# Functionally deficient UBOX5 variants and primary angle-closure glaucoma

## TL;DR

Rare harmful changes in the UBOX5 gene increase the risk of primary angle-closure glaucoma, a major cause of blindness.

## Contribution

Identified UBOX5 as a novel gene associated with primary angle-closure glaucoma through rare variants and their functional impact on BIP ubiquitination.

## Key findings

- UBOX5 variants are associated with a 2.13-fold increased risk of primary angle-closure glaucoma.
- UBOX5 ubiquitinates BIP, and functionally deficient variants are enriched in affected individuals.
- Three individuals with functionally deficient UBOX5 variants were found in 208 cases but none in 600 controls.

## Abstract

Primary angle-closure glaucoma is a major cause of irreversible blindness worldwide afflicting >20 million people. Through whole exome sequencing, we analysed the association between gene-based burden of rare, protein-altering genetic variants and disease risk in 4,667 affected individuals and 5,473 unaffected controls. We tested genes surpassing exome-wide significance (P < 2.5 × 10-6) for replication in a further 2,519 cases and 472,189 controls. We observed carriers of rare, protein-altering variants at UBOX5 (observed in 154 out of 7,186 affected individuals [2.1%] and in 3,975 out of 477,197 unaffected controls [0.83%]) to be associated with 2.13-fold increased risk of PACG (95%ci, 1.69 – 2.69; P = 1.25 × 10-10). We performed substrate trapping assays coupled with mass spectrometry and observed Binding Immunoglobulin Protein (BIP) as a key substrate for UBOX5. Biological assays showed UBOX5 acts by ubiquitinating BIP. We evaluated the functional status of 35 UBOX5 variants and observed that functionally deficient variants were enriched in affected individuals compared to controls. We validated this finding in an independent collection where 3 persons carrying functionally deficient variants were observed out of 208 cases (1.4%), whereas none were observed in 600 controls. Our findings suggest the UBOX5—BIP signalling pathway might be involved in biology of primary angle-closure glaucoma.

Primary angle-closure glaucoma is a leading cause of blindness. Here, the authors identify rare deleterious variants in UBOX5 as risk factors and implicate BIP ubiquitination as a potential disease mechanism.