| Domain | Curated statement | Suggested ontology IDs/terms | Evidence type/strength | Key source/date/PMID or DOI |
|---|---|---|---|---|
| Disease identity | OPTN-related open-angle glaucoma corresponds to the Mendelian glaucoma locus **GLC1E** and is best regarded as a **rare monogenic subset of open-angle glaucoma, often presenting as normal-tension glaucoma (NTG)** rather than a separate common POAG entity. **OMIM 137760 (GLC1E)** is commonly used in the literature; use the broader **MONDO:0005338 open-angle glaucoma** only as a parent term, with caution because a disease-specific MONDO for OPTN-related glaucoma was not confirmed here. | OMIM:137760 (GLC1E, use with caution if local curation confirms); MONDO:0005338 open-angle glaucoma (broader parent); MeSH/ICD disease mapping not verified in current context | Human genetic literature + review synthesis; moderate strength for GLC1E identity, lower strength for ontology cross-mapping gaps (pqac-00000000, pqac-00000013, pqac-00000020) | Rezaie et al. discovery paper cited in reviews; Trivli 2020 DOI:10.3892/mmr.2020.11215; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Source type | This knowledge-base entry should be based on **aggregated disease-level resources and published case/family studies**, not EHR-derived evidence. | ECO conceptually: literature evidence; disease knowledgebase curation | Curatorial statement; high confidence | Review/resource-based synthesis (pqac-00000013, pqac-00000019) |
| Causal gene | **OPTN (optineurin)** is the causal gene implicated in GLC1E; it lies on **chromosome 10p13** and encodes a multifunctional adaptor involved in vesicle trafficking, autophagy, and signaling. | HGNC:17142 OPTN; Ensembl: ENSG00000123240; chromosomal location: 10p13 | Strong human genetic and molecular evidence (pqac-00000000, pqac-00000013, pqac-00000020) | Open Targets context for OPTN–open-angle glaucoma association; Trivli 2020 DOI:10.3892/mmr.2020.11215; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Inheritance | Inheritance is **autosomal dominant** for the clearest familial OPTN-associated disease, especially **E50K**; penetrance appears **age-dependent and incomplete/incompletely defined**. Reviews note segregation of E50K in affected individuals over ~30 years in a large family, while most other alleles have weaker evidence. | HPO inheritance term: HP:0000006 Autosomal dominant inheritance | Human family evidence; moderate for AD, limited for exact penetrance (pqac-00000020, pqac-00000013) | Swarup 2018 DOI:10.3389/fimmu.2018.01287; Trivli 2020 DOI:10.3892/mmr.2020.11215 |
| Variant spectrum | Reported glaucoma-associated OPTN variants are mostly **missense**. The **strongest disease-causing allele is p.Glu50Lys (E50K)**. Other reported variants include **M98K, H26D, H486R, E322K, R545Q** and others, but not all have equivalent evidence. | Sequence Ontology: SO:0001583 missense_variant | Human genetic + mechanistic literature; moderate overall, strongest for E50K (pqac-00000020, pqac-00000001, pqac-00000002) | Swarup 2018 DOI:10.3389/fimmu.2018.01287; Rozpędek-Kamińska 2020 DOI:10.3390/ijms21114171; Venkatesan 2025 DOI:10.3389/fcell.2025.1595121 |
| Variant interpretation: E50K | **E50K** is the best-supported pathogenic OPTN glaucoma allele: dominant family segregation, repeated mechanistic support, and disease-recapitulating mouse/hPSC-RGC models. | HGVS protein: p.Glu50Lys; ClinVar classification not directly verified in current context | Strongest OPTN-specific evidence (human + animal + in vitro) (pqac-00000020, pqac-00000022, pqac-00000015) | Nagabhushana 2010 DOI:10.1186/1471-2121-11-4; Huang 2024 DOI:10.1186/s40478-024-01872-2; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Variant interpretation: M98K | **M98K** is best treated as a **disputed or population-dependent risk/modifier allele**, not a universally established monogenic pathogenic variant. Association appears stronger in some Asian cohorts and weaker/absent in others. | HGVS protein: p.Met98Lys; classify cautiously as risk allele/uncertain modifier unless lab-specific evidence supports pathogenicity | Mixed human association + mechanistic data; lower certainty than E50K (pqac-00000020, pqac-00000021) | Swarup 2018 DOI:10.3389/fimmu.2018.01287; Sirohi 2015 DOI:10.1371/journal.pone.0138289 |
| Variant interpretation: H486R/R545Q/others | **H486R, R545Q, E322K and several other alleles** have been reported, but the current context does not provide enough evidence for definitive pathogenic classification, penetrance, or population frequency. | Use ACMG/AMP categories only after external verification; likely VUS/uncertain in this context | Limited evidence/data gap (pqac-00000001, pqac-00000020) | Rozpędek-Kamińska 2020 DOI:10.3390/ijms21114171; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Epidemiology | OPTN mutations account for only a **small minority of POAG/NTG**, often cited around **~1% or less of sporadic NTG/POAG**, while Mendelian forms overall account for about **5% of POAG**. Disease prevalence for the specific OPTN-related entity is not established. | MONDO:0005338 parent disease epidemiology only; no disease-specific ORDO/MONDO confirmed | Human literature; moderate for rarity, low for exact prevalence (pqac-00000013, pqac-00000020) | Trivli 2020 DOI:10.3892/mmr.2020.11215; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Core phenotype | Typical phenotype is **adult-onset open-angle glaucomatous optic neuropathy**, often **normal-tension glaucoma** with optic disc cupping, RNFL loss, retinal ganglion cell degeneration, and progressive visual field loss despite IOP in the statistically normal range. | HPO: HP:0000505 Visual field defect; HP:0001138 Increased cup-to-disc ratio; HP:0007773 Optic atrophy; HP:0001103 Visual loss; HP:0000548 Abnormality of the optic nerve; parent glaucoma terms as local ontology allows | Human clinical + guideline/review evidence; strong for general NTG phenotype, moderate for OPTN-specific mapping (pqac-00000016, pqac-00000017, pqac-00000020) | Salvetat 2023 DOI:10.3390/ph16081172; Mallick 2016 DOI:10.4103/2008-322X.183914; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Age of onset/course | Onset is usually **adult** and disease course is **chronic and progressive**. E50K familial disease showed age-dependent expression in adults; exact median onset for OPTN-specific disease remains insufficiently quantified here. | HPO: HP:0003581 Adult onset; HP:0003676 Progressive | Human family/review evidence; moderate (pqac-00000020, pqac-00000016) | Swarup 2018 DOI:10.3389/fimmu.2018.01287; Salvetat 2023 DOI:10.3390/ph16081172 |
| IOP phenotype | A substantial subset of OPTN-related disease presents with **IOP consistently <21 mmHg**, i.e., NTG; however, some literature places OPTN within the broader POAG spectrum. | HPO suggestion: Normal intraocular pressure phenotype not confirmed in HPO here; clinical descriptor “normal-tension glaucoma” | Human clinical/review evidence; moderate (pqac-00000016, pqac-00000020) | Salvetat 2023 DOI:10.3390/ph16081172; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Affected anatomy | Primary structures affected: **retina**, **retinal nerve fiber layer**, **optic nerve head**, **optic nerve**, and likely **trabecular meshwork** for some pathway interactions, though the major neurodegenerative target is the RGC/optic nerve axis. | UBERON: retina (UBERON:0000966); optic nerve (UBERON:0000978); optic nerve head (UBERON term should be externally verified); trabecular meshwork (UBERON term externally verify) | Human/animal/in vitro evidence; moderate-strong for retina/optic nerve, weaker for TM relevance (pqac-00000015, pqac-00000018, pqac-00000013) | Huang 2024 DOI:10.1186/s40478-024-01872-2; Tsai 2024 DOI:10.3390/ijms25020906; Trivli 2020 DOI:10.3892/mmr.2020.11215 |
| Cell types | Main vulnerable cells are **retinal ganglion cells (RGCs)**; secondary involvement includes **astrocytes/glia** and possibly **trabecular meshwork cells** in broader glaucoma biology. | CL:0000740 retinal ganglion cell; CL:0000127 astrocyte; trabecular meshwork cell CL term externally verify | Strong for RGCs, moderate for glia/TM (pqac-00000015, pqac-00000018, pqac-00000020) | Huang 2024 DOI:10.1186/s40478-024-01872-2; Tsai 2024 DOI:10.3390/ijms25020906; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Subcellular localization | Relevant subcellular compartments include **Golgi/recycling endosomes**, **autophagosomes/lysosomes**, and **mitochondria/mitophagy machinery**. | GO:0005794 Golgi apparatus; GO:0005768 endosome; GO:0005776 autophagosome; GO:0005764 lysosome; GO:0005739 mitochondrion | Strong mechanistic evidence (pqac-00000022, pqac-00000015, pqac-00000003) | Nagabhushana 2010 DOI:10.1186/1471-2121-11-4; Huang 2024 DOI:10.1186/s40478-024-01872-2; Venkatesan 2025 DOI:10.3389/fcell.2025.1595121 |
| Major mechanism: trafficking | OPTN normally regulates **endocytic recycling/vesicle trafficking**; **E50K impairs transferrin receptor trafficking**, enlarges recycling endosomes, slows vesicle dynamics, and alters Rab8 interactions. | GO:0006897 endocytosis; GO:0006886 intracellular protein transport; GO:0032456 endocytic recycling; GO:0005515 protein binding; RAB8 pathway annotation as local pathway system allows | In vitro mechanistic evidence; strong (pqac-00000022) | Nagabhushana 2010 DOI:10.1186/1471-2121-11-4 |
| Major mechanism: autophagy/mitophagy | OPTN is an **autophagy receptor**; glaucoma-associated mutants perturb **autophagic flux**, cargo sequestration, and **mitophagy**. TBK1-mediated phosphorylation enhances LC3 binding and selective autophagy functions. | GO:0006914 autophagy; GO:0000422 mitophagy; GO:0005776 autophagosome; GO:0016236 macroautophagy; GO:0000045 autophagosome assembly | Strong review + human cell evidence (pqac-00000003, pqac-00000015, pqac-00000020) | Huang 2024 DOI:10.1186/s40478-024-01872-2; Swarup 2018 DOI:10.3389/fimmu.2018.01287; Venkatesan 2025 DOI:10.3389/fcell.2025.1595121 |
| Major mechanism: TBK1 axis | OPTN interacts with **TBK1**, a major partner in NTG biology. For E50K and M98K, altered TBK1 coupling/phosphorylation is implicated in autophagy-related retinal cell death. | GO:0006468 protein phosphorylation; GO:0032480 negative regulation of type I interferon production/innate immune pathways as context-dependent; pathway label “OPTN-TBK1 autophagy axis” | Strong mechanistic support; human genetics indirect, cell/animal strong (pqac-00000003, pqac-00000021, pqac-00000020) | Sirohi 2015 DOI:10.1371/journal.pone.0138289; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Major mechanism: neurodegeneration | Downstream biology includes **RGC neurite retraction, protein accumulation, apoptosis/caspase activation, reactive gliosis, and optic nerve degeneration**. | GO:0043524 negative regulation of neuron apoptotic process (or apoptosis terms as appropriate); GO:0097458 neuron part morphogenesis; GO:0006915 apoptotic process; GO:0006954 inflammatory response | Strong in vitro/animal evidence (pqac-00000005, pqac-00000012, pqac-00000020) | Huang 2024 DOI:10.1186/s40478-024-01872-2; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Signaling/metabolic mechanisms | Recent 2024 hPSC-RGC work links OPTN(E50K) to **impaired autophagic-lysosomal degradation**, **AMPK activation**, and **reduced mTORC1 signaling**; mTORC1 inhibition in control RGCs recapitulated disease features, while mTOR-independent autophagy induction was rescuing. | GO:0005773 vacuole/lysosome system; GO:0010506 regulation of autophagy; GO:0032008 positive regulation of TOR signaling / GO:0031929 TORC1 signaling; AMPK pathway terms via Reactome/GO locally | Strong recent human-cell evidence (pqac-00000015, pqac-00000005, pqac-00000008) | Huang 2024 DOI:10.1186/s40478-024-01872-2 |
| Inflammation/immune involvement | Neuroinflammation is increasingly implicated in NTG models; OPTN biology also intersects innate immune signaling. For OPTN(E50K), reactive gliosis and, in later literature, inflammasome activation are suggested, but OPTN-specific human evidence remains limited. | GO:0006954 inflammatory response; GO:0045087 innate immune response; CL astrocyte/microglia terms locally as needed | Moderate, mostly model/review-based (pqac-00000018, pqac-00000020) | Tsai 2024 DOI:10.3390/ijms25020906; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Risk factors beyond OPTN | General NTG risk factors likely modify disease expression: **older age, female sex, family history, vascular dysregulation, Raynaud phenomenon, migraine, nocturnal hypotension, myopia, smoking, systemic hypertension/impaired glucose tolerance**, and possibly sleep apnea. These are **not OPTN-specific** but clinically relevant modifiers. | HPO/ExO environmental annotations as local system allows; HP:0000822 hypertension; HP:0001279 migraine; myopia term if used locally | General NTG/POAG evidence, extrapolated to OPTN carriers with caution (pqac-00000017, pqac-00000016) | Mallick 2016 DOI:10.4103/2008-322X.183914; Salvetat 2023 DOI:10.3390/ph16081172 |
| Protective factors/data gaps | No well-established **OPTN-specific protective genetic variants** were identified in the current context. Lifestyle or metabolic neuroprotective strategies are experimental and not validated as preventive measures for OPTN carriers. | Data gap | Low/insufficient evidence | No definitive evidence in current context |
| Diagnosis | Diagnosis follows **standard NTG/POAG workup**: Goldmann applanation tonometry, gonioscopy, slit-lamp/fundus examination, OCT/RNFL imaging, and automated perimetry; importantly, clinicians must **exclude nonglaucomatous optic neuropathy** when cupping occurs with normal IOP. | LOINC/NCIT local mapping: tonometry, gonioscopy, OCT, perimetry; HPO phenotypes above | Strong guideline/review evidence for clinical workup; indirect for OPTN-specific diagnosis (pqac-00000016, pqac-00000017) | Salvetat 2023 DOI:10.3390/ph16081172; Mallick 2016 DOI:10.4103/2008-322X.183914 |
| Genetic testing | A practical approach is **multigene glaucoma panel testing** (including OPTN, MYOC, TBK1, WDR36, CYP1B1 and others) in familial/early-onset/NTG cases; recent NGS panel work supports molecular diagnosis but stresses need for segregation and functional follow-up for rare variants. | HGNC genes for panel: OPTN, MYOC, TBK1, WDR36, CYP1B1; sequence analysis | Human molecular diagnostics evidence; moderate (pqac-00000019, pqac-00000013) | Milla 2024 DOI:10.1371/journal.pone.0282133; Trivli 2020 DOI:10.3892/mmr.2020.11215 |
| Differential diagnosis | Differential diagnosis includes **other causes of optic nerve cupping/optic neuropathy** rather than glaucoma alone, especially in normal-IOP presentations. | HPO optic atrophy spectrum; non-glaucomatous optic neuropathy terms locally | Guideline/review evidence; moderate (pqac-00000016) | Salvetat 2023 DOI:10.3390/ph16081172 |
| Prognosis | Disease is typically **progressive** and can lead to irreversible visual disability/blindness if untreated. Even with IOP lowering, some NTG patients continue to progress, implying non-IOP mechanisms. OPTN-specific long-term survival/mortality data are unavailable. | HPO: HP:0003676 Progressive; HP:0001103 Visual loss | Strong for progressive visual morbidity; low for OPTN-specific natural history estimates (pqac-00000016, pqac-00000017) | Salvetat 2023 DOI:10.3390/ph16081172; Mallick 2016 DOI:10.4103/2008-322X.183914 |
| Quality of life | Visual field loss and optic neuropathy reduce **visual function and quality of life**; glaucoma models/reviews emphasize impact on independence and psychological burden, but OPTN-specific QoL studies were not identified. | PROM/QoL terms not specifically mapped here | General glaucoma evidence; indirect for OPTN-specific disease (pqac-00000018, pqac-00000016) | Tsai 2024 DOI:10.3390/ijms25020906; Salvetat 2023 DOI:10.3390/ph16081172 |
| Standard treatment | **No OPTN-specific approved therapy exists.** Management follows NTG/POAG care with **IOP lowering as standard of care**, even when baseline IOP is normal. Typical medical options include prostaglandin analogs, beta-blockers, alpha-agonists, carbonic anhydrase inhibitors; surgery is used when needed. | NCIT examples: prostaglandin analog therapy; trabeculectomy; laser trabeculoplasty; minimally invasive glaucoma surgery | Strong clinical standard-of-care evidence, indirect for genotype specificity (pqac-00000016, pqac-00000017, pqac-00000018) | Salvetat 2023 DOI:10.3390/ph16081172; Mallick 2016 DOI:10.4103/2008-322X.183914; Tsai 2024 DOI:10.3390/ijms25020906 |
| Treatment targets | Reviews commonly cite a target of roughly **30% IOP reduction** in NTG management; this is a clinical principle extrapolated to OPTN-related disease, not a genotype-tested threshold. | Clinical management rule; no ontology term needed | General NTG evidence; indirect to OPTN (pqac-00000017, pqac-00000016) | Mallick 2016 DOI:10.4103/2008-322X.183914; Salvetat 2023 DOI:10.3390/ph16081172 |
| Experimental therapeutics | Preclinical work supports **TBK1-axis modulation**, **autophagy correction**, and **neuroprotective strategies**; in 2024 hPSC-RGCs, **trehalose** rescued neurite/protein-accumulation phenotypes via mTOR-independent autophagy induction. These remain experimental. | CHEBI: trehalose (local CHEBI mapping can be added); GO autophagy terms above | Strong preclinical, no clinical validation (pqac-00000015, pqac-00000005, pqac-00000021) | Huang 2024 DOI:10.1186/s40478-024-01872-2; Sirohi 2015 DOI:10.1371/journal.pone.0138289 |
| Animal models | Key models include **OPTN E50K knock-in/transgenic mice**, which show **RGC loss** and **reactive gliosis**, and are used as NTG-like models beyond IOP elevation. | NCBI Taxon:10090 Mus musculus; phenotype terms: RGC loss, gliosis | Strong model evidence (pqac-00000018, pqac-00000020) | Tsai 2024 DOI:10.3390/ijms25020906; Swarup 2018 DOI:10.3389/fimmu.2018.01287 |
| Human cellular models | **Isogenic hPSC-/iPSC-derived retinal ganglion cells carrying OPTN(E50K)** reproduce neurodegenerative phenotypes, autophagy defects, AMPK activation, mTORC1 reduction, protein accumulation, and neurite retraction; useful for mechanistic studies and drug screening. | CL:0000740 retinal ganglion cell; EFO/pluripotent stem cell terms locally | Strong recent human in vitro evidence (pqac-00000015, pqac-00000005, pqac-00000010) | Huang 2024 DOI:10.1186/s40478-024-01872-2 |
| Evidence gaps/curation cautions | Key gaps: no confirmed disease-specific MONDO ID in current context; limited penetrance estimates; uncertain pathogenicity for several non-E50K alleles; sparse allele-frequency data; minimal OPTN-specific prognosis/QoL/prevention data; many management statements are extrapolated from general NTG/POAG rather than genotype-stratified studies. | Curation flag: evidence gap/needs external verification | High-confidence curation caveat | Synthesized from all cited contexts (pqac-00000000, pqac-00000016, pqac-00000019, pqac-00000020) |


*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.*