{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:09:18Z","timestamp":1781827758517,"version":"3.54.5"},"reference-count":30,"publisher":"BMJ","issue":"12","funder":[{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LR21H120001"],"award-info":[{"award-number":["LR21H120001"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31872724"],"award-info":[{"award-number":["31872724"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81900837"],"award-info":[{"award-number":["81900837"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070939"],"award-info":[{"award-number":["82070939"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Br J Ophthalmol"],"accepted":{"date-parts":[[2022,8,22]]},"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:sec>\n<jats:title>Background\/aims<\/jats:title>\n<jats:p>Congenital cataract is the leading cause of visual disability and blindness in childhood. \u03b2B1-crystallin (CRYBB1) comprises about 1\/10th of crystallin structural proteins, forming heteromers to maintain lens transparency. We previously reported a CRYBB1 mutation (c.347T&gt;C, p.L116P) affecting 16 patients in a congenital nuclear cataract family. In this study, we investigate the underlying pathogenic mechanism of \u03b2B1-L116P.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>Protein isolation, size-exclusion chromatography, spectroscopy, Uncle stability screens and molecular dynamics simulations were used to assess \u03b2A3- and \u03b2B1-crystallin thermal stability, structural properties and heteromer formation.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Cells that overexpressed \u03b2B1-L116P tended to form aggregates and precipitations under heat-shock stress. Thermal denaturation and time-dependent turbidity experiments showed that thermal stability was significantly impaired. Moreover, protein instability appeared to increase with elevated concentrations detected by the Uncle system. Additionally, \u03b2A3 had a relative protective effect on \u03b2B1-L116P after heteromers were formed, although \u03b2A3 was relatively unstable and was usually protected by basic \u03b2-crystallins. Molecular dynamic simulations revealed that L116P mutation altered the hydrophobic residues at the surface around the mutant site, providing solvents more access to the internal and hydrophobic parts of the protein.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Decreased \u03b2B1-crystallin thermal stability in the presence of the cataract-related L116P mutation contributes significantly to congenital cataract formation. Moreover, its formation of heteromers with \u03b2A3 protects against the low thermal stability of \u03b2B1-L116P.<\/jats:p>\n<\/jats:sec>","DOI":"10.1136\/bjo-2022-322247","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T17:31:45Z","timestamp":1662053505000},"page":"1936-1942","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Heteromeric formation with \u03b2A3 protects the low thermal stability of \u03b2B1-L116P"],"prefix":"10.1136","volume":"107","author":[{"given":"Jingjie","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3139-3524","authenticated-orcid":false,"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenqi","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8165-023X","authenticated-orcid":false,"given":"Ke","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0766-3416","authenticated-orcid":false,"given":"Xiangjun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,9,1]]},"reference":[{"key":"2024110109351134000_107.12.1936.1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1146\/annurev-vision-091517-034346","article-title":"Biology of inherited cataracts and opportunities for treatment","volume":"5","author":"Shiels","year":"2019","journal-title":"Annu Rev Vis Sci"},{"key":"2024110109351134000_107.12.1936.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.03.005"},{"key":"2024110109351134000_107.12.1936.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2013.12.006"},{"key":"2024110109351134000_107.12.1936.4","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41594-020-00543-9","article-title":"Imbalances in the eye lens proteome are linked to cataract formation","volume":"28","author":"Schmid","year":"2021","journal-title":"Nat Struct Mol Biol"},{"key":"2024110109351134000_107.12.1936.5","doi-asserted-by":"crossref","DOI":"10.1038\/srep28564","article-title":"Prevalence and epidemiological characteristics of congenital cataract: a systematic review and meta-analysis","volume":"6","author":"Wu","year":"2016","journal-title":"Sci Rep"},{"key":"2024110109351134000_107.12.1936.6","doi-asserted-by":"crossref","first-page":"100008","DOI":"10.1016\/j.aopr.2021.100008","article-title":"Cataract: advances in surgery and whether surgery remains the only treatment in future","volume":"1","author":"Chen","year":"2021","journal-title":"Adv Ophthalmol Pract Res"},{"key":"2024110109351134000_107.12.1936.7","doi-asserted-by":"publisher","DOI":"10.1159\/000442495"},{"key":"2024110109351134000_107.12.1936.8","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.ejmg.2010.07.001","article-title":"Molecular characteristics of inherited congenital cataracts","volume":"53","author":"Huang","year":"2010","journal-title":"Eur J Med Genet"},{"key":"2024110109351134000_107.12.1936.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2007.10.003"},{"key":"2024110109351134000_107.12.1936.10","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1021\/acs.biochem.8b01164","article-title":"Dissimilarity in the contributions of the N-terminal domain hydrophobic core to the structural stability of lens \u03b2\/\u03b3-Crystallins","volume":"58","author":"Zhang","year":"2019","journal-title":"Biochemistry"},{"key":"2024110109351134000_107.12.1936.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2008.10.011"},{"key":"2024110109351134000_107.12.1936.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.03.119"},{"key":"2024110109351134000_107.12.1936.13","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.ijbiomac.2017.05.109","article-title":"Effects of cataract-causing mutations W59C and W151C on \u03b2B2-crystallin structure, stability and folding","volume":"103","author":"Zhao","year":"2017","journal-title":"Int J Biol Macromol"},{"key":"2024110109351134000_107.12.1936.14","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.1016\/j.bbadis.2014.07.022","article-title":"Cataract-causing mutation R233H affects the stabilities of \u03b2B1- and \u03b2A3\/\u03b2B1-crystallins with different pH-dependence","volume":"1842","author":"Xi","year":"2014","journal-title":"Biochimica et Biophysica Acta (BBA) - 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