{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T19:46:13Z","timestamp":1782589573781,"version":"3.54.5"},"reference-count":74,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,10,15]],"date-time":"2018-10-15T00:00:00Z","timestamp":1539561600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004253","name":"Quaid-i-Azam University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004253","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Congenital Anomalies"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:p>Primary congenital glaucoma (PCG) causes blindness in early age. It has an autosomal recessive pattern of inheritance, hence is more prevalent in populations with frequent consanguineous marriages that occur in the Pakistani population. Mutations in the<jats:italic>CYP1B1<\/jats:italic>gene are commonly associated with PCG. The aim of the present study was to identify genetic mutations in the<jats:italic>CYP1B1<\/jats:italic>gene in PCG cases belonging to 38 Pakistani families. DNA was extracted using blood samples collected from all enrolled patients, their available unaffected family members and controls. Direct sequencing of the<jats:italic>CYP1B1<\/jats:italic>gene revealed a novel 3' splice acceptor site causative variant segregating in an autosomal recessive manner in a large consanguineous family with four PCG\u2010affected individuals. The novel variant was not detected in 93 ethnically matched controls. Furthermore, four already reported mutations, including p.G61E, p.R355X, p.R368H, and p.R390H were also detected in patients belonging to nine different families. All identified causative variants were evaluated by computational programs, that is, SIFT, PolyPhen\u20102, and MutationTaster. Pathogenicity of the novel splice site variant identified in this study was analyzed by Human Splicing Finder and MaxEntScan. Ten out of 38 families with PCG had the disease due to<jats:italic>CYP1B1<\/jats:italic>mutations, suggesting<jats:italic>CYP1B1<\/jats:italic>was contributing to PCG in these Pakistani patients. Identification of this novel 3' splice acceptor site variant in intron 2 is the first report for the<jats:italic>CYP1B1<\/jats:italic>gene contributing to genetic heterogeneity of disease.<\/jats:p>","DOI":"10.1111\/cga.12312","type":"journal-article","created":{"date-parts":[[2018,9,30]],"date-time":"2018-09-30T23:07:51Z","timestamp":1538348871000},"page":"152-161","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Mutational analysis of the<i>CYP1B1<\/i>gene in Pakistani primary congenital glaucoma patients: Identification of four known and a novel causative variant at the 3\u2032 splice acceptor site of intron 2"],"prefix":"10.1111","volume":"59","author":[{"given":"Rabia","family":"Afzal","sequence":"first","affiliation":[{"name":"Department of Animal Sciences, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4959-7832","authenticated-orcid":false,"given":"Sabika","family":"Firasat","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiba","family":"Kaul","sequence":"additional","affiliation":[{"name":"Genetics Division, Department of Livestock Production University of Veterinary and Animal Sciences Pattoki Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bashir","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sorath N.","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Department of Pediatric Ophthalmology and Strabismus Al\u2010Shifa Trust Eye Hospital Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saemah N.","family":"Zafar","sequence":"additional","affiliation":[{"name":"Department of Pediatric Ophthalmology and Strabismus Al\u2010Shifa Trust Eye Hospital Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misbah","family":"Shahzadi","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran","family":"Afshan","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,10,15]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"458","article-title":"The development of the trabecular meshwork and its abnormality in primary infantile glaucoma","volume":"79","author":"Anderson DR","year":"1981","journal-title":"Trans Am Ophthalmol Soc"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx205"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kjms.2014.02.009"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.3109\/13816810.2011.596891"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1995.9888"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.03-0404"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.5005\/jp-journals-10008-1192"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.03.017"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10792-017-0508-4"},{"key":"e_1_2_7_11_1","first-page":"1659","article-title":"Primary congenital glaucoma localizes to chromosome 14q24. 2\u201024.3 in two consanguineous Pakistani families","volume":"14","author":"Firasat S","year":"2008","journal-title":"Mol Vis"},{"key":"e_1_2_7_12_1","first-page":"2002","article-title":"Novel CYP1B1 mutations in consanguineous Pakistani families with primary congenital glaucoma","volume":"14","author":"Firasat S","year":"2008","journal-title":"Mol Vis"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/hgv.2016.21"},{"key":"e_1_2_7_14_1","first-page":"991","article-title":"Mutational spectrum of the CYP1B1 gene in Pakistani patients with primary congenital glaucoma: novel variants and genotype\u2010phenotype correlations","volume":"20","author":"Sheikh SA","year":"2014","journal-title":"Mol Vis"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.3.367"},{"key":"e_1_2_7_16_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_7_17_1","first-page":"523","article-title":"Primary congenital glaucoma and Rieger's anomaly: extended haplotypes reveal founder effects for eight distinct CYP1B1 mutations","volume":"12","author":"Chavarria\u2010Soley G","year":"2006","journal-title":"Mol Vis"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.4.641"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/5.8.1199"},{"key":"e_1_2_7_20_1","first-page":"3015","article-title":"The third genetic locus (GLC3C) for primary congenital glaucoma (PCG) maps to chromosome 14q243","volume":"43","author":"Stoilov I","year":"2002","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2005.00411.x"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.08.005"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI85830"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI95545"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/17.20.8390"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp215"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1089\/1066527041410418"},{"key":"e_1_2_7_28_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_7_29_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.05-0912"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.2004.047761"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1159\/000022778"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/IJG.0b013e31815678c3"},{"key":"e_1_2_7_33_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2015\/781294","article-title":"Rare diseases leading to childhood glaucoma: epidemiology, pathophysiogenesis, and management","volume":"2015","author":"Abdolrahimzadeh S","year":"2015","journal-title":"Biomed Res Int"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.3928\/01913913-20040901-11"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-200401000-00001"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1086\/301764"},{"key":"e_1_2_7_37_1","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/S0090-9556(24)15290-7","article-title":"Development of an antipeptide antibody that binds to the C\u2010terminal region of human CYP1B1","volume":"27","author":"Tang YM","year":"1999","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_7_38_1","first-page":"399","article-title":"Primary role of CYP1B1 in Indian juvenile\u2010onset POAG patients","volume":"12","author":"Acharya M","year":"2006","journal-title":"Mol Vis"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0159259"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2777"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.3108805"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.03.014"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg563"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1005663728291"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M310182200"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr481"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36017"},{"key":"e_1_2_7_48_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_7_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2011.07.009"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-014-0109-2"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaapos.2011.01.156"},{"key":"e_1_2_7_52_1","first-page":"748","article-title":"Heterozygous CYP1B1 gene mutations in Spanish patients with primary open\u2010angle glaucoma","volume":"12","author":"L\u00f3pez\u2010Garrido M\u2010P","year":"2006","journal-title":"Mol Vis"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.020024"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1111\/ceo.12369"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2015.07.014"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1086\/301725"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.2353\/jmoldx.2007.060157"},{"key":"e_1_2_7_58_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_7_59_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-200112000-00007"},{"key":"e_1_2_7_60_1","first-page":"696","article-title":"Mutation spectrum of the CYP1B1 gene in Indian primary congenital glaucoma patients","volume":"10","author":"Reddy A","year":"2004","journal-title":"Mol Vis"},{"key":"e_1_2_7_61_1","first-page":"2926","article-title":"Identification of four novel cytochrome P4501B1 mutations (p. I94X, p. H279D, p. Q340H, and p. K433K) in primary congenital glaucoma patients","volume":"15","author":"Tanwar M","year":"2009","journal-title":"Mol Vis"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/eye.2012.159"},{"key":"e_1_2_7_63_1","first-page":"2349","article-title":"Screening of common CYP1B1 mutations in Iranian POAG patients using a microarray\u2010based PrASE protocol","volume":"14","author":"Suri F","year":"2008","journal-title":"Mol Vis"},{"key":"e_1_2_7_64_1","first-page":"1358","article-title":"Identification of novel mutations causing familial primary congenital glaucoma in Indian pedigrees","volume":"43","author":"Panicker SG","year":"2002","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1097\/00061198-200108000-00017"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9197"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2009.04.045"},{"key":"e_1_2_7_68_1","first-page":"2911","article-title":"Screening of CYP1B1 and LTBP2 genes in Saudi families with primary congenital glaucoma: genotype\u2010phenotype correlation","volume":"17","author":"Abu\u2010Amero KK","year":"2011","journal-title":"Mol Vis"},{"key":"e_1_2_7_69_1","first-page":"1200","article-title":"Mutation spectrum of CYP1B1 in north Indian congenital glaucoma patients","volume":"15","author":"Tanwar M","year":"2009","journal-title":"Mol Vis"},{"key":"e_1_2_7_70_1","first-page":"1325","article-title":"Molecular analysis of CYP1B1 in Omani patients with primary congenital glaucoma: a pilot study","volume":"15","author":"El\u2010Gayar S","year":"2009","journal-title":"Mol Vis"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-017-3853-0"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2008.01024.x"},{"key":"e_1_2_7_73_1","first-page":"508","article-title":"Contributions of MYOC and CYP1B1 mutations to JOAG","volume":"14","author":"Bayat B","year":"2008","journal-title":"Mol Vis"},{"key":"e_1_2_7_74_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0090-9556(24)15367-6","article-title":"Biosynthesis of all\u2010trans\u2010retinoic acid from all\u2010trans\u2010retinol: catalysis of all\u2010trans\u2010retinol oxidation by human P\u2010450 cytochromes","volume":"28","author":"Chen H","year":"2000","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.06-1350"}],"container-title":["Congenital Anomalies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcga.12312","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cga.12312","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cga.12312","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cga.12312","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:53:29Z","timestamp":1761062009000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cga.12312"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,15]]},"references-count":74,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,9]]}},"alternative-id":["10.1111\/cga.12312"],"URL":"https:\/\/doi.org\/10.1111\/cga.12312","archive":["Portico"],"relation":{},"ISSN":["0914-3505","1741-4520"],"issn-type":[{"value":"0914-3505","type":"print"},{"value":"1741-4520","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,15]]},"assertion":[{"value":"2018-04-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}