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Functionally deficient UBOX5 variants and primary angle-closure glaucoma.

Zheng Li1, Wee Ling Chng1,2, Zhehao Liu1,2

  • 1Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome #02-01, Singapore, 138672, Republic of Singapore.

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|August 15, 2025
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Summary
This summary is machine-generated.

Genetic variants in the UBOX5 gene significantly increase the risk of primary angle-closure glaucoma (PACG). This gene impacts the UBOX5-BIP signaling pathway, a potential factor in PACG development.

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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.