Variants in the PRPF8 Gene are Associated with Glaucoma

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness globally.
• Existing genetic studies explain only a small fraction of POAG's heritability.
• Identifying novel genetic factors is crucial for understanding POAG pathogenesis.

Purpose of the Study:

• To identify new genetic causes of adult-onset familial primary open-angle glaucoma (POAG).
• To investigate the role of the PRPF8 gene in POAG development.
• To establish genotype-phenotype correlations for PRPF8 mutations.

Main Methods:

• Whole exome sequencing (WES) was used to identify potential pathogenic variants in affected individuals.
• Sanger sequencing was employed for variant segregation analysis in families and targeted gene sequencing in POAG cohorts.
• Case-control association studies were conducted to validate the frequency of identified variants.

Main Results:

• A pathogenic PRPF8 variant (p.Val956Gly) was identified in a Dutch family with POAG.
• Two additional PRPF8 variants (p.Pro13Leu and p.Met25Thr) were found to segregate with POAG in Pakistani families.
• These variants were significantly more prevalent in Pakistani POAG cases than in controls, suggesting a causal role.

Conclusions:

• Mutations in the PRPF8 gene represent a novel genetic cause of primary open-angle glaucoma.
• The location of PRPF8 variants differs between POAG and retinitis pigmentosa, indicating distinct genotype-phenotype relationships.
• These findings expand the spectrum of diseases associated with PRPF8 and offer new insights into glaucoma genetics.