{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:14:46Z","timestamp":1789067686237,"version":"build-2803163510"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T00:00:00Z","timestamp":1669939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The study aims to detect the underlying genetic defect in two autosomal dominant congenital cataract (ADCC) families.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A detailed family history was collected, pedigrees were drawn, and slit-lamp examination and lens photography were performed. Mutation screening was carried out in the genes for crystallins and connexins by PCR and Sanger sequencing. Ethnically matched controls were tested for the identified variants. Different bioinformatics tools were used to assess the pathogenicity of the observed variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In an ADCC family with total cataract, a novel change (c.166A\u2009&amp;gt;\u2009G) (p.Thr56Ala) in <jats:italic>GJA8<\/jats:italic> was identified. In another ADCC family with nuclear cataract, c.134G\u2009&amp;gt;\u2009C (p.Trp45Ser) in <jats:italic>GJA3<\/jats:italic> has been detected. These variants co-segregated completely in patients in their respective families and were neither observed in unaffected family members nor in ethnically matched 100 controls, excluding them as polymorphisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The present study identifies a novel variant c.166A\u2009&amp;gt;\u2009G (p.Thr56Ala) in <jats:italic>GJA8<\/jats:italic> in an ADCC family having total cataract and a previously known mutation c.134G\u2009&amp;gt;\u2009C (p.Trp45Ser) in <jats:italic>GJA3<\/jats:italic> in another ADCC family. Thr56 in <jats:italic>GJA8<\/jats:italic> seems to be a mutation hotspot, as previously an ADCC Mauritanian family harbored a different substitution (p.Thr56Pro) at the same codon, although for a different phenotype (nuclear cataract). Similarly, Trp45 in <jats:italic>GJA3<\/jats:italic> appears as a mutation hotspot, as p.Trp45Ser has previously been reported for nuclear cataract in a Chinese ADCC family. p.Thr56 (GJA8) and p.Trp45 (GJA3<jats:italic>)<\/jats:italic> are in the extracellular loop 1 (EL1) in their respective connexin proteins, which, along with EL2, are essential for gap junction formation, hemichannel docking, and regulating the voltage gating of the channels. Hence, residues in these regions seem crucial for maintaining eye lens transparency.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2022.1003909","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T10:03:33Z","timestamp":1669975413000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Molecular diagnosis of autosomal dominant congenital cataract in two families from North India reveals a novel and a known variant in GJA8 and GJA3"],"prefix":"10.3389","volume":"10","author":[{"given":"Vanita","family":"Vanita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwali","family":"Goyal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailja","family":"Tibrewal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suma","family":"Ganesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1167\/iovs.03-0635","article-title":"Incidence and cumulative risk of childhood cataract in a cohort of 2.6 million Danish children","volume":"45","author":"Haargaard","year":"2004","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B2","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/S0140-6736(17)30544-5","article-title":"Cataracts","volume":"390","author":"Liu","year":"2017","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1034\/j.1399-0004.1999.560507.x","article-title":"Genetic and segregation analysis of congenital cataract in the Indian population","volume":"56","author":"Vanita","year":"1999","journal-title":"Clin Genet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.semcdb.2015.11.015","article-title":"Structural analysis of key gap junction domains\u2014lessons from genome data and disease-linked mutants","volume":"50","author":"Bai","year":"2016","journal-title":"Semin Cell Dev Biol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1083\/jcb.115.4.1077","article-title":"Connexin46, a novel lens gap junction protein, induces voltage-gated currents in nonjunctional plasma membrane of Xenopus oocytes","volume":"115","author":"Paul","year":"1991","journal-title":"J Cell Biol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1091\/mbc.3.7.711","article-title":"Mouse Cx50, a functional member of the connexin family of gap junction proteins, is the lens fiber protein MP70","volume":"3","author":"White","year":"1992","journal-title":"Mol Biol Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"7614","DOI":"10.1167\/iovs.13-13188","article-title":"Connexin50D47A decreases levels of fiber cell connexins and impairs lens fiber cell differentiation","volume":"54","author":"Berthoud","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B8","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1083\/jcb.86.2.576","article-title":"Lens metabolic cooperation: a study of mouse lens transport and permeability visualized with freeze-substitution autoradiography and electron microscopy","volume":"86","author":"Goodenough","year":"1980","journal-title":"J Cell Biol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/j.exer.2003.07.001","article-title":"The lens: local transport and global transparency","volume":"78","author":"Mathias","year":"2004","journal-title":"Exp Eye Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1126\/science.1067582","article-title":"Unique and redundant connexin contributions to lens development","volume":"295","author":"White","year":"2002","journal-title":"Science"},{"key":"B11","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/S0962-8924(98)01372-5","article-title":"Diverse functions of vertebrate gap junctions","volume":"8","author":"Simon","year":"1998","journal-title":"Trends Cell Biol"},{"key":"B12","doi-asserted-by":"publisher","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":"B13","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1007\/BF01408073","article-title":"Recommendations for standardized human pedigree nomenclature","volume":"4","author":"Bennett","year":"1995","journal-title":"J Genet Couns"},{"key":"B14","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1093\/clinchem\/36.2.261","article-title":"Rapid purification of human DNA from whole blood for potential application in clinical chemistry laboratories","volume":"36","author":"Adeli","year":"1990","journal-title":"Clin Chem"},{"key":"B15","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1002\/humu.22932","article-title":"dbNSFP v3.0: a one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs","volume":"37","author":"Liu","year":"2016","journal-title":"Hum Mutat"},{"key":"B16","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1091\/mbc.6.4.459","article-title":"Functional analysis of selective interactions among rodent connexins","volume":"6","author":"White","year":"1995","journal-title":"Mol Biol Cell"},{"key":"B17","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1083\/jcb.125.4.879","article-title":"Selective interactions among the multiple connexin proteins expressed in the vertebrate lens: the second extracellular domain is a determinant of compatibility between connexins","volume":"125","author":"White","year":"1994","journal-title":"J Cell Biol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"19672","DOI":"10.1074\/jbc.M110.204958","article-title":"Asparagine 175 of connexin32 is a critical residue for docking and forming functional heterotypic gap junction channels with connexin26","volume":"286","author":"Nakagawa","year":"2011","journal-title":"J Biol Chem"},{"key":"B19","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3389\/fphar.2013.00043","article-title":"Connexin mutants and cataracts","volume":"4","author":"Beyer","year":"2013","journal-title":"Front Pharmacol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.bbamem.2017.07.003","article-title":"Crucial motifs and residues in the extracellular loops influence the formation and specificity of connexin docking","volume":"1860","author":"Bai","year":"2018","journal-title":"Biochim\u00a0Biophys Acta Biomembr"},{"key":"B21","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/s41586-018-0786-7","article-title":"Structure of native lens connexin 46\/50 intercellular channels by cryo-EM","volume":"564","author":"Myers","year":"2018","journal-title":"Nature"},{"key":"B22","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/nature07869","article-title":"Structure of the connexin 26 gap junction channel at 3.5\u2009\u00c5 resolution","volume":"458","author":"Maeda","year":"2009","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","first-page":"4331","DOI":"10.1038\/s41467-020-18120-5","article-title":"Connexin-46\/50 in a dynamic lipid environment resolved by CryoEM at 1.9 A","volume":"11","author":"Flores","year":"2020","journal-title":"Nat Commun"},{"key":"B24","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/s00232-007-9033-0","article-title":"Connexins in lens development and cataractogenesis","volume":"218","author":"Gong","year":"2007","journal-title":"J Membr Biol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1177\/1120672118804757","article-title":"A novel missense mutation of GJA8 causes congenital cataract in a large Mauritanian family","volume":"29","author":"Hadrami","year":"2019","journal-title":"Eur J Ophthalmol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.bbamem.2005.04.001","article-title":"Structural organization of gap junction channels","volume":"1711","author":"Sosinsky","year":"2005","journal-title":"Biochim Biophys Acta"},{"key":"B27","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.ceb.2007.09.001","article-title":"Gap junction channel structure in the early 21st century: facts and fantasies","volume":"19","author":"Yeager","year":"2007","journal-title":"Curr Opin Cell Biol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1136\/bjo.2005.075184","article-title":"Two novel mutations of connexin genes in Chinese families with autosomal dominant congenital nuclear cataract","volume":"89","author":"Ma","year":"2005","journal-title":"Br J Ophthalmol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3820","DOI":"10.1073\/pnas.89.9.3820","article-title":"A domain substitution procedure and its use to analyze voltage dependence of homotypic gap junctions formed by connexins 26 and 32","volume":"89","author":"Rubin","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B30","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s12860-020-00252-7","article-title":"In silico analysis of non-synonymous single nucleotide polymorphisms (nsSNPs) in the human GJA3 gene associated with congenital cataract","volume":"21","author":"Zhang","year":"2020","journal-title":"BMC Mol Cell Biol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1371\/journal.pone.0184440","article-title":"Identification of a GJA3 mutation in a Chinese family with congenital nuclear cataract using exome sequencing","volume":"50","author":"Guo","year":"2013","journal-title":"Indian J Biochem Biophys"},{"key":"B32","first-page":"323","article-title":"A novel mutation in GJA8 associated with jellyfish-like cataract in a family of Indian origin","volume":"14","author":"Vanita","year":"2008","journal-title":"Mol Vis"},{"key":"B33","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1038\/s41433-018-0277-y","article-title":"Unique presentation of congenital cataract concurrent with microcornea, microphthalmia plus posterior capsule defect in monozygotic twins caused by a novel GJA8 mutation","volume":"33","author":"Zhang","year":"2019","journal-title":"Eye (Lond)"},{"key":"B34","doi-asserted-by":"publisher","first-page":"288","DOI":"10.22038\/IJBMS.2017.8358","article-title":"Mutation analysis of connexin 50 gene among Iranian families with autosomal dominant cataracts","volume":"20","author":"Mohebi","year":"2017","journal-title":"Iran J Basic Med Sci"},{"key":"B35","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1002\/ajmg.c.31837","article-title":"Molecular diagnostic challenges for non-retinal developmental eye disorders in the United Kingdom","volume":"184","author":"Jackson","year":"2020","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1007\/s00439-018-1875-2","article-title":"New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies","volume":"138","author":"Ceroni","year":"2019","journal-title":"Hum Genet"},{"key":"B37","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s40246-014-0019-6","article-title":"Exome sequencing identifies novel and recurrent mutations in GJA8 and CRYGD associated with inherited cataract","volume":"8","author":"Mackay","year":"2014","journal-title":"Hum Genomics"},{"key":"B38","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.bbamem.2012.02.007","article-title":"Evolutionary analyses of gap junction protein families","volume":"1828","author":"Abascal","year":"2013","journal-title":"Biochim Biophys Acta Biomembr"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.1003909\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T10:03:40Z","timestamp":1669975420000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.1003909\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,2]]},"references-count":38,"alternative-id":["10.3389\/fped.2022.1003909"],"URL":"https:\/\/doi.org\/10.3389\/fped.2022.1003909","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,2]]},"article-number":"1003909"}}