OPTN-Related Open-Angle Glaucoma: Disease-Characteristics Research Report

Executive summary

OPTN-related open-angle glaucoma—historically GLC1E—is a rare Mendelian form of open-angle glaucoma caused most convincingly by heterozygous pathogenic variation in OPTN, particularly p.Glu50Lys (E50K). It usually manifests as adult-onset normal-tension glaucoma (NTG): progressive retinal ganglion-cell (RGC) and optic-nerve degeneration, optic-disc cupping, retinal nerve-fiber-layer (RNFL) thinning, and corresponding visual-field loss despite untreated intraocular pressure (IOP) remaining below 21 mmHg. It should be distinguished from common, complex primary open-angle glaucoma (POAG), in which OPTN variants generally explain only a small fraction of disease. (trivli2020primaryopenangle pages 1-2, salvetat2023pharmaceuticalapproachesto pages 1-2, swarup2018alteredfunctionsand pages 1-3)

The evidence hierarchy is important. E50K has family segregation, cellular, animal-model, and human stem-cell evidence. By contrast, M98K is better regarded as a population-dependent susceptibility/modifier allele, and many other reported variants remain insufficiently validated. Current treatment is not genotype-specific: clinicians lower IOP even when it is statistically normal, monitor structural and functional progression, and escalate to laser or surgery when necessary. No approved OPTN-directed therapy or qualifying OPTN-specific interventional clinical trial was identified. (salvetat2023pharmaceuticalapproachesto pages 1-2, swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)

The following table provides a compact ontology-ready summary; the narrative below expands the evidence and identifies gaps.

Table: This table summarizes ontology-ready core facts for OPTN-related open-angle glaucoma, separating well-supported evidence such as the E50K/GLC1E association from broader NTG extrapolations and unresolved data gaps. It is designed to support structured disease knowledge-base curation.

1. Disease information

Definition and scope

Glaucoma is a chronic progressive optic neuropathy defined by loss of RGC bodies and axons, RNFL thinning, characteristic optic-nerve-head cupping, and irreversible visual-field defects. NTG is the open-angle subtype in which glaucomatous structural and functional damage occurs without measured untreated IOP elevation. The 2023 Japanese definition cited in a recent review describes NTG as POAG in which IOP remains within the statistically normal range during development of glaucomatous optic neuropathy. (salvetat2023pharmaceuticalapproachesto pages 1-2)

For knowledge-base purposes, OPTN-related open-angle glaucoma should be modeled as a rare genetic child of open-angle glaucoma/NTG, not as synonymous with all NTG. Open Targets records an OPTN–open-angle-glaucoma association for ENSG00000123240 and the broader disease MONDO:0005338, supported by five evidence records and literature including PMID 11834836. (OpenTargets Search: open-angle glaucoma-OPTN)

Identifiers and synonyms

• Preferred name: OPTN-related open-angle glaucoma
• Common synonyms: glaucoma 1, open-angle, E; GLC1E; optineurin-related glaucoma; OPTN-associated glaucoma; familial normal-tension glaucoma due to OPTN
• Gene: OPTN, optineurin; Ensembl ENSG00000123240; chromosome 10p13. (OpenTargets Search: open-angle glaucoma-OPTN, trivli2020primaryopenangle pages 1-2)
• OMIM: 137760 is commonly used for GLC1E in secondary disease resources; confirm against the live OMIM record before production ingestion.
• MONDO: no disease-specific OPTN child identifier was verified by the available tools; use MONDO:0005338, open-angle glaucoma, as a parent rather than claiming it uniquely denotes OPTN disease. (OpenTargets Search: open-angle glaucoma-OPTN)
• ICD-10-CM: typically coded clinically under primary open-angle or low/normal-tension glaucoma, with eye and stage modifiers; there is no OPTN-genotype-specific ICD-10 code.
• ICD-11/MeSH/Orphanet: no genotype-specific identifier was verified in the retrieved evidence. Map to open-angle/normal-tension glaucoma and preserve OPTN as the molecular qualifier.

This report is based on aggregated disease-level databases, published families, cohorts, reviews, and experimental models, not individual EHR-derived observations.

Landmark discovery

Rezaie and colleagues reported “Adult-onset primary open-angle glaucoma caused by mutations in optineurin” in Science on 8 February 2002, DOI 10.1126/science.1066901, PMID 11834836. Subsequent synthesis reports OPTN variants in 16.7% of the originally studied linked families, but only about 1% or less of sporadic NTG; thus the original family statistic must not be interpreted as population prevalence. E50K segregated with glaucoma in affected members older than approximately 30 years. (OpenTargets Search: open-angle glaucoma-OPTN, swarup2018alteredfunctionsand pages 1-3)

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

The clearest etiology is a heterozygous germline OPTN variant with dominant toxic or altered-function effects, especially E50K. OPTN is a multifunctional cytoplasmic adaptor involved in Golgi integrity, endosomal trafficking, autophagy/mitophagy, and inflammatory signaling. Disease is principally a neurodegeneration of RGCs and their axons rather than an infectious, neoplastic, or primary metabolic disorder. (venkatesan2025proteinmisfoldingand pages 6-7, trivli2020primaryopenangle pages 1-2, swarup2018alteredfunctionsand pages 1-3)

Genetic risk factors

• E50K/p.Glu50Lys: strongest causal evidence; dominant segregation and extensive functional/model support.
• M98K/p.Met98Lys: mechanistically active in experimental systems, but human association is stronger in some Asian populations and absent or weak in several Caucasian studies; curate as a risk/modifier allele unless case-level segregation and classification justify otherwise. (swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)
• H26D, E322K, H486R, R545Q and other reported missense alleles: evidence is heterogeneous and generally weaker than for E50K. Do not automatically label all as pathogenic. (rozpedekkaminska2020thegeneticand pages 26-28, venkatesan2025proteinmisfoldingand pages 8-9, swarup2018alteredfunctionsand pages 1-3)
• Modifier/cognate pathway genes: TBK1 is a strong mechanistic partner and an independent cause of familial NTG through copy-number gain; MYOC, WDR36 and CYP1B1 are relevant differential or panel genes. OPTN overexpression can increase endogenous MYOC in trabecular-meshwork cells, but a reproducible OPTN-specific modifier architecture has not been established. (trivli2020primaryopenangle pages 1-2)

Environmental and systemic modifiers

No exposure is known to create the germline disorder. General NTG/POAG factors may affect penetrance or progression: age, family history, myopia, thin central cornea, vascular dysregulation, migraine, Raynaud phenomenon, nocturnal hypotension, excessive antihypertensive treatment, smoking, metabolic disease, and sleep apnea/hypoxic stress. These data are extrapolated from general NTG, not demonstrated OPTN-specific gene–environment interactions. (trivli2020primaryopenangle pages 1-2, mallick2016updateonnormal pages 1-2)

Mechanistically plausible interactions include oxidative stress, hypoxia/ischemia–reperfusion, and aging increasing autophagic and mitochondrial demand in already vulnerable OPTN-mutant RGCs. However, prospective carrier studies quantifying such interactions are lacking.

Protective factors

No validated OPTN protective allele, diet, supplement, or lifestyle intervention is established. Avoidance of smoking, treatment of sleep apnea, review of excessive nocturnal blood-pressure reduction, and general cardiovascular health are reasonable clinical measures but are not proven to prevent OPTN glaucoma. Experimental autophagy-enhancing or metabolic interventions cannot yet be considered protective therapy.

3. Phenotypes

Core manifestations

1. Glaucomatous optic neuropathy—clinical sign; chronic and progressive; commonly bilateral but potentially asymmetric. Suggested HPO: Abnormality of the optic nerve (HP:0000587) and optic atrophy (HP:0000648; verify current HPO label/ID before ingestion).
2. Optic-disc excavation/increased cup-to-disc ratio—clinical sign detected by fundoscopy/OCT. Suggested HPO: Increased cup-to-disc ratio (HP:0001138).
3. RNFL thinning and RGC loss—structural signs; progressive and irreversible. Suggested HPO: abnormal retinal morphology/RNFL thinning; use exact current HPO child after ontology validation.
4. Visual-field defect—functional sign, initially often arcuate, paracentral, or nasal-step loss; may advance to severe constriction. Suggested HPO: Visual field defect (HP:0001123; validate current ID).
5. Reduced vision/blindness—late morbidity rather than an early symptom. Suggested HPO: Visual impairment and blindness.
6. Normal untreated IOP—laboratory/physiologic characteristic in the predominant NTG presentation, conventionally consistently <21 mmHg. (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2)
7. Open anterior-chamber angle—gonioscopic sign required for classification as open-angle disease. (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2)

Onset, frequency, severity, and progression

Disease is generally adult-onset, insidious, chronic, and progressive. E50K expression was age-dependent in the landmark family, with segregation reported in affected people older than 30 years. Exact median onset, sex ratio, bilateral frequency, and phenotype-specific percentages have not been robustly established for molecularly confirmed OPTN cases. E50K has repeatedly been described as the most severe OPTN glaucoma allele, but quantitative genotype-specific natural-history datasets remain small. (swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)

Patients may be asymptomatic until substantial field loss occurs. Severity varies from mild structural damage to advanced, disabling visual-field loss and blindness. There is no episodic or relapsing-remitting pattern and no spontaneous restoration of dead RGCs.

Quality of life

Loss of peripheral and central visual field affects mobility, driving, reading, fall risk, independence, and psychological well-being. The chronic threat of irreversible blindness and the burden of lifelong drops and surveillance further reduce quality of life. No EQ-5D, SF-36, PROMIS, or glaucoma-specific quality-of-life dataset restricted to OPTN carriers was identified. General glaucoma evidence should therefore be labeled indirect. (salvetat2023pharmaceuticalapproachesto pages 1-2, tsai2024glaucomaanimalmodels pages 1-2)

4. Genetic and molecular information

Gene and protein

OPTN encodes a 577-amino-acid adaptor containing coiled-coil regions, an LC3-interacting region, a ubiquitin-binding domain and a C-terminal zinc finger. It is expressed in retina, brain and multiple other tissues and participates in vesicular trafficking, autophagy, mitophagy, innate immune signaling and cellular homeostasis. Relevant partners include TBK1, LC3, RAB8, myosin VI, TBC1D17, huntingtin and transferrin receptor. (venkatesan2025proteinmisfoldingand pages 6-7, swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)

Pathogenic-variant curation

Most reported glaucoma alleles are missense. The disease is germline, not somatic. Precise gnomAD/TOPMed frequencies and current ClinVar classifications could not be verified with the available tools and should not be inferred. Similarly, no recurrent pathogenic large chromosomal rearrangement at OPTN was established; TBK1 duplication is a separate NTG cause.

Penetrance, modifiers, and epigenetics

Penetrance is incomplete and age-dependent, but no reliable numeric penetrance curve is available. Expressivity is variable. Anticipation, germline mosaicism, consanguinity effects, and a specific founder effect have not been established. No validated OPTN-specific DNA-methylation or histone-modification biomarker is available. Reported microRNA/long-noncoding-RNA changes in E50K mice are exploratory and not clinical epigenetic tests.

5. Environmental information

There is no infectious agent, toxin, radiation exposure, or occupational exposure known to be necessary or sufficient. General NTG literature implicates vascular insufficiency, disturbed autoregulation, nocturnal hypotension, vasospasm, transient hypoxia, oxidative stress and possibly sleep apnea. Smoking and high BMI have been associated with glaucoma-related traits, but neither is an OPTN-specific causal exposure. (mallick2016updateonnormal pages 1-2)

No vaccine or antimicrobial intervention is applicable.

6. Mechanism and pathophysiology

Integrated causal chain

Upstream trigger: heterozygous mutant OPTN—most convincingly E50K—alters OPTN conformation, localization and partner binding.

Intermediate cellular defects:

1. Vesicular trafficking failure. In vitro, E50K enlarged recycling endosomes, slowed mutant vesicle dynamics, reduced transferrin uptake, enhanced association with RAB8/transferrin receptor and slowed RAB8 vesicles. The authors concluded: “The E50K mutant impairs trafficking at the recycling endosomes due to altered interactions with Rab8 and transferrin receptor.” DOI 10.1186/1471-2121-11-4, published January 2010. (nagabhushana2010regulationofendocytic pages 1-2)

2. OPTN–TBK1/autophagy dysregulation. TBK1 phosphorylates OPTN near its LC3-interacting region, enhancing cargo capture. E50K can enhance OPTN–TBK1 interaction and disturb RAB8 trafficking/autophagosome formation. M98K experimentally activates TBK1 and increases Ser177-dependent autophagosome formation and retinal-cell death; TBK1 knockdown or inhibition reduced these effects. (venkatesan2025proteinmisfoldingand pages 6-7, sirohi2015aglaucomaassociatedvariant pages 1-2)

3. Autophagic-lysosomal failure and altered mitophagy. OPTN normally links ubiquitinated cargo and damaged mitochondria to LC3-positive autophagosomes. E50K can reduce effective cargo clearance and promote protein accumulation, whereas M98K may drive maladaptive excessive autophagic degradation. Thus “more” versus “less” autophagy is context- and variant-dependent; autophagic flux, rather than static LC3 abundance, is the relevant measure. (venkatesan2025proteinmisfoldingand pages 8-9, huang2024acquisitionofneurodegenerative pages 1-2, sirohi2015aglaucomaassociatedvariant pages 1-2)

4. Energy-stress signaling. The major 2024 development was an isogenic human hPSC-RGC study. Its abstract states: “We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor AMPK, along with subsequent neurodegeneration in OPTN(E50K) RGCs.” Pharmacologic mTORC1 inhibition produced disease-like changes in control RGCs, while mTOR-independent autophagy induction reduced protein accumulation and restored neurite outgrowth. Acta Neuropathologica Communications, 16 October 2024, DOI 10.1186/s40478-024-01872-2. (huang2024acquisitionofneurodegenerative pages 1-2)

5. Mitochondrial dysfunction, oxidative stress and apoptosis. Defective mitophagy permits damaged mitochondria, energetic failure and reactive-oxygen stress; downstream caspase activation, neurite retraction and RGC death follow. RGCs are especially vulnerable because of their long axons and high energetic demand. (venkatesan2025proteinmisfoldingand pages 8-9, huang2023elucidatingcellularmechanisms pages 46-51, tsai2024glaucomaanimalmodels pages 1-2)

6. Glial/inflammatory amplification. E50K mice display persistent reactive gliosis. General glaucoma models implicate microglia, astrocytes, innate immunity and oxidative/ischemic injury; direct OPTN-specific human inflammatory evidence remains limited. (tsai2024glaucomaanimalmodels pages 1-2, swarup2018alteredfunctionsand pages 1-3)

Clinical endpoint: progressive RGC somal and axonal loss → RNFL thinning and optic-disc cupping → corresponding visual-field loss → irreversible visual disability/blindness.

Ontology suggestions

• GO biological processes: autophagy (GO:0006914), mitophagy (GO:0000422), autophagosome assembly (GO:0000045), endocytic recycling, intracellular vesicle-mediated transport, protein phosphorylation, apoptotic process (GO:0006915), inflammatory response (GO:0006954), response to oxidative stress (GO:0006979).
• GO cellular components: Golgi apparatus (GO:0005794), endosome (GO:0005768), autophagosome (GO:0005776), lysosome (GO:0005764), mitochondrion (GO:0005739).
• Cell Ontology: retinal ganglion cell (CL:0000740), astrocyte (CL:0000127); retinal microglial and trabecular-meshwork cell IDs should be checked against the current CL release.

Molecular profiling and advanced technologies

The 2023 precursor hPSC-RGC work found 75 downregulated and 117 upregulated genes, with changes involving protein clearance, trafficking and neurite outgrowth; mutant cells also showed LC3 accumulation, active caspase-3 elevation and increased excitability. (huang2023elucidatingcellularmechanisms pages 39-46, huang2023elucidatingcellularmechanisms pages 46-51)

The 2024 study used isogenic CRISPR-edited embryonic-stem-cell and patient-iPSC pairs, RGC differentiation, autophagy sensors, immunoblotting, microscopy and morphometry. Trehalose treatment restored neurite morphology and shifted LC3-II and pS6 toward control values; for example, reported treatment comparisons included p=0.03 for LC3-II and p=0.029 for pS6. (huang2024acquisitionofneurodegenerative pages 14-16, huang2023elucidatingcellularmechanisms pages 82-86, huang2024acquisitionofneurodegenerative pages 16-18)

No validated OPTN-specific clinical single-cell, spatial-transcriptomic, proteomic, metabolomic or lipidomic signature was identified. These remain research opportunities.

7. Anatomical structures affected

• Organ: eye; secondary extension along the central visual pathway may occur as a consequence of optic-nerve degeneration.
• Primary tissues: neural retina/RNFL, optic-nerve head including lamina region, and optic nerve.
• Principal cell: RGC; secondary reactive cells include astrocytes and microglia. Trabecular-meshwork cells are relevant to conventional POAG and OPTN/MYOC interactions, but E50K NTG is principally an RGC/optic-nerve disease. (trivli2020primaryopenangle pages 1-2, huang2024acquisitionofneurodegenerative pages 1-2, tsai2024glaucomaanimalmodels pages 1-2)
• Suggested UBERON: retina UBERON:0000966; optic nerve UBERON:0000978. Validate optic-nerve-head, RNFL and trabecular-meshwork child terms before ingestion.
• Subcellular sites: Golgi, recycling endosome, autophagosome, lysosome and mitochondrion.
• Lateralization: commonly bilateral, often asymmetric; robust OPTN-specific proportions are unavailable.

8. Temporal development

The typical course is adult-onset and insidious. A genetically susceptible RGC may compensate for decades before aging, metabolic demand, vascular stress or declining proteostasis crosses a threshold. Early disease consists of OCT/RNFL or optic-disc changes with little subjective impairment; intermediate disease shows reproducible field loss; advanced disease threatens fixation and functional independence. Disease is chronic and lifelong, with variable progression. (salvetat2023pharmaceuticalapproachesto pages 1-2, swarup2018alteredfunctionsand pages 1-3)

There is no spontaneous remission. IOP-lowering treatment can slow progression, but cannot restore dead RGCs. The critical intervention window is therefore before substantial RNFL and field loss, supporting cascade testing and surveillance of at-risk relatives.

9. Inheritance and population

Inheritance

The best-established pattern is autosomal dominant with age-dependent, incomplete penetrance and variable expressivity. Each child of a heterozygous carrier has a 50% probability of inheriting the variant, although inheritance does not predict age of onset or severity. Genetic anticipation is not established. (swarup2018alteredfunctionsand pages 1-3)

Epidemiology

A disease-specific prevalence or incidence per 100,000 has not been established. Reviews estimate that approximately 5% of all POAG is Mendelian, whereas OPTN mutations explain approximately 1% or less of sporadic NTG and around 1–2% of POAG in some summaries. These estimates vary by ancestry, ascertainment and variant interpretation. (trivli2020primaryopenangle pages 1-2, swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)

For context—not OPTN-specific—NTG represents about 20–40% of POAG in Caucasian or African populations and 47–92% in some Asian POAG series. A 2023 review estimated NTG at 30–40% of all glaucoma cases. These figures must not be used as OPTN prevalence. (salvetat2023pharmaceuticalapproachesto pages 1-2)

M98K association appears ancestry-dependent, stronger in some Asian datasets. No reliable carrier frequency, sex ratio, founder distribution, or geographic incidence for pathogenic E50K was identified. Consanguinity is not expected to be a major determinant of a dominant disorder.

10. Diagnostics

Clinical diagnosis

A diagnosis requires evidence that the eye truly has glaucoma and that the angle is open, while excluding mimics. Core investigations are:

1. history, pedigree, medication and vascular-risk review;
2. repeated Goldmann applanation tonometry, preferably including diurnal assessment when indicated;
3. pachymetry because thin cornea can cause IOP underestimation;
4. gonioscopy confirming an open angle;
5. dilated stereoscopic optic-disc examination and photography;
6. OCT of peripapillary RNFL and macular ganglion-cell complex;
7. standard automated perimetry, repeated to establish a reproducible defect and progression;
8. selected blood-pressure monitoring, neuroimaging or neuro-ophthalmic assessment when the pattern is atypical. (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2)

Direct abstract quote: “Goldmann applanation tonometry, gonioscopy, slit lamp biomicroscopy, optical coherence tomography and visual field analysis are the main tools of investigation for the diagnosis of NTG.” DOI 10.4103/2008-322X.183914, published April 2016. (mallick2016updateonnormal pages 1-2)

Genetic testing

A multigene glaucoma panel is generally preferable to isolated OPTN sequencing for familial NTG, early-onset disease, or a strong pedigree. At minimum, relevant genes include OPTN, TBK1 with deletion/duplication analysis, MYOC, WDR36 and CYP1B1, with broader validated panels adding other glaucoma/optic-neuropathy genes. Sanger confirmation and family segregation are particularly important for non-E50K findings.

A 2024 72-gene panel study found nine rare variants in 16% of 61 POAG patients, distributed across CYP1B1, SIX6, CARD10, MFN1, OPTC, OPTN and WDR36. The authors cautioned that segregation and functional work are needed to establish contribution. PLOS ONE, 19 January 2024, DOI 10.1371/journal.pone.0282133. (milla2024nextgenerationsequencingbasedgene pages 1-2)

• Single-gene sequencing: reasonable when a known familial OPTN variant is present.
• Panel: preferred first-line assay in genetically heterogeneous glaucoma.
• WES/WGS: useful when panel testing is negative in a strongly familial case; WGS may detect noncoding or structural variants but interpretation remains difficult.
• CMA/karyotype/FISH: not routine; targeted copy-number testing is more appropriate for TBK1.
• Mitochondrial DNA and repeat-expansion testing: not routine for classic OPTN glaucoma, but may be used for an alternative inherited optic-neuropathy phenotype.
• RNA/proteomics/metabolomics/liquid biopsy: research only.

Differential diagnosis

Exclude ocular hypertension without neuropathy, high-tension POAG with missed peaks, angle-closure or secondary glaucoma, physiologic cupping, high-myopia-related disc changes, ischemic or compressive optic neuropathy, optic neuritis, hereditary optic atrophy (e.g., OPA1) and mitochondrial optic neuropathy. Atypical pallor exceeding cupping, marked color-vision loss, vertical-meridian field defects, rapid decline, pain, or neurologic signs should prompt neuro-ophthalmic investigation.

Screening

There is no newborn screening. Offer cascade variant testing and lifelong ophthalmic surveillance to adult relatives when a pathogenic familial variant is known. A negative test for the familial variant substantially reduces that monogenic risk but does not eliminate ordinary population POAG risk.

11. Outcome and prognosis

OPTN glaucoma affects morbidity rather than general survival. No disease-specific mortality or reduced life expectancy is established. Visual prognosis depends on baseline damage, age, rate of RNFL/field loss, IOP achieved, adherence, vascular factors and treatment response.

Untreated progression can produce irreversible bilateral visual disability or blindness. Lowering IOP reduces risk but does not eliminate it, because OPTN-linked autophagic, mitochondrial and axonal mechanisms are not directly corrected. No validated molecular prognostic biomarker beyond genotype itself exists. E50K may signal a relatively severe phenotype, but current data do not support a precise individualized progression calculator. (salvetat2023pharmaceuticalapproachesto pages 1-2, swarup2018alteredfunctionsand pages 1-3)

Recovery of lost RGCs or established visual field is not expected with present care. Treatment aims to preserve remaining function.

12. Treatment

Standard clinical management

There is no approved OPTN-specific therapy. Management follows NTG/POAG algorithms:

1. establish baseline structural and functional damage and an individualized target IOP;
2. lower IOP even if it begins in the normal range—often approximately 30% below untreated baseline, commonly toward 12–14 mmHg when safely achievable;
3. reassess OCT, disc and visual fields and lower the target further if progression continues;
4. address adherence, drop technique, nocturnal hypotension and relevant systemic/vascular factors;
5. escalate to laser or surgery when drops are inadequate or poorly tolerated. (salvetat2023pharmaceuticalapproachesto pages 1-2, mallick2016updateonnormal pages 1-2)

Pharmacotherapy

• Prostaglandin analogues—increase uveoscleral outflow; generally first-line.
• Beta-blockers—reduce aqueous production; monitor bradycardia, bronchospasm and nocturnal hypotension.
• Alpha-2 agonists such as brimonidine—reduce production and increase outflow.
• Topical carbonic-anhydrase inhibitors—reduce aqueous production.
• Rho-kinase inhibitors—increase trabecular outflow where approved.
• Fixed combinations may reduce bottle burden.

Suggested NCIt intervention concepts: pharmacologic IOP reduction, prostaglandin analogue therapy, beta-adrenergic antagonist therapy, carbonic-anhydrase inhibitor therapy and alpha-2 adrenergic agonist therapy; exact NCIt codes should be checked against the current release.

Adverse effects include ocular hyperemia/irritation, surface disease, prostaglandin-associated iris/periocular changes, beta-blocker cardiopulmonary effects and alpha-agonist allergy or fatigue. No OPTN pharmacogenomic dosing guideline exists.

Laser and surgery

Selective laser trabeculoplasty can be considered when sufficient trabecular outflow reserve exists, although absolute pressure reduction may be limited at low baseline IOP. Trabeculectomy, tube surgery and selected minimally invasive glaucoma surgery are options when progression continues, but NTG requires careful balancing of very low target pressure against hypotony risk. (tsai2024glaucomaanimalmodels pages 1-2)

Suggested NCIt concepts: laser trabeculoplasty, trabeculectomy, glaucoma drainage-device implantation, and minimally invasive glaucoma surgery.

Experimental precision therapies

• Autophagy modulation: in 2024 human E50K RGCs, mTOR-independent induction with trehalose reduced protein accumulation and restored neurite outgrowth. This is preclinical and does not justify clinical trehalose prescribing. (huang2024acquisitionofneurodegenerative pages 18-20, huang2024acquisitionofneurodegenerative pages 14-16)
• TBK1 modulation: TBK1 inhibition reduced M98K-driven autophagy/cell death in vitro, but systemic TBK1 has important immune functions, creating on-target safety concerns. (swarup2018alteredfunctionsand pages 1-3, sirohi2015aglaucomaassociatedvariant pages 1-2)
• Mitochondrial/neuroprotective therapies: antioxidants, metabolic support, caspase inhibition and regenerative RGC strategies remain experimental.
• Gene replacement/editing, ASO/siRNA and cell replacement: no validated OPTN clinical implementation. Dominant altered-function E50K may require allele-specific silencing or correction rather than simple gene addition.

The clinical-trial search returned no relevant OPTN-directed glaucoma interventional trial and no NCT identifier suitable for inclusion. This negative result should be periodically rechecked.

13. Prevention

Primary prevention

The inherited allele cannot currently be prevented after conception. No vaccine, chemoprophylaxis or proven lifestyle program prevents disease in carriers. Reproductive options after counseling may include prenatal diagnosis or preimplantation genetic testing when a clearly pathogenic familial variant is known; these are individual choices, not treatment recommendations.

Secondary prevention

This is the most actionable level: cascade genetic testing, periodic tonometry, gonioscopy, disc photography, OCT and perimetry can identify presymptomatic structural change and permit early pressure lowering. Testing should focus on a known familial pathogenic variant or use a validated panel when the familial cause is unknown.

Tertiary prevention

Adherence to IOP-lowering treatment, serial progression analysis, low-vision referral when needed, fall-risk reduction, driving assessment and timely laser/surgery help prevent advanced disability. Review excessive nocturnal antihypertensive effects and treat relevant sleep or vascular disorders in coordination with the patient’s physician; evidence remains general NTG rather than OPTN-specific. (mallick2016updateonnormal pages 1-2)

14. Other species and natural disease

Homo sapiens: NCBI Taxon 9606; human OPTN is the disease gene.

No well-established naturally occurring OPTN-related glaucoma syndrome in a companion-animal breed or wildlife population was identified. Accordingly, no VBO breed annotation, veterinary prevalence or zoonotic significance can be assigned. The disease is noninfectious and nontransmissible.

OPTN structure and autophagy functions are evolutionarily conserved, permitting mouse and vertebrate experimental modeling. This conservation is mechanistically valuable, but species differences in RGC subtype composition, optic-nerve anatomy and lifespan limit direct prediction of human penetrance and treatment response. (huang2024acquisitionofneurodegenerative pages 1-2, tsai2024glaucomaanimalmodels pages 1-2)

15. Model organisms and experimental systems

Mouse models

• E50K transgenic and knock-in mice, Mus musculus (Taxon 10090): reproduce RGC loss, retinal/optic-nerve injury and reactive gliosis without requiring chronic IOP elevation; useful for NTG neurodegeneration, inflammation, autophagy and neuroprotection. (tsai2024glaucomaanimalmodels pages 1-2, swarup2018alteredfunctionsand pages 1-3)
• Limitations: expression level and promoter may not match the human heterozygous state; mice lack a human-like macula and have different RGC subtype distributions. Reviews emphasize that each glaucoma model captures only part of human disease. (tsai2024glaucomaanimalmodels pages 1-2)

Human stem-cell models

Isogenic CRISPR-edited hESC/iPSC-derived RGCs carrying E50K are the strongest recent human model. They show normal initial RGC generation followed by smaller somata, reduced neurite complexity/length, altered excitability, OPTN/protein accumulation, impaired autophagic-lysosomal degradation, AMPK activation and reduced mTORC1 signaling. Correction or isogenic wild-type comparators reduce background-genome confounding. (huang2023elucidatingcellularmechanisms pages 39-46, huang2024acquisitionofneurodegenerative pages 1-2)

Their main applications are causal-pathway analysis, temporal profiling and phenotype-based drug screening. Limitations include developmental immaturity, absence of full lamina/vascular/immune architecture and incomplete modeling of decades-long aging.

Conventional cell systems

HeLa and retinal-cell cultures have established trafficking and TBK1/autophagy mechanisms. However, the historical RGC-5 line has identity and differentiation limitations, and findings should be confirmed in primary RGCs, human isogenic RGCs or in vivo models. (swarup2018alteredfunctionsand pages 1-3, nagabhushana2010regulationofendocytic pages 1-2)

Other induced models

Ocular-hypertension, optic-nerve-crush, ischemia–reperfusion, excitotoxic and autoimmune glaucoma models help dissect downstream injury but do not reproduce the initiating OPTN genotype. The 2024 hPSC study validated selected autophagy findings in a mouse ocular-hypertension model, supporting pathway convergence across genetic and pressure-mediated glaucoma. (huang2024acquisitionofneurodegenerative pages 14-16, tsai2024glaucomaanimalmodels pages 1-2)

Evidence assessment and critical gaps

1. High confidence: OPTN is linked to GLC1E/open-angle glaucoma; E50K is the best-supported dominant allele; the core phenotype is frequently NTG; RGC/optic-nerve degeneration and trafficking/autophagy dysfunction are central.
2. Moderate confidence: E50K generally confers severe, age-dependent disease and TBK1/mitochondrial pathways materially contribute.
3. Low or variant-dependent confidence: pathogenicity of M98K, H486R, R545Q and many rare variants; precise penetrance; founder effects and ancestry-specific risk.
4. Major missing data: molecularly confirmed prevalence/incidence, prospective carrier natural history, allele-frequency tables, genotype-specific treatment response, quality-of-life measures, protective factors, clinical omics biomarkers and OPTN-directed trials.
5. Curation rule: do not transfer general NTG statistics or interventions into an OPTN-specific field without labeling them as extrapolated evidence.

Selected primary and recent sources

• Rezaie T, et al. Science. 8 February 2002. “Adult-onset primary open-angle glaucoma caused by mutations in optineurin.” PMID 11834836; DOI: 10.1126/science.1066901. (OpenTargets Search: open-angle glaucoma-OPTN, swarup2018alteredfunctionsand pages 1-3)
• Nagabhushana A, et al. BMC Cell Biology. January 2010. E50K and endocytic recycling. DOI: 10.1186/1471-2121-11-4. (nagabhushana2010regulationofendocytic pages 1-2)
• Sirohi K, et al. PLOS ONE. 16 September 2015. M98K–TBK1–Ser177/autophagy mechanism. DOI: 10.1371/journal.pone.0138289. (sirohi2015aglaucomaassociatedvariant pages 1-2)
• Salvetat ML, et al. Pharmaceuticals. 17 August 2023. Current NTG treatment review. DOI: 10.3390/ph16081172. (salvetat2023pharmaceuticalapproachesto pages 1-2)
• Milla E, et al. PLOS ONE. 19 January 2024. Adult-glaucoma NGS panel study. DOI: 10.1371/journal.pone.0282133. (milla2024nextgenerationsequencingbasedgene pages 1-2)
• Tsai T, et al. International Journal of Molecular Sciences. 11 January 2024. Animal models beyond chronic IOP elevation. DOI: 10.3390/ijms25020906. (tsai2024glaucomaanimalmodels pages 1-2)
• Huang KC, et al. Acta Neuropathologica Communications. October 2024. Isogenic OPTN(E50K) human RGCs, autophagy and mTORC1. DOI: 10.1186/s40478-024-01872-2. (huang2024acquisitionofneurodegenerative pages 18-20, huang2024acquisitionofneurodegenerative pages 1-2)

References

1. (trivli2020primaryopenangle pages 1-2): Alexandra Trivli, Maria Zervou, George Goulielmos, Demetrios Spandidos, and Efstathios Detorakis. Primary open angle glaucoma genetics: the common variants and their clinical associations. Molecular Medicine Reports, 22:1103-1110, Jun 2020. URL: https://doi.org/10.3892/mmr.2020.11215, doi:10.3892/mmr.2020.11215. This article has 47 citations and is from a peer-reviewed journal.

2. (salvetat2023pharmaceuticalapproachesto pages 1-2): Maria Letizia Salvetat, Francesco Pellegrini, Leopoldo Spadea, Carlo Salati, and Marco Zeppieri. Pharmaceutical approaches to normal tension glaucoma. Pharmaceuticals, 16:1172, Aug 2023. URL: https://doi.org/10.3390/ph16081172, doi:10.3390/ph16081172. This article has 39 citations.

3. (swarup2018alteredfunctionsand pages 1-3): Ghanshyam Swarup and Zuberwasim Sayyad. Altered functions and interactions of glaucoma-associated mutants of optineurin. Frontiers in Immunology, Jun 2018. URL: https://doi.org/10.3389/fimmu.2018.01287, doi:10.3389/fimmu.2018.01287. This article has 86 citations and is from a peer-reviewed journal.

4. (sirohi2015aglaucomaassociatedvariant pages 1-2): Kapil Sirohi, Asha Kumari, Vegesna Radha, and Ghanshyam Swarup. A glaucoma-associated variant of optineurin, m98k, activates tbk1 to enhance autophagosome formation and retinal cell death dependent on ser177 phosphorylation of optineurin. PLOS ONE, 10:e0138289, Sep 2015. URL: https://doi.org/10.1371/journal.pone.0138289, doi:10.1371/journal.pone.0138289. This article has 54 citations and is from a peer-reviewed journal.

5. (OpenTargets Search: open-angle glaucoma-OPTN): Open Targets Query (open-angle glaucoma-OPTN, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

6. (milla2024nextgenerationsequencingbasedgene pages 1-2): Elena Milla, Javier Laguna, Mª. Socorro Alforja, Beatriz Pascual, María José Gamundi, Emma Borràs, Imma Hernán, María Jesús Muniesa, Marta Pazos, Susana Duch, Miguel Carballo, and Meritxell Jodar. Next-generation sequencing-based gene panel tests for the detection of rare variants and hypomorphic alleles associated with primary open-angle glaucoma. PLOS ONE, 19:e0282133, Jan 2024. URL: https://doi.org/10.1371/journal.pone.0282133, doi:10.1371/journal.pone.0282133. This article has 6 citations and is from a peer-reviewed journal.

7. (rozpedekkaminska2020thegeneticand pages 26-28): Wioletta Rozpędek-Kamińska, Radosław Wojtczak, Jacek P. Szaflik, Jerzy Szaflik, and Ireneusz Majsterek. The genetic and endoplasmic reticulum-mediated molecular mechanisms of primary open-angle glaucoma. International Journal of Molecular Sciences, 21:4171, Jun 2020. URL: https://doi.org/10.3390/ijms21114171, doi:10.3390/ijms21114171. This article has 31 citations.

8. (venkatesan2025proteinmisfoldingand pages 8-9): Arunkumar Venkatesan and Audrey M. Bernstein. Protein misfolding and mitochondrial dysfunction in glaucoma. Frontiers in Cell and Developmental Biology, Apr 2025. URL: https://doi.org/10.3389/fcell.2025.1595121, doi:10.3389/fcell.2025.1595121. This article has 20 citations.

9. (nagabhushana2010regulationofendocytic pages 1-2): Ananthamurthy Nagabhushana, Madhavi L Chalasani, Nishant Jain, Vegesna Radha, Nandini Rangaraj, Dorairajan Balasubramanian, and Ghanshyam Swarup. Regulation of endocytic trafficking of transferrin receptor by optineurin and its impairment by a glaucoma-associated mutant. BMC Cell Biology, 11:4-4, Jan 2010. URL: https://doi.org/10.1186/1471-2121-11-4, doi:10.1186/1471-2121-11-4. This article has 133 citations.

10. (huang2024acquisitionofneurodegenerative pages 1-2): Kang-Chieh Huang, Cátia Gomes, Yukihiro Shiga, Nicolas Belforte, Kirstin B. VanderWall, Sailee S. Lavekar, Clarisse M. Fligor, Jade Harkin, Shelby M. Hetzer, Shruti V. Patil, Adriana Di Polo, and Jason S. Meyer. Acquisition of neurodegenerative features in isogenic optn(e50k) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mtorc1 signaling reduction. Acta Neuropathologica Communications, Oct 2024. URL: https://doi.org/10.1186/s40478-024-01872-2, doi:10.1186/s40478-024-01872-2. This article has 10 citations and is from a peer-reviewed journal.

11. (mallick2016updateonnormal pages 1-2): Jyotiranjan Mallick, Lily Devi, PradeepK Malik, and Jogamaya Mallick. Update on normal tension glaucoma. Journal of Ophthalmic & Vision Research, 11:204-208, Apr 2016. URL: https://doi.org/10.4103/2008-322x.183914, doi:10.4103/2008-322x.183914. This article has 213 citations and is from a peer-reviewed journal.

12. (tsai2024glaucomaanimalmodels pages 1-2): Teresa Tsai, Sabrina Reinehr, Leonie Deppe, Alexandra Strubbe, Nils Kluge, H. Burkhard Dick, and Stephanie C. Joachim. Glaucoma animal models beyond chronic iop increase. International Journal of Molecular Sciences, 25:906, Jan 2024. URL: https://doi.org/10.3390/ijms25020906, doi:10.3390/ijms25020906. This article has 25 citations.

13. (venkatesan2025proteinmisfoldingand pages 6-7): Arunkumar Venkatesan and Audrey M. Bernstein. Protein misfolding and mitochondrial dysfunction in glaucoma. Frontiers in Cell and Developmental Biology, Apr 2025. URL: https://doi.org/10.3389/fcell.2025.1595121, doi:10.3389/fcell.2025.1595121. This article has 20 citations.

14. (huang2024acquisitionofneurodegenerative pages 18-20): Kang-Chieh Huang, Cátia Gomes, Yukihiro Shiga, Nicolas Belforte, Kirstin B. VanderWall, Sailee S. Lavekar, Clarisse M. Fligor, Jade Harkin, Shelby M. Hetzer, Shruti V. Patil, Adriana Di Polo, and Jason S. Meyer. Acquisition of neurodegenerative features in isogenic optn(e50k) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mtorc1 signaling reduction. Acta Neuropathologica Communications, Oct 2024. URL: https://doi.org/10.1186/s40478-024-01872-2, doi:10.1186/s40478-024-01872-2. This article has 10 citations and is from a peer-reviewed journal.

15. (huang2023elucidatingcellularmechanisms pages 46-51): Kang-Chieh Huang. Elucidating cellular mechanisms underlying retinal ganglion cell neurodegeneration in a human pluripotent stem cell-derived model. Text, Jan 2023. URL: https://doi.org/10.25394/pgs.21585657.v1, doi:10.25394/pgs.21585657.v1. This article has 0 citations and is from a peer-reviewed journal.

16. (huang2024acquisitionofneurodegenerative pages 14-16): Kang-Chieh Huang, Cátia Gomes, Yukihiro Shiga, Nicolas Belforte, Kirstin B. VanderWall, Sailee S. Lavekar, Clarisse M. Fligor, Jade Harkin, Shelby M. Hetzer, Shruti V. Patil, Adriana Di Polo, and Jason S. Meyer. Acquisition of neurodegenerative features in isogenic optn(e50k) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mtorc1 signaling reduction. Acta Neuropathologica Communications, Oct 2024. URL: https://doi.org/10.1186/s40478-024-01872-2, doi:10.1186/s40478-024-01872-2. This article has 10 citations and is from a peer-reviewed journal.

17. (huang2024acquisitionofneurodegenerative pages 16-18): Kang-Chieh Huang, Cátia Gomes, Yukihiro Shiga, Nicolas Belforte, Kirstin B. VanderWall, Sailee S. Lavekar, Clarisse M. Fligor, Jade Harkin, Shelby M. Hetzer, Shruti V. Patil, Adriana Di Polo, and Jason S. Meyer. Acquisition of neurodegenerative features in isogenic optn(e50k) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mtorc1 signaling reduction. Acta Neuropathologica Communications, Oct 2024. URL: https://doi.org/10.1186/s40478-024-01872-2, doi:10.1186/s40478-024-01872-2. This article has 10 citations and is from a peer-reviewed journal.

18. (huang2023elucidatingcellularmechanisms pages 39-46): Kang-Chieh Huang. Elucidating cellular mechanisms underlying retinal ganglion cell neurodegeneration in a human pluripotent stem cell-derived model. Text, Jan 2023. URL: https://doi.org/10.25394/pgs.21585657.v1, doi:10.25394/pgs.21585657.v1. This article has 0 citations and is from a peer-reviewed journal.

19. (huang2023elucidatingcellularmechanisms pages 82-86): Kang-Chieh Huang. Elucidating cellular mechanisms underlying retinal ganglion cell neurodegeneration in a human pluripotent stem cell-derived model. Text, Jan 2023. URL: https://doi.org/10.25394/pgs.21585657.v1, doi:10.25394/pgs.21585657.v1. This article has 0 citations and is from a peer-reviewed journal.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.