Major review: Molecular genetics of primary open-angle glaucoma. Exp Eye Res. 160:62–84. 2017. View Article : Google Scholar : PubMed/NCBI

64 

Stone EM, Fingert JH, Alward WL, Nguyen TD, Polansky JR, Sunden SL, Nishimura D, Clark AF, Nystuen A, Nichols BE, et al: Identification of a gene that causes primary open angle glaucoma. Science. 275:668–670. 1997. View Article : Google Scholar : PubMed/NCBI

65 

Kumar S, Malik MA, Goswami S, Sihota R and Kaur J: Candidate genes involved in the susceptibility of primary open angle glaucoma. Gene. 577:119–131. 2016. View Article : Google Scholar : PubMed/NCBI

66 

Sarfarazi M, Child A, Stoilova D, Brice G, Desai T, Trifan OC, Poinoosawmy D and Crick RP: Localization of the fourth locus (GLC1E) for adult-onset primary open-angle glaucoma to the 10p15-p14 region. Am J Hum Genet. 62:641–652. 1998. View Article : Google Scholar : PubMed/NCBI

67 

Miyazawa A, Fuse N, Mengkegale M, Ryu M, Seimiya M, Wada Y and Nishida K: Association between primary open-angle glaucoma and WDR36 DNA sequence variants in Japanese. Mol Vis. 13:1912–1919. 2007.PubMed/NCBI

68 

Mookherjee S, Chakraborty S, Vishal M, Banerjee D, Sen A and Ray K: WDR36 variants in East Indian primary open-angle glaucoma patients. Mol Vis. 17:2618–2627. 2011.PubMed/NCBI

69 

Jia LY, Tam PO, Chiang SW, Ding N, Chen LJ, Yam GH, Pang CP and Wang NL: Multiple gene polymorphisms analysis revealed a different profile of genetic polymorphisms of primary open-angle glaucoma in northern Chinese. Mol Vis. 15:89–98. 2009.PubMed/NCBI

70 

Pasutto F, Matsumoto T, Mardin CY, Sticht H, Brandstätter JH, Michels-Rautenstrauss K, Weisschuh N, Gramer E, Ramdas WD, van Koolwijk LM, et al: Heterozygous NTF4 mutations impairing neurotrophin-4 signaling in patients with primary open-angle glaucoma. Am J Hum Genet. 85:447–456. 2009. View Article : Google Scholar : PubMed/NCBI

71 

Pasutto F, Keller KE, Weisschuh N, Sticht H, Samples JR, Yang YF, Zenkel M, Schlötzer-Schrehardt U, Mardin CY, Frezzotti P, et al: Variants in ASB10 are associated with open-angle glaucoma. Hum Mol Genet. 21:1336–1349. 2012. View Article : Google Scholar : PubMed/NCBI

72 

Fuse N: Genetic basies for glaucoma. Tohoku J Exp Med. 221:1–10. 2010. View Article : Google Scholar : PubMed/NCBI

73 

Gemenetzi M, Yang Y and Lotery AJ: Current concepts on primary open-angle glaucoma genetics: A contribution to disease pathophysiology and future treatment. Eye (Lond). 26:355–369. 2012. View Article : Google Scholar : PubMed/NCBI

74 

Allingham RR, Liu Y and Rhee DJ: The genetics of primary open-angle glaucoma: A review. Exp Eye Res. 88:837–844. 2009. View Article : Google Scholar : PubMed/NCBI

75 

Davis LK, Meyer KJ, Schindler EI, Beck JS, Rudd DS, Grundstad AJ, Scheetz TE, Braun TA, Fingert JH, Alward WL, et al: Copy number variations and primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 52:7122–7133. 2011. View Article : Google Scholar : PubMed/NCBI

76 

Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, et al: Global variation in copy number in the human genome. Nature. 444:444–454. 2006. View Article : Google Scholar : PubMed/NCBI

77 

Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Héon E, Krupin T, Ritch R, Kreutzer D, et al: Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 295:1077–1079. 2002. View Article : Google Scholar : PubMed/NCBI

78 

Monemi S, Spaeth G, DaSilva A, Popinchalk S, Ilitchev E, Liebmann J, Ritch R, Héon E, Crick RP, Child A and Sarfarazi M: Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1. Hum Mol Genet. 14:725–733. 2005. View Article : Google Scholar : PubMed/NCBI

79 

Rangachari K, Dhivya M, Pandaranayaka Eswari PJ, Prasanthi N, Sundaresan P, Krishnadas SR and Krishnaswamy S: Glaucoma database. Bioinformation. 5:398–399. 2011. View Article : Google Scholar : PubMed/NCBI

80 

Fingert JH, Robin AL, Stone JL, Roos BR, Davis LK, Scheetz TE, Bennett SR, Wassink TH, Kwon YH, Alward WL, et al: Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Hum Mol Genet. 20:2482–2494. 2011. View Article : Google Scholar : PubMed/NCBI

81 

Porter LF, Urquhart JE, O'Donoghue E, Spencer AF, Wade EM, Manson FD and Black GC: Identification of a novel locus for autosomal dominant primary open angle glaucoma on 4q35.1-q35.2. Invest Ophthalmol Vis Sci. 52:7859–7865. 2011. View Article : Google Scholar : PubMed/NCBI

82 

Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, et al: Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet. 84:664–671. 2009. View Article : Google Scholar : PubMed/NCBI

83 

Kaur K, Mandal AK and Chakrabarti S: Primary congenital glaucoma and the involvement of CYP1B1. Middle East Afr J Ophthalmol. 18:7–16. 2011. View Article : Google Scholar : PubMed/NCBI

84 

Fuchshofer R and Tamm ER: The role of TGF-β in the pathogenesis of primary open-angle glaucoma. Cell Tissue Res. 347:279–290. 2012. View Article : Google Scholar : PubMed/NCBI

85 

Millá E, Hernan I, Gamundi MJ, Martínez-Gimeno M and Carballo M: Novel LMX1B mutation in familial nail-patella syndrome with variable expression of open angle glaucoma. Mol Vis. 13:639–648. 2007.PubMed/NCBI

86 

Vishal M, Sharma A, Kaurani L, Alfano G, Mookherjee S, Narta K, Agrawal J, Bhattacharya I, Roychoudhury S, Ray J, et al: Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma. BMC Med Genomics. 9:152016. View Article : Google Scholar : PubMed/NCBI

87 

Al-Dabbagh N, Al-Shahrani H, Al-Dohayan N, Mustafa M, Arfin M and Al-Asmari AK: The SPARC-related modular calcium binding protein 2 (SMOC2) gene polymorphism in primary glaucoma: A case-control study. Clin Ophthalmol. 11:549–555. 2017. View Article : Google Scholar : PubMed/NCBI

88 

Chakrabarti S, Kaur K, Rao KN, Mandal AK, Kaur I, Parikh RS and Thomas R: The transcription factor gene FOXC1 exhibits a limited role in primary congenital glaucoma. Invest Ophthalmol Vis Sci. 50:75–83. 2009. View Article : Google Scholar : PubMed/NCBI

89 

Moazzeni H, Akbari MT, Yazdani S and Elahi E: Expression of CXCL6 and BBS5 that may be glaucoma relevant genes is regulated by PITX2. Gene. 593:76–83. 2016. View Article : Google Scholar : PubMed/NCBI

90 

Othman MI, Sullivan SA, Skuta GL, Cockrell DA, Stringham HM, Downs CA, Fornés A, Mick A, Boehnke M, Vollrath D and Richards JE: Autosomal dominant nanophthalmos (NNO1)with high hyperopia and angle-closure glaucomamaps to chromosome 11. Am J Hum Genet. 63:1411–8. 1998. View Article : Google Scholar : PubMed/NCBI

91 

Nongpiur ME, Khor CC, Jia H, Cornes BK, Chen LJ, Qiao C, Nair KS, Cheng CY, Xu L, George R, et al: ABCC5, a gene that influences the anterior chamber depth, is associated with primary angle closure glaucoma. PLoS Genet. 10:e10040892014. View Article : Google Scholar : PubMed/NCBI

92 

Simpson A, Avdic A, Roos BR, DeLuca A, Miller K, Schnieders MJ, Scheetz TE, Alward WL and Fingert JH: LADD syndrome with glaucoma is caused by a novel gene. Mol Vis. 23:179–184. 2017.PubMed/NCBI

93 

Wu MY, Wu Y, Zhang Y, Liu CY, Deng CY, Peng L and Zhou L: Associations between matrix metalloproteinase gene polymorphisms and glaucoma susceptibility: A meta-analysis. BMC Ophthalmol. 17:482017. View Article : Google Scholar : PubMed/NCBI

94 

Micheal S, Saksens NTM, Hogewind BF, Khan MI, Hoyng CB and den Hollander AI: Identification of TP53BP2 as a novel candidate gene for primary open angle glaucoma by whole exome sequencing in a large multiplex family. Mol Neurobiol. 55:1387–1395. 2018. View Article : Google Scholar : PubMed/NCBI

95 

Liao RF, Zhong ZL, Ye MJ, Han LY, Ye DQ and Chen JJ: Identification of mutations in myocilin and beta-1,4-galactosyltransferase 3 genes in a Chinese family with primary open-angle glaucoma. Chin Med J (Engl). 129:2810–2815. 2016. View Article : Google Scholar : PubMed/NCBI

96 

Vithana EN, Aung T, Khor CC, Cornes BK, Tay WT, Sim X, Lavanya R, Wu R, Zheng Y, Hibberd ML, et al: Collagen-related genes influence the glaucoma risk factor, central corneal thickness. Hum Mol Genet. 20:649–658. 2011. View Article : Google Scholar : PubMed/NCBI

97 

Janssen SF, Gorgels TG, van der Spek PJ, Jansonius NM and Bergen AA: In silico analysis of the molecular machinery underlying aqueous humor production: Potential implications for glaucoma. J Clin Bioinforma. 3:212013. View Article : Google Scholar : PubMed/NCBI

98 

Tezel G: TNF-alpha signaling in glaucomatous neurodegeneration. Prog Brain Res. 173:409–421. 2008. View Article : Google Scholar : PubMed/NCBI

99 

Fujikawa K, Iwata T, Inoue K, Akahori M, Kadotani H, Fukaya M, Watanabe M, Chang Q, Barnett EM and Swat W: VAV2 and VAV3 as candidate disease genes for spontaneous glaucoma in mice and humans. PLoS One. 5:e90502010. View Article : Google Scholar : PubMed/NCBI

100 

Cao D, Liu X, Guo X, Cong Y, Huang J and Mao Z: Investigation of the association between CALCRL polymorphisms and primary angle closure glaucoma. Mol Vis. 15:2202–2208. 2009.PubMed/NCBI

101 

Awadalla MS, Burdon KP, Thapa SS, Hewitt AW and Craig JE: A cross-ethnicity investigation of genes previously implicated in primary angle closure glaucoma. Mol Vis. 18:2247–2254. 2012.PubMed/NCBI

102 

Mabuchi F, Sakurada Y, Kashiwagi K, Yamagata Z, Iijima H and Tsukahara S: Association between genetic variants associated with vertical cup-to-disc ratio and phenotypic features of primary open-angle glaucoma. Ophthalmology. 119:1819–1825. 2012. View Article : Google Scholar : PubMed/NCBI

103 

Junglas B, Kuespert S, Seleem AA, Struller T, Ullmann S, Bösl M, Bosserhoff A, Köstler J, Wagner R, Tamm ER and Fuchshofer R: Connective tissue growth factor causes glaucoma by modifying the actin cytoskeleton of the trabecular meshwork. Am J Pathol. 180:2386–2403. 2012. View Article : Google Scholar : PubMed/NCBI

104 

Wang CY, Shen YC, Wei LC, Lin KH, Feng SC, Yang YY, Chiu CH and Tsai HY: Polymorphism in the TNF-α(−863) locus associated with reduced risk of primary open angle glaucoma. Mol Vis. 18:779–785. 2012.PubMed/NCBI

105 

Dursun O, Yilmaz A, Ayaz L and Tamer L: Serum levels and H/L gene polymorphism of mannose-binding lectin in primary open angle glaucoma. Curr Eye Res. 37:212–217. 2012. View Article : Google Scholar : PubMed/NCBI

106 

Kang JH, Wiggs JL, Haines J, Abdrabou W and Pasquale LR: Reproductive factors and NOS3 variant interactions in primary open-angle glaucoma. Mol Vis. 17:2544–2551. 2011.PubMed/NCBI

107 

Awadalla MS, Thapa SS, Burdon KP, Hewitt AW and Craig JE: The association of hepatocyte growth factor (HGF) gene with primary angle closure glaucoma in the Nepalese population. Mol Vis. 17:2248–2254. 2011.PubMed/NCBI

108 

Wittström E, Ponjavic V, Bondeson ML and Andréasson S: Anterior segment abnormalities and angle-closure glaucoma in a family with a mutation in the BEST1 gene and Best vitelliform macular dystrophy. Ophthalmic Genet. 32:217–227. 2011. View Article : Google Scholar : PubMed/NCBI

109 

Fernández-Martínez L, Letteboer S, Mardin CY, Weisschuh N, Gramer E, Weber BH, Rautenstrauss B, Ferreira PA, Kruse FE, Reis A, et al: Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma. Eur J Hum Genet. 19:445–451. 2011. View Article : Google Scholar : PubMed/NCBI

110 

Mookherjee S, Banerjee D, Chakraborty S, Banerjee A, Mukhopadhyay I, Sen A and Ray K: Association of IL1A and IL1B loci with primary open angle glaucoma. BMC Med Genet. 11:992010. View Article : Google Scholar : PubMed/NCBI

111 

Zhou T, Souzeau E, Sharma S, Siggs OM, Goldberg I, Healey PR, Graham S, Hewitt AW, Mackey DA, Casson RJ, et al: Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma. Mol Genet Genomic Med. 4:624–633. 2016. View Article : Google Scholar : PubMed/NCBI

112 

Álvarez L, García M, González-Iglesias H, Escribano J, Rodríguez-Calvo PP, Fernández-Vega L and Coca-Prados M: LOXL1 gene variants and their association with pseudoexfoliation glaucoma (XFG) in Spanish patients. BMC Med Genet. 16:722015. View Article : Google Scholar : PubMed/NCBI

113 

Khawaja AP, Bailey Cooke JN, Kang JH, Allingham RR, Hauser MA, Brilliant M, Budenz DL, Christen WG, Fingert J, Gaasterland D, et al: Assessing the association of mitochondrial genetic variation with primary open-angle glaucoma using gene-set analyses. Invest Ophthalmol Vis Sci. 57:5046–5052. 2016. View Article : Google Scholar : PubMed/NCBI

114 

Bailey JN, Loomis SJ, Kang JH, Allingham RR, Gharahkhani P, Khor CC, Burdon KP, Aschard H, Chasman DI, Igo RP Jr, et al: Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet. 48:189–194. 2016. View Article : Google Scholar : PubMed/NCBI

115 

Lascaratos G, Garway-Heath DF, Willoughby CE, Chau KY and Schapira AH: Mitochondrial dysfunction in glaucoma: Understanding genetic influences. Mitochondrion. 12:202–212. 2012. View Article : Google Scholar : PubMed/NCBI

116 

Liu Y, Bailey JC, Helwa I, Dismuke WM, Cai J, Drewry M, Brilliant MH, Budenz DL, Christen WG, Chasman DI, et al: A common variant in MIR182 is associated with primary open-angle glaucoma in the NEIGHBORHOOD consortium. Invest Ophthalmol Vis Sci. 57:3974–3981. 2016. View Article : Google Scholar : PubMed/NCBI

117 

Chandra A, Abbas S, Raza ST, Singh L, Rizvi S and Mahdi F: Polymorphism of CYP46A1 and PPARγ2 genes in risk prediction of primary open angle glaucoma among North Indian population. Middle East Afr J Ophthalmol. 23:172–176. 2016. View Article : Google Scholar : PubMed/NCBI

118 

Shah MH, Tabanera N, Krishnadas SR, Pillai MR, Bovolenta P and Sundaresan P: Identification and characterization of variants and a novel 4 bp deletion in the regulatory region of SIX6, a risk factor for primary open-angle glaucoma. Mol Genet Genomic Med. 5:323–335. 2017. View Article : Google Scholar : PubMed/NCBI

119 

Skowronska-Krawczyk D, Zhao L, Zhu J, Weinreb RN, Cao G, Luo J, Flagg K, Patel S, Wen C, Krupa M, et al: P16INK4a upregulation mediated by SIX6 defines retinal ganglion cell pathogenesis in glaucoma. Mol Cell. 59:931–940. 2015. View Article : Google Scholar : PubMed/NCBI

120 

Shin HY, Park SW, Jung SH, Park HY, Jung KI, Chung YJ and Park CK: No evidence of association of heterozygous galactosylceramidase deletion with normal-tension glaucoma in a Korean population. J Glaucoma. 25:e504–e506. 2016. View Article : Google Scholar : PubMed/NCBI

121 

Nowak A, Majsterek I, Przybyłowska-Sygut K, Pytel D, Szymanek K, Szaflik J and Szaflik JP: Analysis of the expression and polymorphism of APOE, HSP, BDNF, and GRIN2B genes associated with the neurodegeneration process in the pathogenesis of primary open angle glaucoma. Biomed Res Int. 2015:2582812015. View Article : Google Scholar : PubMed/NCBI

122 

Chen Y, Lin Y, Vithana EN, Jia L, Zuo X, Wong TY, Chen LJ, Zhu X, Tam PO, Gong B, et al: Common variants near ABCA1 and in PMM2 are associated with primary open-angle glaucoma. Nat Genet. 46:1115–1119. 2014. View Article : Google Scholar : PubMed/NCBI

123 

Ayub H, Khan MI, Micheal S, Akhtar F, Ajmal M, Shafique S, Ali SH, den Hollander AI, Ahmed A, Qamar R, et al: Association of eNOS and HSP70 gene polymorphisms with glaucoma in Pakistani cohorts. Mol Vis. 16:18–25. 2010.PubMed/NCBI

124 

Carbone MA, Chen Y, Hughes GA, Weinreb RN, Zabriskie NA, Zhang K and Anholt RR: Genes of the unfolded protein response pathway harbor risk alleles for primary open angle glaucoma. PLoS One. 6:e206492011. View Article : Google Scholar : PubMed/NCBI

125 

Ayub H, Micheal S, Akhtar F, Khan MI, Bashir S, Waheed NK, Ali M, Schoenmaker-Koller FE, Shafique S, Qamar R and Hollander AI: Association of a polymorphism in the BIRC6 gene with pseudoexfoliative glaucoma. PLoS One. 9:e1050232014. View Article : Google Scholar : PubMed/NCBI

126 

Chen Y, Chen X, Wang L, Hughes G, Qian S and Sun X: Extended association study of PLEKHA7 and COL11A1 with primary angle closure glaucoma in a Han Chinese population. Invest Ophthalmol Vis Sci. 55:3797–3802. 2014. View Article : Google Scholar : PubMed/NCBI

127 

Cuchra M, Szaflik JP, Przybylowska-Sygut K, Gacek M, Kaminska A, Szaflik J and Majsterek I: The role of the 148 Asp/Glu polymorphism of the APE1 gene in the development and progression of primary open angle glaucoma development in the Polish population. Pol J Pathol. 64:296–302. 2013. View Article : Google Scholar : PubMed/NCBI

128 

Surgucheva I and Surguchov A: Expression of caveolin in trabecular meshwork cells and its possible implication in pathogenesis of primary open angle glaucoma. Mol Vis. 17:2878–2888. 2011.PubMed/NCBI

129 

Thorleifsson G, Walters GB, Hewitt AW, Masson G, Helgason A, DeWan A, Sigurdsson A, Jonasdottir A, Gudjonsson SA, Magnusson KP, et al: Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet. 42:906–909. 2010. View Article : Google Scholar : PubMed/NCBI

130 

Yu-Wai-Man P, Stewart JD, Hudson G, Andrews RM, Griffiths PG, Birch MK and Chinnery PF: OPA1 increases the risk of normal but not high tension glaucoma. J Med Genet. 47:120–125. 2010. View Article : Google Scholar : PubMed/NCBI

131 

Mossböck G, Weger M, Faschinger C, Schmut O and Renner W: Plasminogen activator inhibitor-1 4G/5G gene polymorphism and primary open-angle glaucoma. Mol Vis. 14:1240–1244. 2008.PubMed/NCBI

132 

Wang WH, McNatt LG, Pang IH, Hellberg PE, Fingert JH, McCartney MD and Clark AF: Increased expression of serum amyloid A in glaucoma and its effect on intraocular pressure. Invest Ophthalmol Vis Sci. 49:1916–1923. 2008. View Article : Google Scholar : PubMed/NCBI

133 

Micheal S, Hogewind BF, Khan MI, Siddiqui SN, Zafar SN, Akhtar F, Qamar R, Hoyng CB and den Hollander AI: Variants in the PRPF8 gene are associated with glaucoma. Mol Neurobiol. 55:4504–4510. 2018.PubMed/NCBI

134 

Woo SJ, Kim JY, Kim DM, Park SS, Ko HS and Yoo T: Investigation of the association between 677C>T and 1298A>C 5,10-methylenetetra-hydrofolate reductase gene polymorphisms and normal-tension glaucoma. Eye Lond. 23:17–24. 2009. View Article : Google Scholar : PubMed/NCBI

135 

Clement CI, Goldberg I, Healey PR and Graham SL: Plasma homocysteine, MTHFR gene mutation, and open-angle glaucoma. J Glaucoma. 18:73–78. 2009. View Article : Google Scholar : PubMed/NCBI

136 

Bhattacharya SK, Rockwood EJ, Smith SD, Bonilha VL, Crabb JS, Kuchtey RW, Robertson NG, Peachey NS, Morton CC and Crabb JW: Proteomics reveal Cochlin deposits associated with glaucomatous trabecular meshwork. J Biol Chem. 280:6080–6084. 2005. View Article : Google Scholar : PubMed/NCBI

137 

Bhattacharya SK, Crabb JS, Bonilha VL, Gu X, Takahara H and Crabb JW: Proteomics implicates peptidyl arginine deiminase 2 and optic nerve citrullination in glaucoma pathogenesis. Invest Ophthalmol Vis Sci. 47:2508–2514. 2006. View Article : Google Scholar : PubMed/NCBI

138 

Vishal M, Sharma A, Kaurani L, Alfano G, Mookherjee S, Narta K, Agrawal J, Bhattacharya I, Roychoudhury S, Ray JB, et al: Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma. MC Med Genomics. 9:152016. View Article : Google Scholar

139 

Lu Y, Vitart V, Burdon KP, Khor CC, Bykhovskaya Y, Mirshahi A, Hewitt AW, Koehn D, Hysi PG, Ramdas WD, et al: Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus. Nat Genet. 45:155–163. 2013. View Article : Google Scholar : PubMed/NCBI

140 

Othman MI, Sullivan SA, Skuta GL, Cockrell DA, Stringham HM, Downs CA, Fornés A, Mick A, Boehnke M, Vollrath D and Richards JE: Autosomal dominant nanophthalmos (NNO1) with high hyperopia and angle-closure glaucoma maps to chromosome 11. Am J Hum Genet. 63:1411–1418. 1998. View Article : Google Scholar : PubMed/NCBI

141 

Schlötzer-Schrehardt U: New pathogenetic insights into pseudoexfoliation syndrome/glaucoma. Therapeutically relevant? Ophthalmologe. 109:944–951. 2012.(In German). View Article : Google Scholar : PubMed/NCBI

142 

Fingert JH, Héon E, Liebmann JM, Yamamoto T, Craig JE, Rait J, Kawase K, Hoh ST, Buys YM, Dickinson J, et al: Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet. 8:899–905. 1999. View Article : Google Scholar : PubMed/NCBI

143 

Sheffield VC, Stone EM, Alward WL, Drack AV, Johnson AT, Streb LM and Nichols BE: Genetic linkage of familial open angle glaucoma to chromosome 1q21-q31. Nat Genet. 4:47–50. 1993. View Article : Google Scholar : PubMed/NCBI

144 

Rasnitsyn A, Doucette L, Seifi M, Footz T, Raymond V and Walter MA: FOXC1 modulates MYOC secretion through regulation of the exocytic proteins RAB3GAP1, RAB3GAP2 and SNAP25. PLoS One. 12:e01785182017. View Article : Google Scholar : PubMed/NCBI

145 

Kubota R, Kudoh J, Mashima Y, Asakawa S, Minoshima S, Hejtmancik JF, Oguchi Y and 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. View Article : Google Scholar : PubMed/NCBI

146 

Michels-Rautenstrauss KG, Mardin CY, Budde WM, Liehr T, Polansky J, Nguyen T, Timmerman V, Van Broeckhoven C, Naumann GO, Pfeiffer RA and Rautenstrauss BW: Juvenile open angle glaucoma: Fine mapping of the TIGR gene to 1q24.3-q25.2 and mutation analysis. Hum Genet. 102:103–106. 1998. View Article : Google Scholar : PubMed/NCBI

147 

Nguyen TD, Chen P, Huang WD, Chen H, Johnson D and Polansky JR: Gene structure and properties of TIGR, an olfactomedin-related glycoprotein cloned from glucocorticoid-induced trabecular meshwork cells. J Biol Chem. 273:6341–6350. 1998. View Article : Google Scholar : PubMed/NCBI

148 

Johnson DH: Myocilin and glaucoma: A TIGR by the tail? Arch Ophthalmol. 118:974–978. 2000.PubMed/NCBI

149 

Karali A, Russell P, Stefani FH and Tamm ER: Localization of myocilin/trabecular meshwork-inducible glucocorticoid response protein in the human eye. Invest Ophthalmol Vis Sci. 41:729–740. 2000.PubMed/NCBI

150 

Abu-Amero KK, Azad TA, Spaeth GL, Myers J, Katz LJ, Moster M and Bosley TM: Unaltered myocilin expression in the blood of primary open angle glaucoma patients. Mol Vis. 18:1004–1009. 2012.PubMed/NCBI

151 

Jacobson N, Andrews M, Shepard AR, Nishimura D, Searby C, Fingert JH, Hageman G, Mullins R, Davidson BL, Kwon YH, et al: Non-secretion of mutant proteins of the glaucoma gene myocilin in cultured trabecular meshwork cells and in aqueous humor. Hum Mol Genet. 10:117–125. 2001. View Article : Google Scholar : PubMed/NCBI

152 

Joe MK, Sohn S, Hur W, Moon Y, Choi YR and Kee C: Accumulation of mutant myocilins in ER leads to ER stress and potential cytotoxicity in human trabecular meshwork cells. Biochem Biophys Res Commun. 312:592–600. 2003. View Article : Google Scholar : PubMed/NCBI

153 

Gobeil S, Rodrigue MA, Moisan S, Nguyen TD, Polansky JR, Morissette J and Raymond V: Intracellular sequestration of hetero-oligomers formed by wild-type and glaucoma-causing myocilin mutants. Invest Ophthalmol Vis Sci. 45:3560–3567. 2004. View Article : Google Scholar : PubMed/NCBI

154 

Liu Y and Vollrath D: Reversal of mutant myocilin non-secretion and cell killing: Implications for glaucoma. Hum Mol Genet. 13:1193–1204. 2004. View Article : Google Scholar : PubMed/NCBI

155 

Kwon YH, Fingert JH, Kuehn MH and Alward WL: Primary open-angle glaucoma. N Engl J Med. 360:1113–1124. 2009. View Article : Google Scholar : PubMed/NCBI

156 

Tamm ER: The functional role of myocilin in glaucoma ophthalmology research: Mechanisms of the glaucomas. Humana Press; Totowa: pp. 219–231. 2009

157 

Carbone MA, Ayroles JF, Yamamoto A, Morozova TV, West SA, Magwire MM, Mackay TF and Anholt RR: Overexpression of myocilin in the Drosophila eye activates the unfolded protein response: Implications for glaucoma. PLoS One. 4:e42162009. View Article : Google Scholar : PubMed/NCBI

158 

Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA and Mallucci GR: Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med. 5:206ra1382013. View Article : Google Scholar : PubMed/NCBI

159 

Wentz-Hunter K, Ueda J, Shimizu N and Yue BY: Myocilin is associated with mitochondria in human trabecular meshwork cells. J Cell Physiol. 190:46–53. 2002. View Article : Google Scholar : PubMed/NCBI

160 

Wentz-Hunter K, Shen X and Yue BY: Distribution of myocilin, a glaucoma gene product, in human corneal fibroblasts. Mol Vis. 9:308–314. 2003.PubMed/NCBI

161 

He Y, Leung KW, Zhuo YH and Ge J: Pro370Leu mutant myocilin impairs mitochondrial functions in human trabecular meshwork cells. Mol Vis. 15:815–825. 2009.PubMed/NCBI

162 

Kumar A, Basavaraj MG, Gupta SK, Qamar I, Ali AM, Bajaj V, Ramesh TK, Prakash DR, Shetty JS and Dorairaj SK: Role of CYP1B1, MYOC, OPTN, and OPTC genes in adult-onset primary open-angle glaucoma: predominance of CYP1B1 mutations in Indian patients. Mol Vis. 13:667–676. 2007.PubMed/NCBI

163 

Fan BJ, Wang DY, Fan DS, Tam PO, Lam DS, Tham CC, Lam CY, Lau TC and Pang CP: SNPs and interaction analyses of myocilin, optineurin, and apolipoprotein E in primary open angle glaucoma patients. Mol Vis. 11:625–631. 2005.PubMed/NCBI

164 

Forsman E, Lemmelä S, Varilo T, Kristo P, Forsius H, Sankila EM and Järvelä I: The role of TIGR and OPTN in Finnish glaucoma families: A clinical and molecular genetic study. Mol Vis. 9:217–222. 2003.PubMed/NCBI

165 

Rakhmanov VV, Nikitina NIa, Zakharova FM, Astakhov IuS, Kvasova MD, Vasil'ev VB, Golubkov VI and Mandel'shtam MIu: Mutations and polymorphisms in the genes for myocilin and optineur in as the risk factors of primary open-angle glaucoma. Genetika. 41:1567–1574. 2005.(In Russian). PubMed/NCBI

166 

Yao HY, Cheng CY, Fan BJ, Tam OS, Tham CY, Wang DY, Lam SC and Pang CP: Polymorphisms of myocilin and optineurin in primary open angle glaucoma patients. Zhonghua Yi Xue Za Zhi. 86:554–559. 2006.(In Chinese). PubMed/NCBI

167 

Park BC, Tibudan M, Samaraweera M, Shen X and Yue BY: Interaction between two glaucoma genes, optineurin and myocilin. Genes Cells. 12:969–979. 2007. View Article : Google Scholar : PubMed/NCBI

168 

Vincent AL, Billingsley G, Buys Y, Levin AV, Priston M, Trope G, Williams-Lyn D and Héon E: Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet. 70:448–460. 2002. View Article : Google Scholar : PubMed/NCBI

169 

Kaur K, Reddy AB, Mukhopadhyay A, Mandal AK, Hasnain SE, Ray K, Thomas R, Balasubramanian D and Chakrabarti S: Myocilin gene implicated in primary congenital glaucoma. Clin Genet. 67:335–340. 2005. View Article : Google Scholar : PubMed/NCBI

170 

Cai SP, Muhemaiti P, Yin Y, Cheng H, Di Ya A, Keyimu M, Cao X, Fan N, Jiang L, Yan N, et al: A novel MYOC heterozygous mutation identified in a Chinese Uygur pedigree with primary open-angle glaucoma. Mol Vis. 18:1944–1951. 2012.PubMed/NCBI

171 

Tanwar M, Kumar M, Dada T, Sihota R and Dada R: MYOC and FOXC1 gene analysis in primary congenital glaucoma. Mol Vis. 16:1996–2006. 2010.PubMed/NCBI

172 

Sirohi K and Swarup G: Defects in autophagy caused by glaucoma-associated mutations in optineurin. Exp Eye Res. 144:54–63. 2016. View Article : Google Scholar : PubMed/NCBI

173 

Lopez-Martinez F, Lopez-Garrido MP, Sanchez-Sanchez F, Campos-Mollo E, Coca-Prados M and Escribano J: Role of MYOC and OPTN sequence variations in Spanish patients with primary open-angle glaucoma. Mol Vis. 13:862–872. 2007.PubMed/NCBI

174 

Funayama T, Ishikawa K, Ohtake Y, Tanino T, Kurasaka D, Kimura I, Suzuki K, Ideta H, Nakamoto K, Yasuda N, et al: Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma. Invest Ophthal Vis Sci. 45:4359–4367. 2004. View Article : Google Scholar : PubMed/NCBI

175 

Nagabhushana A, Chalasani ML, Jain N, Radha V, Rangaraj N, Balasubramanian D and Swarup G: Regulation of endocytic trafficking of transferrin receptor by optineurin and its impairment by a glaucoma-associated mutant. BMC Cell Biol. 11:42010. View Article : Google Scholar : PubMed/NCBI

176 

Sripriya S, Nirmaladevi J, George R, Hemamalini A, Baskaran M, Prema R, Ve Ramesh S, Karthiyayini T, Amali J, Job S, et al: OPTN gene: Profile of patients with glaucoma from India. Mol Vis. 12:816–820. 2006.PubMed/NCBI

177 

Mukhopadhyay A, Komatireddy S, Acharya M, Bhattacharjee A, Mandal AK, Thakur SK, Chandrasekhar G, Banerjee A, Thomas R, Chakrabarti S and Ray K: Evaluation of Optineurin as a candidate gene in Indian patients with primary open angle glaucoma. Mol Vis. 11:792–797. 2005.PubMed/NCBI

178 

Footz TK, Johnson JL, Dubois S, Boivin N, Raymond V and Walter MA: Glaucoma-associated WDR36 variants encode functional defects in a yeast model system. Hum Mol Genet. 18:1276–1287. 2009. View Article : Google Scholar : PubMed/NCBI

179 

Fingert JH, Alward WL, Kwon YH, Shankar SP, Andorf JL, Mackey DA, Sheffield VC and Stone EM: No association between variations in the WDR36 gene and primary open-angle glaucoma. Arch Ophthalmol. 125:434–436. 2007. View Article : Google Scholar : PubMed/NCBI

180 

Liu Y, Liu W, Crooks K, Schmidt S, Allingham RR and Hauser MA: No evidence of association of heterozygous NTF4 mutations in patients with primary open-angle glaucoma. Am J Hum Genet. 86:498–499. 2010. View Article : Google Scholar : PubMed/NCBI

181 

Chen LJ, Ng TK, Fan AH, Leung DY, Zhang M, Wang N, Zheng Y, Liang XY, Chiang SW, Tam PO, et al: Evaluation of NTF4 as a causative gene for primary open-angle glaucoma. Mol Vis. 18:1763–1772. 2012.PubMed/NCBI

182 

Vithana EN, Nongpiur ME, Venkataraman D, Chan SH, Mavinahalli J and Aung T: Identification of a novel mutation in the NTF4 gene that causes primary open-angle glaucoma in a Chinese population. Mol Vis. 16:1640–1645. 2010.PubMed/NCBI

183 

Murakami K, Meguro A, Ota M, Shiota T, Nomura N, Kashiwagi K, Mabuchi F, Iijima H, Kawase K, Yamamoto T, et al: Analysis of microsatellite polymorphisms within the GLC1F locus in Japanese patients with normal tension glaucoma. Mol Vis. 16:462–466. 2010.PubMed/NCBI

184 

Keller KE, Yang YF, Sun YY, Sykes R, Acott TS and Wirtz MK: Ankyrin repeat and suppressor of cytokine signaling box containing protein-10 is associated with ubiquitin-mediated degradation pathways in trabecular meshwork cells. Mol Vis. 19:1639–1655. 2013.PubMed/NCBI

185 

Mackay DS, Bennett TM and Shiels A: Exome sequencing identifies a missense variant in EFEMP1 co-segregating in a family with autosomal dominant primary open-angle glaucoma. PLoS One. 10:e01325292015. View Article : Google Scholar : PubMed/NCBI

186 

Springelkamp H, Mishra A, Hysi PG, Gharahkhani P, Höhn R, Khor CC, Bailey Cooke JN, Luo X, Ramdas WD, Vithana E, et al: Meta-analysis of genome-wide association studies identifies novel loci associated with optic disc morphology. Genet Epidemiol. 39:207–216. 2015. View Article : Google Scholar : PubMed/NCBI

187 

Junglas B, Kuespert S, Seleem AA, Struller T, Ullmann S, Bösl M, Bosserhoff A, Köstler J, Wagner R, Tamm ER and Fuchshofer R: Connective tissue growth factor causes glaucoma by modifying the actin cytoskeleton of the trabecular meshwork. Am J Pathol. 180:2386–2403. 2012. View Article : Google Scholar : PubMed/NCBI

188 

Fuchshofer R, Stephan DA, Russell P and Tamm ER: Gene expression profiling of TGFbeta2- and/or BMP7-treated trabecular meshwork cells: Identification of Smad7 as a critical inhibitor of TGF-beta2 signaling. Exp Eye Res. 88:1020–1032. 2009. View Article : Google Scholar : PubMed/NCBI

189 

Keller KE, Yang YF, Sun YY, Sykes R, Gaudette ND, Samples JR, Acott TS and Wirtz MK: Interleukin-20 receptor expression in the trabecular meshwork and its implication in glaucoma. J Ocul Pharmacol Ther. 30:267–276. 2014. View Article : Google Scholar : PubMed/NCBI

190 

Wirtz MK and Keller KE: The role of the IL-20 subfamily in glaucoma. Mediators Inflamm. 2016:40837352016. View Article : Google Scholar : PubMed/NCBI

191 

Howell GR, Walton DO, King BL, Libby RT and John SW: Datgan, a reusable software system for facile interrogation and visualization of complex transcription profiling data. BMC Genomics. 12:4292011. View Article : Google Scholar : PubMed/NCBI

192 

Narooie-Nejad M, Paylakhi SH, Shojaee S, Fazlali Z, Kanavi Rezaei M, Nilforushan N, Yazdani S, Babrzadeh F, Suri F, Ronaghi M, et al: Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma. Hum Mol Genet. 18:3969–3977. 2009. View Article : Google Scholar : PubMed/NCBI

193 

Sarfarazi M: Recent advances in molecular genetics of glaucomas. Hum Mol Genet. 6:1667–1677. 1997. View Article : Google Scholar : PubMed/NCBI

194 

Choudhary D, Jansson I, Rezaul K, Han DK, Sarfarazi M and Schenkman JB: Cyp1b1 protein in the mouse eye during development: An immunohistochemical study. Drug Metab Dispos. 35:987–994. 2007. View Article : Google Scholar : PubMed/NCBI

195 

Li N, Zhou Y, Du L, Wei M and Chen X: Overview of cytochrome P450 1B1 gene mutations in patients with primary congenital glaucoma. Exp Eye Res. 93:572–579. 2011. View Article : Google Scholar : PubMed/NCBI

196 

Plásilová M, Stoilov I, Sarfarazi M, Kádasi L, Feráková E and Ferák V: Identification of a single ancestral CYP1B1 mutation in Slovak Gypsies (Roms) affected with primary congenital glaucoma. J Med Genet. 36:290–294. 1999.PubMed/NCBI

197 

Do T, Shei W, Chau PT, Trang DL, Yong VH, Ng XY, Chen YM, Aung T and Vithana EN: CYP1B1 and MYOC mutations in vietnamese primary congenital glaucoma patients. J Glaucoma. 25:e491–e498. 2016. View Article : Google Scholar : PubMed/NCBI

198 

Hogewind BF, Gaplovska-Kysela K, Theelen T, Cremers FP, Yam GH, Hoyng CB and Mukhopadhyay A: Identification and functional characterization of a novel MYOC mutation in two primary open angle glaucoma families from The Netherlands. Mol Vis. 13:1793–1801. 2007.PubMed/NCBI

199 

Patel HY, Richards AJ, De Karolyi B, Best SJ, Danesh-Meyer HV and Vincent AL: Screening glaucoma genes in adult glaucoma suggests a multiallelic contribution of CYP1B1 to open-angle glaucoma phenotypes. Clin Exp Ophthalmol. 40:e208–e217. 2012. View Article : Google Scholar : PubMed/NCBI

200 

López-Garrido MP, Sánchez-Sánchez F, López-Martínez F, Aroca-Aguilar JD, Blanco-Marchite C, Coca-Prados M and Escribano J: Heterozygous CYP1B1 gene mutations in Spanish patients with primary open-angle glaucoma. Mol Vis. 12:748–755. 2006.PubMed/NCBI

201 

Acharya M, Mookherjee S, Bhattacharjee A, Bandyopadhyay AK, Thakur Daulat SK, Bhaduri G, Sen A and Ray K: Primary role of CYP1B1 in Indian juvenile-onset POAG patients. Mol Vis. 12:399–404. 2006.PubMed/NCBI

202 

Zenteno JC, Hernandez-Merino E, Mejia-Lopez H, Matías-Florentino M, Michel N, Elizondo-Olascoaga C, Korder-Ortega V, Casab-Rueda H and Garcia-Ortiz JE: Contribution of CYP1B1 mutations and founder effect to primary congenital glaucoma in Mexico. J Glaucoma. 17:189–192. 2008. View Article : Google Scholar : PubMed/NCBI

203 

Faiq MA, Dada R, Qadri R and Dada T: CYP1B1-mediated pathobiology of primary congenital glaucoma. J Curr Glaucoma Pract. 9:77–80. 2015. View Article : Google Scholar : PubMed/NCBI

204 

Sarfarazi M and Stoilov I: Molecular genetics of primary congenital glaucoma. Eye Lond. 14:422–428. 2000. View Article : Google Scholar : PubMed/NCBI

205 

Kakiuchi-Matsumoto T, Isashiki Y, Ohba N, Kimura K, Sonoda S and Unoki K: Cytochrome P450 1B1 gene mutations in Japanese patients with primary congenital glaucoma(1). Am J Ophthalmol. 131:345–350. 2001. View Article : Google Scholar : PubMed/NCBI

206 

Kabra M, Zhang W, Rathi S, Mandal AK, Senthil S, Pyatla G, Ramappa M, Banerjee S, Shekhar K, Marmamula S, et al: Angiopoietin receptor TEK interacts with CYP1B1 in primary congenital glaucoma. Hum Genet. 136:941–949. 2017. View Article : Google Scholar : PubMed/NCBI

207 

Mohanty K, Tanwar M, Dada R and Dada T: Screening of the LTBP2 gene in a north Indian population with primary congenital glaucoma. Mol Vis. 19:78–84. 2013.PubMed/NCBI

208 

Safari I, Akbarian S, Yazdani S and Elahi E: A possible role for LTBP2 in the etiology of primary angle closure glaucoma. J Ophthalmic Vis Res. 10:123–129. 2015. View Article : Google Scholar : PubMed/NCBI

209 

Chen X, Chen Y, Fan BJ, Xia M, Wang L and Sun X: Screening of the LTBP2 gene in 214 Chinese sporadic CYP1B1-negative patients with primary congenital glaucoma. Mol Vis. 22:528–535. 2016.PubMed/NCBI

210 

Souma T, Tompson SW, Thomson BR, Siggs OM, Kizhatil K, Yamaguchi S, Feng L, Limviphuvadh V, Whisenhunt KN, Maurer-Stroh S, et al: Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. J Clin Invest. 126:2575–2587. 2016. View Article : Google Scholar : PubMed/NCBI

211 

Kizhatil K, Ryan M, Marchant JK, Henrich S and John SW: Schlemm's canal is a unique vessel with a combination of blood vascular and lymphatic phenotypes that forms by a novel developmental process. PLoS Biol. 12:e10019122014. View Article : Google Scholar : PubMed/NCBI

212 

Kasetti RB, Phan TN, Millar JC and Zode GS: Expression of mutant myocilin induces abnormal intracellular accumulation of selected extracellular matrix proteins in the trabecular meshwork. Invest Ophthalmol Vis Sci. 57:6058–6069. 2016. View Article : Google Scholar : PubMed/NCBI

213 

Williams AL, Eason J, Chawla B and Bohnsack BL: Cyp1b1 regulates ocular fissure closure through a retinoic acid-independent pathway. Invest Ophthalmol Vis Sci. 58:1084–1097. 2017. View Article : Google Scholar : PubMed/NCBI

214 

García-Antón MT, Salazar JJ, de Hoz R, Rojas B, Ramírez AI, Triviño A, Aroca-Aguilar JD, García-Feijoo J, Escribano J and Ramírez JM: Goniodysgenesis variability and activity of CYP1B1 genotypes in primary congenital glaucoma. PLoS One. 12:e01763862017. View Article : Google Scholar : PubMed/NCBI

215 

Reis LM, Tyler RC, Weh E, Hendee KE, Kariminejad A, Abdul-Rahman O, Ben-Omran T, Manning MA, Yesilyurt A, McCarty CA, et al: Analysis of CYP1B1 in pediatric and adult glaucoma and other ocular phenotypes. Mol Vis. 22:1229–1238. 2016.PubMed/NCBI

216 

Jain A, Zode G, Kasetti RB, Ran FA, Yan W, Sharma TP, Bugge K, Searby CC, Fingert JH, Zhang F, et al: CRISPR-Cas9-based treatment of myocilin-associated glaucoma. Proc Natl Acad Sci USA. 114:11199–11204. 2017. View Article : Google Scholar : PubMed/NCBI

217 

Daliri K, Ljubimov AV and Hekmatimoghaddam S: Glaucoma, stem cells, and gene therapy: Where are we now? Int J Stem Cells. 10:119–128. 2017. View Article : Google Scholar : PubMed/NCBI

218 

Shah SZA, Zhao D, Hussain T and Yang L: The role of unfolded protein response and mitogen-activated protein kinase signaling in neurodegenerative diseases with special focus on prion diseases. Front Aging Neurosci. 9:1202017. View Article : Google Scholar : PubMed/NCBI

219 

Chong WC, Shastri MD and Eri R: Endoplasmic reticulum stress and oxidative stress: A vicious nexus implicated in bowel disease pathophysiology. Int J Mol Sci. 18:pii: E771. 2017. View Article : Google Scholar

220 

Lindholm D, Korhonen L, Eriksson O and Kõks S: Recent insights into the role of unfolded protein response in er stress in health and disease. Front Cell Dev Biol. 5:482017. View Article : Google Scholar : PubMed/NCBI

221 

Jackrel ME and Shorter J: Protein-remodeling factors as potential therapeutics for neurodegenerative disease. Front Neurosci. 11:992017. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

July-2018
Volume 18 Issue 1

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Wang HW, Sun P, Chen Y, Jiang LP, Wu HP, Zhang W and Gao F: Research progress on human genes involved in the pathogenesis of glaucoma (Review). Mol Med Rep 18: 656-674, 2018
APA
Wang, H., Sun, P., Chen, Y., Jiang, L., Wu, H., Zhang, W., & Gao, F. (2018). Research progress on human genes involved in the pathogenesis of glaucoma (Review). Molecular Medicine Reports, 18, 656-674. https://doi.org/10.3892/mmr.2018.9071
MLA
Wang, H., Sun, P., Chen, Y., Jiang, L., Wu, H., Zhang, W., Gao, F."Research progress on human genes involved in the pathogenesis of glaucoma (Review)". Molecular Medicine Reports 18.1 (2018): 656-674.
Chicago
Wang, H., Sun, P., Chen, Y., Jiang, L., Wu, H., Zhang, W., Gao, F."Research progress on human genes involved in the pathogenesis of glaucoma (Review)". Molecular Medicine Reports 18, no. 1 (2018): 656-674. https://doi.org/10.3892/mmr.2018.9071