Functionally deficient UBOX5 variants and primary angle-closure glaucoma

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Primary angle-closure glaucoma (PACG) is a leading cause of irreversible blindness globally, affecting over 20 million people.
• Understanding the genetic underpinnings of PACG is crucial for developing effective prevention and treatment strategies.

Purpose of the Study:

• To identify genetic variants associated with an increased risk of primary angle-closure glaucoma.
• To elucidate the molecular mechanism involving the identified gene and its role in PACG pathogenesis.

Main Methods:

• Whole exome sequencing was performed on 4,667 PACG cases and 5,473 controls to analyze gene-based burden of rare variants.
• Exome-wide significant genes were tested for replication in a larger cohort (2,519 cases, 472,189 controls).
• Substrate trapping assays, mass spectrometry, and biological assays were used to investigate the function of UBOX5 and its interaction with Binding Immunoglobulin Protein (BIP).

Main Results:

• Rare, protein-altering variants in the UBOX5 gene were significantly associated with a 2.13-fold increased risk of PACG (P = 1.25 × 10⁻¹⁰).
• UBOX5 was found to ubiquitinate BIP, identifying BIP as a key substrate in the UBOX5 signaling pathway.
• Functionally deficient UBOX5 variants were enriched in PACG patients compared to controls, further supporting the gene's role in the disease.

Conclusions:

• The UBOX5 gene and its interaction with BIP represent a novel genetic and molecular pathway implicated in primary angle-closure glaucoma.
• Targeting the UBOX5-BIP signaling pathway may offer new therapeutic avenues for preventing or treating PACG.