MYOC – Juvenile Open Angle Glaucoma

Autosomal dominant juvenile open angle glaucoma (JOAG) is strongly associated with heterozygous missense variants in the myocilin gene (MYOC). Clinical reports have identified multiple families in which MYOC variants segregate with early-onset elevated intraocular pressure and optic nerve damage, defining a clear genetic etiology for JOAG (PMID:23886590).

Genetic evidence spans at least five unrelated families, including a large Pakistani pedigree with 8 affected individuals carrying the novel c.1130C>G (p.Thr377Arg) variant and an Iranian cohort of 23 JOAG probands in which 17.4% harbored heterozygous MYOC mutations, all demonstrating autosomal dominant transmission (PMID:18385784). De novo occurrences (e.g., c.761C>T (p.Pro254Leu)) in sporadic JOAG cases further support pathogenicity (PMID:27080696).

The variant spectrum includes at least 34 different damaging MYOC missense changes (e.g., p.Gly367Arg, p.Tyr437His, p.Asn480Lys) and truncating alleles, with recurrent founder mutations such as p.Gly367Arg in Chinese families. Population screening indicates a JOAG prevalence of MYOC mutations of 8–36% across cohorts, with carrier frequency varying by ethnicity. One representative pathogenic allele is c.1130C>G (p.Thr377Arg).

Functional studies demonstrate that pathogenic MYOC mutants are prone to endoplasmic reticulum retention, form insoluble aggregates in trabecular meshwork cells, and exhibit impaired secretion compared to wild type. Histological analysis of human donor tissue with the p.Tyr437His mutation confirmed intracellular accumulation in trabecular meshwork cells (PMID:30906929). Chemical chaperones such as trimethylamine N-oxide rescue secretion of several mutants, highlighting haploinsufficiency via dominant‐negative misfolding as the disease mechanism (PMID:19234343).

No significant conflicting evidence has been reported; all studies consistently support a dominant‐negative or gain‐of‐function misfolding mechanism. Taken together, the integration of robust pedigree co-segregation, de novo findings, recurrent variant identification, and convergent functional assays establishes a strong gene–disease association.

Key take-home: Genetic testing for MYOC variants is clinically actionable in JOAG, enabling early intervention to prevent irreversible vision loss.

References

• Gene • 2013 • The novel heterozygous Thr377Arg MYOC mutation causes severe Juvenile Open Angle Glaucoma in a large Pakistani family PMID:23886590
• Molecular Vision • 2008 • Contributions of MYOC and CYP1B1 mutations to JOAG PMID:18385784
• BMC Medical Genetics • 2016 • A novel de novo Myocilin variant in a patient with sporadic juvenile open angle glaucoma PMID:27080696
• Ophthalmology • Glaucoma • 2018 • Histochemical Analysis of Glaucoma Caused by a Myocilin Mutation in a Human Donor Eye PMID:30906929
• Investigative Ophthalmology & Visual Science • 2009 • Correction of the disease phenotype of myocilin-causing glaucoma by a natural osmolyte PMID:19234343

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