Functionally deficient UBOX5 variants and primary angle-closure glaucoma

Li Z, Chng WL, Liu Z, Do T, Nakano M, Chen LJ, Loo Y, Chan AS, Topouzis F, Nongpiur ME, Ozaki M, Nakano S, Kubota T, Perera SA, Husain R, Wong TT, Cheng CY, Ho CL, Abu-Amero K, Wong HT, Melo MBd, Hien NDTN, Van Trinh N, Huong NTT, Azhany Y, Perez-Grossmann R, Chan PP, Stuart KV, Biradar MI, Szabo A, Anastasopoulos E, Giannoulis DA, Ntonti P, Papakonstantinou E, Lambropoulos A, Chatzikyriakidou A, Kilintzis V, Ayub H, Micheal S, Aung YY, Leuenberger EU, Fea A, Mon NN, Anajao A, Bi X, Kok YJ, Chong RS, Boey PY, Tan DZJ, Sin WWL, Chowbay B, Khaing CC, Aung YM, Reyes RD, Panagiotou ES, Mikropoulos DG, Voudouragkaki IC, Panos GD, Xie Z, Chen XY, Lim YT, Meah WY, Lee YS, Ho CEH, Yeo PMX, Ikeda Y, Tokuda Y, Tanaka M, Omi N, Ueno M, de Vasconcellos JP, Costa VP, Abe RY, de Souza BB, Fong GB, Castro VV, Fujita R, Guevara-Fujita ML, Akhtar F, Ali M, Catacutan MAT, Felarca IR, Liao CS, Lavia C, Than HM, Oo KT, Soe-Kyaw PP, Frezzotti P, Pasutto F, Quino R, Minn-Din Z, Oo NL, Dallorto L, Set SH, Doan VH, Qamar R, Neto JM, Al-Obeidan S, Tham CC, Mori K, Sotozono C, Kinoshita S, Konstas AG, Liza-Sharmini AT, Zenteno JC, Do NH, Foster PJ, Tashiro K, Pang CP, Khawaja AP, Aung T, Wang Z, Khor CC (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 16

Article Number: 7620

Journal Issue: 1

DOI: 10.1038/s41467-025-62775-x

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.

Authors with CRIS profile

Involved external institutions

Aristotle University of Thessaloniki Greece (GR) Moorfields Eye Hospital NHS Foundation Trust United Kingdom (GB) National University of Singapore (NUS) Singapore (SG) Bioprocessing Technology Institute (BTI) Singapore (SG) The Chinese University of Hong Kong (CUHK) China (CN) National Cancer Centre Singapore (NCCS) Singapore (SG) Grand Hantha International Hospital Viet Nam (VN) Oita University / 大分大学 Japan (JP) Genome Institute of Singapore Singapore (SG) King Khaled Eye Specialist Hospital Saudi Arabia (SA) Tan Tock Seng Hospital Singapore (SG) Universidade Estadual de Campinas (UNICAMP) / University of Campinas Brazil (BR) Asian Eye Institute Philippines (PH) University of Turin / Università degli Studi di Torino (UNITO) Italy (IT) North Okkalapa General Hospital Myanmar (MM) Kyoto Prefectural University of Medicine / 京都府立医科大学 Japan (JP) Vietnam National Institute of Ophthalmology (VNIO) Viet Nam (VN) Asian Hospital and Medical Center Philippines (PH) Universidad de San Martín de Porres (USMP) Peru (PE) Al-Shifa Trust Eye Hospital Pakistan (PK) Università degli Studi di Siena (UNISI) / University of Siena Italy (IT) University of Science Malaysia (USM) / Universiti Sains Malaysia Malaysia (MY) Hue University / Đại học Huế Viet Nam (VN) Hospital Nacional Arzobispo Loayza Peru (PE) National Autonomous University of Mexico / Universidad Nacional Autónoma de México (UNAM) Mexico (MX) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL)

How to cite

APA:

Li, Z., Chng, W.L., Liu, Z., Do, T., Nakano, M., Chen, L.J.,... Khor, C.C. (2025). Functionally deficient UBOX5 variants and primary angle-closure glaucoma. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-62775-x

MLA:

Li, Zheng, et al. "Functionally deficient UBOX5 variants and primary angle-closure glaucoma." Nature Communications 16.1 (2025).

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