{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:44:08Z","timestamp":1792179848414,"version":"4.4.0"},"reference-count":26,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2016,4,6]],"date-time":"2016-04-06T00:00:00Z","timestamp":1459900800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["FI12\/00287"],"award-info":[{"award-number":["FI12\/00287"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["RD07\/0062\/0014"],"award-info":[{"award-number":["RD07\/0062\/0014"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["RD12\/0034\/0003"],"award-info":[{"award-number":["RD12\/0034\/0003"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI11\/00662"],"award-info":[{"award-number":["PI11\/00662"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Ophthalmologica"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>To evaluate the function of eight missense <jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>1B1<\/jats:italic> single nucleotide variants (<jats:styled-content style=\"fixed-case\">SNV<\/jats:styled-content>s) previously identified in patients with primary congenital glaucoma (PCG).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The eight variants were obtained by site\u2010directed mutagenesis and transiently expressed in human embryonic kidney 293\u2010T (<jats:styled-content style=\"fixed-case\">HEK<\/jats:styled-content>\u2010293T) cells. The catalytic activity, protein stability and subcellular localization of the different recombinant <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>1B1 variants were assessed in this cell line.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Six of the mutant <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>1B1 proteins (p.L89P, p.A106D, p.R390S, p.P437L, p.C470Y and S485F) showed catalytic activity values ranging from 0% to 4% of those of the wild\u2010type protein and were considered null variants. The activity values of the two remaining variants (p.F123L and p.A237E) were close to 20% of that of the wild\u2010type enzyme and were classified as hypomorphic variants. Reduced protein stability contributed partially to the decreased catalytic activity of two of the mutant enzymes (p.L89P and p.A106D). None of the <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>1B1 variants showed intracellular aggregation and they all displayed a normal subcellular localization in the endoplasmic reticulum, suggesting that they had folded into a wild\u2010type\u2010like structure. The enzymatic activity associated with the different genotypes in which these <jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>1B1<\/jats:italic> variants were present was estimated to range from 0% to 10% of that of the wild\u2010type genotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results confirm the pathogenicity of the analysed missense <jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>1B1<\/jats:italic> variants and further support the concept that either absent or very low <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>1B1 activity levels are the primary molecular defect involved in <jats:styled-content style=\"fixed-case\">PCG<\/jats:styled-content> pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aos.13017","type":"journal-article","created":{"date-parts":[[2016,4,10]],"date-time":"2016-04-10T13:23:12Z","timestamp":1460294592000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Functional characterization of eight rare missense <i><scp>CYP<\/scp>1B1<\/i> variants involved in congenital glaucoma and their association with null genotypes"],"prefix":"10.1111","volume":"94","author":[{"given":"Cristina","family":"Medina\u2010Trillo","sequence":"first","affiliation":[{"name":"Area of Genetics Faculty of Medicine\/IDINA University of Castilla\u2010La Mancha Albacete Spain"},{"name":"Cooperative Research Network on Age\u2010Related Ocular Pathology Visual and Life Quality Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas\u2010Jos\u00e9","family":"Ferre\u2010Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Area of Genetics Faculty of Medicine\/IDINA University of Castilla\u2010La Mancha Albacete Spain"},{"name":"Cooperative Research Network on Age\u2010Related Ocular Pathology Visual and Life Quality Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9\u2010Daniel","family":"Aroca\u2010Aguilar","sequence":"additional","affiliation":[{"name":"Area of Genetics Faculty of Medicine\/IDINA University of Castilla\u2010La Mancha Albacete Spain"},{"name":"Cooperative Research Network on Age\u2010Related Ocular Pathology Visual and Life Quality Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan\u2010Manuel","family":"Bonet\u2010Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Area of Genetics Faculty of Medicine\/IDINA University of Castilla\u2010La Mancha Albacete Spain"},{"name":"Cooperative Research Network on Age\u2010Related Ocular Pathology Visual and Life Quality Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Escribano","sequence":"additional","affiliation":[{"name":"Area of Genetics Faculty of Medicine\/IDINA University of Castilla\u2010La Mancha Albacete Spain"},{"name":"Cooperative Research Network on Age\u2010Related Ocular Pathology Visual and Life Quality Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,4,6]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.106.085498"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501340200"},{"key":"e_1_2_5_4_1","first-page":"1458","article-title":"Mutational screening of CYP1B1 in Turkish PCG families and functional analyses of newly detected mutations","volume":"13","author":"Bagiyeva S","year":"2007","journal-title":"Mol Vis"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1086\/301725"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M513629200"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1550"},{"key":"e_1_2_5_8_1","first-page":"417","article-title":"CYP1B1 mutations in Spanish patients with primary congenital glaucoma: phenotypic and functional variability","volume":"15","author":"Campos\u2010Mollo E","year":"2009","journal-title":"Mol Vis"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20786"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e3282ff5a36"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1159\/000309028"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.3928\/01913913-20040901-11"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-200112000-00007"},{"key":"e_1_2_5_14_1","first-page":"645","article-title":"Congenital glaucoma due to dominant goniodysgenesis. A new concept of the heredity of glaucoma","volume":"35","author":"Jerndal T","year":"1983","journal-title":"Am J Hum Genet"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1006\/abio.1994.1476"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2009.01284.x"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2012.09.016"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0039-6257(83)90174-1"},{"key":"e_1_2_5_19_1","first-page":"2211","article-title":"Novel cytochrome P4501B1 (CYP1B1) gene mutations in Japanese patients with primary congenital glaucoma","volume":"42","author":"Mashima Y","year":"2001","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0119272"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(98)01208-0"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M609608200"},{"key":"e_1_2_5_23_1","first-page":"1149","article-title":"[Congenital glaucoma of dominant autosomal transmission apropos of a family Management]","volume":"89","author":"Simha N","year":"1989","journal-title":"Bull Soc Ophtalmol Fr"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.4.641"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1086\/301764"},{"key":"e_1_2_5_26_1","first-page":"1820","article-title":"Molecular genetics of primary congenital glaucoma in Brazil","volume":"43","author":"Stoilov IR","year":"2002","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00856-13"}],"container-title":["Acta Ophthalmologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Faos.13017","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/aos.13017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,16]],"date-time":"2023-09-16T20:35:42Z","timestamp":1694896542000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/aos.13017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,6]]},"references-count":26,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2016,11]]}},"alternative-id":["10.1111\/aos.13017"],"URL":"https:\/\/doi.org\/10.1111\/aos.13017","archive":["Portico"],"relation":{},"ISSN":["1755-375X","1755-3768"],"issn-type":[{"value":"1755-375X","type":"print"},{"value":"1755-3768","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,6]]},"assertion":[{"value":"2015-07-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-01-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-04-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}