MYOC – Congenital Glaucoma

The MYOC gene MYOC encodes the secreted glycoprotein myocilin and is well known for its role in primary open-angle glaucoma. Emerging evidence also implicates MYOC variants in congenital glaucoma Congenital glaucoma. The allelic spectrum of MYOC spans juvenile-onset through congenital forms, suggesting a continuum of disease severity.

Genetic evidence originates from a cohort of 60 individuals with juvenile or early-onset glaucoma, in which MYOC variants were detected in 8 probands PMID:11774072, including cases presenting with congenital onset. In one autosomal dominant pedigree, carriers of both the MYOC c.1334C>T (p.Ala445Val) and CYP1B1 c.1103G>A (p.Arg368His) mutations exhibited an earlier mean age at onset compared to those with MYOC mutation alone (PMID:11774072). This segregation data underscores a modifying effect of MYOC in congenital glaucoma.

Functionally, MYOC pathogenic variants cluster within the C-terminal olfactomedin domain and display aberrant biochemical properties: mutant proteins are Triton-insoluble, fail normal endoproteolytic cleavage, and accumulate intracellularly in trabecular meshwork cells (PMID:10545602); chemical chaperones such as trimethylamine N-oxide restore solubility and secretion of mutants including p.Asp384Asn (PMID:19234343); and temperature shifts rescue folding-defective variants in vitro (PMID:20334347).

Collectively, these data support a dominant-negative or toxic gain-of-function mechanism for MYOC in congenital glaucoma, with digenic interactions modulating age of onset. Although congenital glaucoma has a strong association with CYP1B1, MYOC variants contribute to the phenotypic spectrum and warrant inclusion in gene panels, especially in cases negative for CYP1B1.

Key Take‐home: MYOC screening is recommended for congenital glaucoma to capture allelic variants that may modify disease onset and guide clinical management via targeted genetic testing.

References

• American Journal of Human Genetics • 2002 • Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. PMID:11774072
• Human Molecular Genetics • 1999 • A cellular assay distinguishes normal and mutant TIGR/myocilin protein. PMID:10545602
• Investigative Ophthalmology & Visual Science • 2009 • Correction of the disease phenotype of myocilin-causing glaucoma by a natural osmolyte. PMID:19234343
• ACS Chemical Biology • 2010 • Rescue of glaucoma-causing mutant myocilin thermal stability by chemical chaperones. PMID:20334347

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