Functionally deficient UBOX5 variants and primary angle-closure glaucoma

Functionally deficient UBOX5 variants and primary angle-closure glaucoma

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 individua...

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Main Authors: Zheng Li, Wee Ling Chng, Zhehao Liu, Tan Do, Masakazu Nakano, Li Jia Chen, Yunhua Loo, Anita S. Y. Chan, Fotis Topouzis, Monisha E. Nongpiur, Mineo Ozaki, Satoko Nakano, Toshiaki Kubota, Shamira A. Perera, Rahat Husain, Tina T. L. Wong, Ching-Yu Cheng, Ching Lin Ho, Khaled Abu-Amero, Hon-Tym Wong, Mônica Barbosa de Melo, Nguyen Do Thi Ngoc Hien, Nguyen Van Trinh, Nguyen Thi Thanh Huong, Yaakub Azhany, Rodolfo Perez-Grossmann, Poemen PM Chan, Kelsey V. Stuart, Mahantesh I. Biradar, Anita Szabo, Eleftherios Anastasopoulos, Dimitrios A. Giannoulis, Panagiota Ntonti, Evangelia Papakonstantinou, Alexandros Lambropoulos, Anthoula Chatzikyriakidou, Vassilis Kilintzis, Humaira Ayub, Shazia Micheal, Yee Yee Aung, Edgar U. Leuenberger, Antonio Fea, Naing Naing Mon, Amihan Anajao, Xuezhi Bi, Yee Jiun Kok, Rachel S. Chong, Pui-Yi Boey, Darrell Zi Jing Tan, Wendy Wan Ling Sin, Balram Chowbay, Chaw Chaw Khaing, Yin Mon Aung, Rigo Daniel Reyes, Evangelia S. Panagiotou, Dimitrios G. Mikropoulos, Irini C. Voudouragkaki, Georgios D. Panos, Zhicheng Xie, Xiao Yin Chen, Yi Ting Lim, Wee Yang Meah, Ying Shi Lee, Candice Ee Hua Ho, Pearlyn Mei Xin Yeo, Yoko Ikeda, Yuichi Tokuda, Masami Tanaka, Natsue Omi, Morio Ueno, José P. C. de Vasconcellos, Vital P. Costa, Ricardo Y. Abe, Bruno B. de Souza, Guillermo B. Fong, Vania V. Castro, Ricardo Fujita, Maria L. Guevara-Fujita, Farah Akhtar, Mahmood Ali, Mary Ann T. Catacutan, Irene R. Felarca, Chona S. Liao, Carlo Lavia, Hlaing May Than, Khin Thida Oo, Phyu P. Soe-Kyaw, Paolo Frezzotti, Francesca Pasutto, Raquel Quino, Zaw Minn-Din, Nay Lin Oo, Laura Dallorto, Saw Htoo Set, Vi Huyen Doan, Raheel Qamar, Jamil Miguel Neto, Saleh Al-Obeidan, Clement C. Tham, Kazuhiko Mori, Chie Sotozono, Shigeru Kinoshita, Anastasios G. Konstas, Ahmad Tajudin Liza-Sharmini, Juan C. Zenteno, Nhu Hon Do, Paul J. Foster, Kei Tashiro, Chi Pui Pang, Anthony P. Khawaja, Tin Aung, Zhenxun Wang, Chiea Chuen Khor
Format: Article
Language:English
Published: Nature Portfolio 2025-08-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-62775-x
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Summary: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.
ISSN:2041-1723

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