A novel mutation in PCK2 gene causes primary angle-closure glaucoma

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Primary angle-closure glaucoma (PACG) is an ophthalmic condition where iris and trabecular meshwork contact obstructs aqueous humor outflow.
• The precise genetic factors contributing to PACG development remain largely unknown.
• Understanding the genetic basis of PACG is crucial for diagnosis and treatment.

Observation:

• Whole-genome sequencing was employed to investigate a five-generation Chinese family with a history of PACG.
• A novel heterozygous missense mutation, c.977C>T, in the PCK2 gene was identified in affected individuals.
• This mutation, resulting in a p.Pro326Leu substitution, was absent in unaffected family members and unrelated healthy controls.

Findings:

• In vitro assays using RGC-5 cells revealed that the p.Pro326Leu mutation induces cell cycle arrest and apoptosis.
• The mutation led to decreased BcL-XL expression and increased levels of P53, P27, P21, AKT, and P-GSK3α.
• These cellular changes indicate that the PCK2 mutation impairs the AKT/GSK3α signaling pathway.

Implications:

• The identified PCK2 gene mutation is a potential cause of PACG.
• This finding advances our understanding of PACG pathogenesis.
• Further research into the AKT/GSK3α pathway may reveal novel therapeutic targets for PACG.