MYOC – Glaucoma

MYOC encodes the secreted glycoprotein myocilin, mutations of which cause autosomal dominant primary open-angle glaucoma (POAG), including juvenile-onset (JOAG) and adult-onset forms. MYOC variants account for approximately 2–4% of POAG cases and 8–36% of JOAG cases worldwide (PMID:10196380).

1. Clinical Validity

MYOC–glaucoma association is Definitive, based on segregation in multiple multi-generation pedigrees, replication in large case–control cohorts over >20 years, and concordant functional data. Segregation of c.821C>G (p.Pro274Arg) in five additional affected relatives supports autosomal dominant inheritance (PMID:15255110).

2. Genetic Evidence

Autosomal dominant inheritance with high penetrance in familial JOAG. In a four-generation Indian pedigree, c.821C>G (p.Pro274Arg) completely co-segregated with disease in five relatives (PMID:15255110). In 716 POAG patients, 33 probands (4.6%) carried one of six probable disease-causing MYOC mutations (PMID:9535666). A multi-population screen of 1703 glaucoma patients identified 58 probands (3.4%) with 21 pathogenic variants, notably p.Gln368Ter in 27 probands (PMID:10196380).

3. Variant Spectrum

Over 180 MYOC variants documented, predominantly missense within the olfactomedin (OLF) domain. Recurrent/founder alleles include p.Gln368Ter (founder in Caucasians) and p.Gly252Arg (shared haplotype) (PMID:17210859). Loss-of-function variants (e.g., p.Arg46Ter) are less common and show variable expressivity.

4. Phenotypic & Penetrance Spectrum

Clinical spectrum ranges from early-onset JOAG (first decade; IOP >25 mm Hg) to adult POAG and normal-tension glaucoma (IOP ≤21 mm Hg). The common p.Gln368Ter variant shows reduced penetrance (12.5–19.4% in European cohorts) (PMID:28038983).

5. Functional / Experimental Evidence

MYOC mutations disrupt OLF domain folding, producing Triton X-100 insoluble, secretion-defective protein aggregates that accumulate in the ER, trigger ER stress, and inhibit endoproteolytic cleavage at Arg226 (PMID:10545602; PMID:15795224). Dominant-negative hetero-oligomerization further reduces extracellular processed myocilin, impairing trabecular meshwork cell function.

6. Conflicting Evidence

Reduced penetrance of p.Gln368Ter in population studies highlights the role of genetic modifiers and environmental factors in glaucoma risk (PMID:28038983).

7. Integration & Conclusion

Genetic and experimental data conclusively establish MYOC mutations as a cause of autosomal dominant glaucoma via a toxic gain-of-function misfolding mechanism. MYOC molecular testing supports early diagnosis, risk assessment, and tailored interventions.

Key Take-home: MYOC variant screening is clinically actionable for familial glaucoma risk stratification and guiding early therapeutic intervention.

References

• The New England journal of medicine • 1998 • Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A) PMID:9535666
• Human molecular genetics • 1999 • Analysis of myocilin mutations in 1703 glaucoma patients from five different populations PMID:10196380
• Ophthalmic genetics • 2004 • Genetic analysis of an Indian family with members affected with juvenile-onset primary open-angle glaucoma PMID:15255110
• Archives of ophthalmology • 2007 • Myocilin Gly252Arg mutation and glaucoma of intermediate severity in Caucasian individuals PMID:17210859
• Human molecular genetics • 1999 • A cellular assay distinguishes normal and mutant TIGR/myocilin protein PMID:10545602
• The Journal of biological chemistry • 2005 • Myocilin mutations causing glaucoma inhibit the intracellular endoproteolytic cleavage of myocilin between amino acids Arg226 and Ile227 PMID:15795224
• Ophthalmology • 2017 • Evaluation of the Myocilin Mutation Gln368Stop Demonstrates Reduced Penetrance for Glaucoma in European Populations PMID:28038983

Evidence Based Scoring (AI generated)

Gene–Disease Association Definitive Segregation in multiple multi-generation pedigrees over >20 years, replicated in large cohorts with functional concordance Genetic Evidence Strong 33 probands in 716 patients (PMID:9535666) and 58 probands in 1703 patients (PMID:10196380), co-segregation in 5 relatives (PMID:15255110) Functional Evidence Moderate Mutant myocilin is Triton-insoluble, secretion-defective, forms ER aggregates and inhibits cleavage in cell assays (PMID:10545602; PMID:15795224)