Functionally deficient UBOX5 variants and primary angle-closure glaucoma

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<sup>-6</sup>) 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<sup>-10</sup>). 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.

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Journal
Nature Communications
Published
2025-08-15
DOI
https://doi.org/10.1038/s41467-025-62775-x
Primary Topic
Glaucoma and retinal disorders
Type
article
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0.00

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article

Functionally deficient UBOX5 variants and primary angle-closure glaucoma

Chie Sotozono, Evangelia S. Panagiotou, Ahmad Tajudin Liza-Sharmini, Ricardo Y. Abe et al.
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Nature Communications
Glaucoma and retinal disorders
article

Functionally deficient UBOX5 variants and primary angle-closure glaucoma

Chie Sotozono, Evangelia S. Panagiotou, Ahmad Tajudin Liza-Sharmini, Ricardo Y. Abe, Anthoula Chatzikyriakidou, Xiao Yin Chen, José Paulo Cabral de Vasconcellos, Yin Mon Aung, Shamira Perera, Edgar U. Leuenberger, Chona S Liao, Francesca Pasutto, Masami Tanaka, Rodolfo A. Perez-Grossmann, Toshiaki Kubota, Wee Yang Meah, Vi Huyen Doan, Laura Dallorto, Y. Tokuda, Raheel Qamar, Alexandros Lambropoulos, Nguyễn Văn Hiền, Tina Wong, S Nakano, Azhany Yaakub, Masakazu Nakano, Saw Htoo Set, Balram Chowbay, Zhicheng Xie, Farah Akhtar, Tin Aung, María L. Guevara, Paolo Frezzotti, Clement Chee Yung Tham, Khaled K. Abu‐Amero, Donald Tan, Yi Wee Lim, Shigeru Kinoshita, Poemen P. Chan, Ching‐Yu Cheng, Li Jia Chen, Irini C. Voudouragkaki, Yunhua Loo, Ricardo Fujita, Fotis Topouzis, Eleftherios Anastasopoulos, Georgios D. Panos, Panagiota Ntonti, Mahmood Ali, Khin Thida Oo, Kelsey V. Stuart, Rahat Husain, Rachel S. Chong, Nay Lin Oo, Evangelia Papakonstantinou, Guillermo Barreto Fong, Yee Yee Aung, Vital Paulino Costa, Mineo Ozaki, Anita Sook Yee Chan, Ching Lin Ho, Anthony P. Khawaja, Naing Naing Mon, Paul J. Foster, Dimitrios A. Giannoulis, Shazia Micheal, Pearlyn Yeo, Ying Shi Lee, Chaw Chaw Khaing, Candice Ho, Raquel Quino, Dimitrios G. Mikropoulos, Juan Carlos Zenteno, Kei Tashiro, Vassilis Kilintzis, Jamil Miguel Neto, Irene R Felarca, Xuezhi Bi, Chi Pui Pang, Nhu Hon, Mahantesh I. Biradar, Monisha E. Nongpiur, Anita Szabó, Chiea Chuen Khor, Mary Ann T Catacutan, Hlaing May Than, Mônica Barbosa de Melo, Bruno Batista de Souza, Carlo Lavia, Saleh A. Al‐Obeidan, Humaira Ayub, Rigo Daniel Reyes, Yee Jiun Kok, Zheng Li, Nguyễn Thị Thanh Hương, Morio Ueno, Zhehao Liu, Tan Do, Zhenxun Wang, Antonio Maria Fea, Yoko Ikeda, Kazuhiko Mori, Wee Ling Chng, Nguyen Van Trinh, Vânia Castro, Natsue Omi, Pui-Yi Boey, Hon‐Tym Wong, A. G. P. Konstas, Amihan Anajao, Wendy Wan Ling Sin, Phyu P Soe-Kyaw, Zaw Minn-Din
article en

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<sup>-6</sup>) 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<sup>-10</sup>). 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.

Nature CommunicationsVol. 16(1)
University of Siena (IT), Agency for Science, Technology and Research (SG), Mohammed V University (MA), Moorfields Eye Hospital NHS Foundation Trust (GB), Mandalay University (MM), University of Nottingham (GB), Radboud University Nijmegen (NL), National University of Singapore (SG), Chinese University of Hong Kong (HK), Universidade Estadual de Campinas (UNICAMP) (BR), Oita University (JP), Aristotle University of Thessaloniki (GR), Universidad de San Martín de Porres (PE), Singapore National Eye Center (SG), East Yangon General Hospital (MM), University of Haripur (PK), Asian Hospital and Medical Center (PH), King Saud University (SA), University of Medicine Mandalay (MM), Tan Tock Seng Hospital (SG), University Hospitals Coventry and Warwickshire NHS Trust (GB), North Okkalapa General Hospital (MM), Radboud University Medical Center (NL), Pakistan Academy of Sciences (PK), University of Da Nang (VN), President Ramon Magsaysay State University (PH), Kyoto Prefectural University of Medicine (JP), Universitätsklinikum Erlangen (DE), Hospital Universiti Sains Malaysia (MY), Hue University (VN), King Khaled Eye Specialist Hospital (SA), University of the East Ramon Magsaysay Memorial Medical Center (PH), Singapore Eye Research Institute (SG), Asian Eye Institute (PH), Duke-NUS Medical School (SG), Institute of Ophthalmology (MX), Institute of Peruvian Studies (PE), University of Miyazaki Hospital (JP), National Cancer Centre Singapore (SG), Bioprocessing Technology Institute (SG), Vietnam National Children's Hospital (VN), Miyata Eye Hospital (JP), Universidad de Ciencias Médicas de la Habana (CU), Universidad Latina (MX), Yangon ENT Hospital (MM), University College London (GB), University of Turin (IT), University of the Philippines Manila (PH), Genome Institute of Singapore (SG)
Glaucoma Research Foundation, Velux Stiftung, National Institute for Health and Care Research, Lister Institute of Preventive Medicine, National Research Foundation, Agency for Science, Technology and Research, National Research Foundation Singapore, Fundação de Amparo à Pesquisa do Estado de São Paulo, King Saud University, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Universiti Sains Malaysia, Moorfields Eye Hospital NHS Foundation Trust, Moorfields Eye Charity, Medical Research Council, National Medical Research Council, Biomedical Research Council, Alcon Research Institute
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Glaucoma and retinal disorders
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