MYOC – OPTN-related Open-Angle Glaucoma

Myocilin (MYOC) encodes a secreted glycoprotein highly expressed in the trabecular meshwork, with key roles in aqueous humor outflow and intraocular pressure regulation. Heterozygous MYOC variants cause autosomal dominant primary open-angle glaucoma, here denoted OPTN-related open-angle glaucoma (MONDO:0100553). The initial Gly367Arg variant was identified in a Japanese pedigree of eight carriers, four of whom developed adult-onset glaucoma with mean age at onset of 36.7 years (PMID:10974305). Subsequent studies have confirmed MYOC as a POAG gene across diverse populations, accounting for 3–4% of cases worldwide.

Inheritance is autosomal dominant with incomplete age-related penetrance. In a French-Canadian family of 142 members, 40 individuals with POAG or ocular hypertension co-segregated a founder haplotype (PMID:7762566; PMID:12189160). Eight pedigrees harboring the Gln368Ter variant showed 29 carriers with a penetrance of 82% by age 65 years (PMID:11535458; PMID:11535458). Compound heterozygotes for Gln368Ter and Thr377Met in one family displayed earlier onset (mean age 28 years) and more severe hypertension (PMID:23304066). Across multiple pedigrees, at least 19 additional affected relatives segregate pathogenic MYOC alleles, supporting a Strong ClinGen gene–disease association.

Over 80 unique MYOC coding variants have been reported, including missense, nonsense, frameshift, and insertion alleles clustered in the olfactomedin domain. The most recurrent variant, c.1102C>T (p.Gln368Ter), appears in 4.27% of POAG patients in Western Switzerland and in 0.91% of normal-tension glaucoma cases (PMID:11803488; PMID:30816940). Other hotspots include p.Pro370Leu, p.Tyr437His and p.Cys433Arg, each associated with early onset and high intraocular pressure requiring surgical intervention (PMID:12671463; PMID:30612094). A Brazilian family demonstrated an insertion c.1187_1188insCCCAGA (p.Asp395_Glu396insAspPro) causing juvenile-onset glaucoma in four members (PMID:23566828).

Functional studies demonstrate that glaucoma-causing MYOC variants misfold and accumulate in the endoplasmic reticulum, triggering ER stress and impaired secretion. Triton X-100 solubility assays distinguish insoluble mutants from soluble wild-type MYOC (PMID:10545602). Pathogenic variants inhibit normal endoproteolytic cleavage at Arg226–Ile227, leading to intracellular aggregation (PMID:15795224). Chemical chaperones such as trimethylamine N-oxide and sarcosine can rescue folding defects and restore secretion in vitro (PMID:20334347).

Benign polymorphisms, including p.Asp208Glu and p.Arg76Lys, are fully secreted and show no ER retention, illustrating genotype-phenotype specificity. Truncating variants such as Arg46Ter exhibit incomplete penetrance and are found in unaffected elderly controls, suggesting some loss-of-function alleles do not invariably cause disease (PMID:10798654). No consistent evidence links MYOC to steroid-induced or normal-tension glaucoma outside the p.Gln368Ter context.

In summary, MYOC is definitively implicated in autosomal dominant OPTN-related open-angle glaucoma. Strong genetic evidence from >200 probands across multiple families, coupled with concordant functional data demonstrating mutant protein misfolding and ER stress, underpins its clinical utility. Genetic testing for MYOC variants, particularly p.Gln368Ter and other olfactomedin domain mutations, enables early diagnosis, risk stratification, and targeted monitoring of at-risk relatives. Key take-home: AD MYOC testing informs presymptomatic screening and guides prophylactic intervention to preserve vision.

References

• Japanese journal of ophthalmology • 2000 • The Gly367Arg mutation in the myocilin gene causes adult-onset primary open-angle glaucoma. PMID:10974305
• Molecular vision • 2012 • Compound heterozygote myocilin mutations in a pedigree with high prevalence of primary open-angle glaucoma. PMID:23304066
• Ophthalmic genetics • 2001 • MYOC mutation frequency in primary open-angle glaucoma patients from Western Switzerland. PMID:11803488
• JAMA ophthalmology • 2019 • Myocilin Mutations in Patients With Normal-Tension Glaucoma. PMID:30816940
• Journal of glaucoma • 2003 • Penetrance and phenotype of the Cys433Arg myocilin mutation in a family pedigree with primary open-angle glaucoma. PMID:12671463
• Human molecular genetics • 2002 • Founder TIGR/myocilin mutations for glaucoma in the Québec population. PMID:12189160
• 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

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