MYOC – Primary Open-Angle Glaucoma

Primary open-angle glaucoma (POAG) is a progressive optic neuropathy characterized by elevated intraocular pressure and corresponding visual field loss. MYOC encodes the secreted glycoprotein myocilin, variants in which disrupt aqueous humor outflow, leading to ocular hypertension (HP:0007906) and glaucomatous visual field defects (HP:0007854). Pathogenic MYOC mutations follow an autosomal dominant inheritance mode with variable penetrance and onset ranging from juvenile to adult (>35 y).

1 Clinical Validity (ClinGen Definitive)

MYOC has a definitive association with POAG based on segregation in multiple large pedigrees and functional concordance. In a Chinese juvenile-onset pedigree, a heterozygous c.1109C>T (p.Pro370Leu) variant segregated with disease in 16 affected relatives among 24 members (PMID:18728751). A Northern French founder family carried an Asn480Lys mutation in 71 patients across six kindreds (PMID:9556305). Concordant functional studies demonstrate intracellular aggregation and impaired secretion of mutant protein.

2 Genetic Evidence (Strong)

Autosomal dominant POAG is reported in multiple families with >50 probands harboring MYOC variants (PMID:10617918, PMID:10873982). Variant spectrum includes missense, nonsense, frameshift, and splice-site changes. Recurrent alleles such as c.1109C>T (p.Pro370Leu) and c.1102C>T (p.Gln368Ter) account for ~2–4% of POAG cases worldwide. Founder mutations (e.g., Asn480Lys) and de novo events underline disease causality.

3 Functional Evidence (Strong)

Mutant myocilin variants are Triton X-100–insoluble and accumulate in the endoplasmic reticulum of trabecular meshwork cells, whereas wild-type is soluble and secreted (PMID:10545602). Pathogenic mutations abolish normal endoproteolytic cleavage between Arg226 and Ile227, forming intracellular aggregates (PMID:15795224). Chemical chaperones such as TMAO restore mutant solubility and secretion in cell models (PMID:20334347).

4 Phenotypic Spectrum & Penetrance

Clinical presentations range from childhood-onset JOAG with rapid progression to adult-onset POAG, often requiring trabeculectomy. Penetrance is incomplete (50–70%), and severity correlates with variant thermal stability. Population-based screens show MYOC mutations in ~3% of OAG cohorts (PMID:12107514).

5 Integration & Clinical Utility

Definitive genetic and functional data support MYOC testing in families with POAG or early-onset glaucoma. Identifying mutation carriers enables targeted surveillance, early intervention to preserve optic nerve function, and informed genetic counseling. Key take-home: MYOC variant screening is clinically actionable for risk stratification and management of POAG.

References

• Ophthalmic genetics • 1999 • Childhood-onset primary open angle glaucoma in a Canadian kindred: clinical and molecular genetic features. PMID:10617918
• Molecular vision • 2008 • Pro370Leu MYOC gene mutation in a large Chinese family with juvenile-onset open angle glaucoma: correlation between genotype and phenotype. PMID:18728751
• American journal of medical genetics • 1998 • Founder effect in GLC1A-linked familial open-angle glaucoma in Northern France. PMID:9556305
• 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
• ACS chemical biology • 2010 • Rescue of glaucoma-causing mutant myocilin thermal stability by chemical chaperones. PMID:20334347
• Graefe's archive for clinical and experimental ophthalmology • 2002 • Myocilin mutations in a population-based sample of cases with open-angle glaucoma: the Rotterdam Study. PMID:12107514

Evidence Based Scoring (AI generated)