PAPPA2 c.392G>C Heterozygous Mutation Associates Primary Open-Angle Glaucoma in a Chinese Family

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Primary open-angle glaucoma (POAG) has a strong familial component, with relatives of patients facing a tenfold higher risk.
• Genetic factors are implicated in POAG pathogenesis, necessitating further investigation into specific gene mutations.

Purpose of the Study:

• To investigate the role of the PAPPA2 gene in POAG pathogenesis within a Chinese family.
• To elucidate the functional impact of a novel PAPPA2 mutation on the PAPPA2-IGFBP5 axis and its contribution to POAG.

Main Methods:

• Identified and characterized a PAPPA2 c.392G>C heterozygous mutation in affected family members.
• Assessed PAPPA2 protein levels and its interaction with IGFBP5 in human aqueous humor and trabecular meshwork cells.
• Utilized mRNA sequencing, western blotting, and immunofluorescence in a mouse model to evaluate the functional consequences of PAPPA2 deficiency.

Main Results:

• The identified PAPPA2 mutation decreased PAPPA2 protein levels.
• Reduced PAPPA2 and elevated IGFBP5 levels were observed in POAG patients' aqueous humor.
• Overexpression of IGFBP5 promoted fibrosis-related gene expression in human trabecular meshwork cells.
• Pappa2 deficiency in mice recapitulated POAG-like phenotypes.

Conclusions:

• The PAPPA2-IGFBP5 axis plays a critical role in regulating extracellular matrix homeostasis in the eye.
• Dysregulation of this axis contributes to trabecular meshwork fibrosis and the pathogenesis of POAG.
• The PAPPA2 c.392G>C mutation is a potential cause of POAG.