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Abstract #127117 Published in IGR 25-3
Functionally deficient UBOX5 variants and primary angle-closure glaucoma
Li Z; Chng WL; Liu Z; Do T; Nakano M; Chen LJ; Loo Y; Loo Y; Chan ASY; Topouzis F; Nongpiur ME; Ozaki M; Nakano S; Kubota T; Perera SA; Husain R; Wong TTL; Cheng CY; Ho CL; Abu-Amero K; Wong HT; Melo MB; Hien NDTN; Van Trinh N; Huong NTT; Azhany Y; Perez-Grossmann R; Chan PP; Stuart KV; Biradar MI; Szabo A; 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 JPC; 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 CCNature communications 2025; 16: 7620
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) 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). 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.
Genome 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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