MYOC – Ocular Hypertension

Primary ocular hypertension (OHT) is defined by elevated intraocular pressure without glaucomatous optic neuropathy and represents a key risk factor for glaucoma. The MYOC gene encodes a secreted glycoprotein expressed in the trabecular meshwork; pathogenic variants disturb aqueous outflow and predispose to OHT and glaucoma.

In a 5-generation pedigree, the nonsense variant c.1102C>T (p.Gln368Ter) segregates with 19 individuals diagnosed with primary open-angle glaucoma and 5 with ocular hypertension under an autosomal dominant model, exhibiting age-dependent penetrance and incomplete expressivity (PMID:10815160). This large multigenerational segregation provides strong evidence for MYOC’s role in OHT and related glaucomatous phenotypes.

Compound heterozygosity for p.Gln368Ter and p.Thr377Met in a separate family results in marked early-onset OHT and glaucoma in four siblings and one unaffected carrier, highlighting a dosage-sensitive effect and reinforcing pathogenicity of both alleles (PMID:23304066).

Population screens using DHPLC identified the recurrent p.Gln368Ter allele in three Scottish kindreds with variable OHT and glaucoma severity, sharing a common haplotype and confirming a founder effect (PMID:11815346).

Functional assays demonstrate that p.Gln368Ter and other disease-associated MYOC variants become Triton X-100–insoluble, accumulate intracellularly, and inhibit normal C-terminal endoproteolysis at Arg226, consistent with a dominant-negative mechanism impairing trabecular meshwork function (PMID:10545602; PMID:15795224). Chemical chaperones partially restore mutant secretion in vitro, suggesting avenues for therapeutic intervention.

Integrating genetic and experimental data yields a Strong association between MYOC and ocular hypertension, supported by multigenerational segregation, recurrent founder variants, and concordant functional studies. Molecular testing for MYOC, especially the c.1102C>T (p.Gln368Ter) variant, is recommended in familial OHT to enable early diagnosis, risk stratification, and targeted monitoring.

Key take-home: MYOC mutation screening, particularly for p.Gln368Ter, offers significant clinical utility for early detection and management of ocular hypertension.

References

• Archives of ophthalmology (Chicago, Ill. : 1960) • 2000 • Myocilin Gln368stop mutation and advanced age as risk factors for late-onset primary open-angle glaucoma. PMID:10815160
• Molecular Vision • 2012 • Compound heterozygote myocilin mutations in a pedigree with high prevalence of primary open-angle glaucoma. PMID:23304066
• The British Journal of Ophthalmology • 2002 • Rapid mutation detection by the transgenomic wave analyser DHPLC identifies MYOC mutations in patients with ocular hypertension and/or open angle glaucoma. PMID:11815346
• 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

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