{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:21:50Z","timestamp":1776298910922,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T00:00:00Z","timestamp":1588723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology (BRC-D-CON 546795)","award":["(BRC-D-CON 546795)"],"award-info":[{"award-number":["(BRC-D-CON 546795)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Pediatric cataract is clinically and genetically heterogeneous and is the most common cause of childhood blindness worldwide. In this study, we aimed to identify disease-causing variants in three large British families and one isolated case with autosomal dominant congenital cataract, using whole exome sequencing. We identified four different heterozygous variants, three in the large families and one in the isolated case. Family A, with a novel missense variant (c.178G&gt;C, p.Gly60Arg) in GJA8 with lamellar cataract; family B, with a recurrent variant in GJA8 (c.262C&gt;T, p.Pro88Ser) associated with nuclear cataract; and family C, with a novel variant in GJA3 (c.771dupC, p.Ser258GlnfsTer68) causing a lamellar phenotype. Individual D had a novel variant in GJA3 (c.82G&gt;T, p.Val28Leu) associated with congenital cataract. Each sequence variant was found to co-segregate with disease. Here, we report three novel and one recurrent disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract. Our study further extends the mutation spectrum of these genes and further facilitates clinical diagnosis. A recurrent p.P88S variant in GJA8 causing isolated nuclear cataract provides evidence of further phenotypic heterogeneity associated with this variant.<\/jats:p>","DOI":"10.3390\/genes11050512","type":"journal-article","created":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T04:46:07Z","timestamp":1588826767000},"page":"512","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Whole Exome Sequencing Reveals Novel and Recurrent Disease-Causing Variants in Lens Specific Gap Junctional Protein Encoding Genes Causing Congenital Cataract"],"prefix":"10.3390","volume":"11","author":[{"given":"Vanita","family":"Berry","sequence":"first","affiliation":[{"name":"UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK"},{"name":"Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Ionides","sequence":"additional","affiliation":[{"name":"Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1782-4711","authenticated-orcid":false,"given":"Nikolas","family":"Pontikos","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK"},{"name":"Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3653-2327","authenticated-orcid":false,"given":"Ismail","family":"Moghul","sequence":"additional","affiliation":[{"name":"UCL Cancer Institute, University College London, London WC1E 6BT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony T.","family":"Moore","sequence":"additional","affiliation":[{"name":"Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK"},{"name":"Ophthalmology Department, University of California School of Medicine, San Francisco, CA 94158, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0644-4123","authenticated-orcid":false,"given":"Roy A.","family":"Quinlan","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Durham, Upper Mountjoy Science Site, Durham DH1 3LE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel","family":"Michaelides","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK"},{"name":"Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1136\/archdischild-2016-310532","article-title":"Epidemiology of blindness in children","volume":"102","author":"Solebo","year":"2017","journal-title":"Arch. Dis. Child."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3928\/00904481-20110117-07","article-title":"Pediatric Cataract","volume":"40","author":"Mickler","year":"2011","journal-title":"Pediatr. Ann."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1136\/bjo.83.7.802","article-title":"Clinical and genetic heterogeneity in autosomal dominant cataract","volume":"83","author":"Ionides","year":"1999","journal-title":"Br. J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1136\/jmg.37.7.481","article-title":"The genetics of childhood cataract","volume":"37","author":"Francis","year":"2000","journal-title":"J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Berry, V., Georgiou, M., Fujinami, K., Quinlan, R., Moore, A., and Michaelides, M. (2020). Inherited cataracts: Molecular genetics, clinical features, disease mechanisms and novel therapeutic approaches. Br. J. Ophthalmol.","DOI":"10.1136\/bjophthalmol-2019-315282"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1098\/rstb.2010.0227","article-title":"Clinical and experimental advances in congenital and paediatric cataracts","volume":"366","author":"Churchill","year":"2011","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_7","first-page":"2007","article-title":"Cat-Map: Putting cataract on the map","volume":"16","author":"Shiels","year":"2010","journal-title":"Mol. Vis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1111\/cge.12182","article-title":"Genetics of human cataract","volume":"84","author":"Shiels","year":"2013","journal-title":"Clin. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S1043-4682(10)80007-8","article-title":"The crystalline lens. A system networked by gap junctional intercellular communication","volume":"3","author":"Goodenough","year":"1992","journal-title":"Semin. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1152\/physrev.00034.2009","article-title":"Lens gap junctions in growth, differentiation, and homeostasis","volume":"90","author":"Mathias","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","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":"ref_12","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.1093\/bioinformatics\/btx147","article-title":"Phenopolis: An open platform for harmonization and analysis of genetic and phenotypic data","volume":"33","author":"Pontikos","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1093\/bioinformatics\/btr540","article-title":"Kaviar: An accessible system for testing SNV novelty","volume":"27","author":"Glusman","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Berthoud, V.M., and Ngezahayo, A. (2017). Focus on lens connexins. BMC Cell Biol., 18.","DOI":"10.1186\/s12860-016-0116-6"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1042\/BJ20051922","article-title":"Life cycle of connexins in health and disease","volume":"394","author":"Laird","year":"2006","journal-title":"Biochem. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.cardiores.2003.11.013","article-title":"Gap junctions and the connexin protein family","volume":"62","author":"Sohl","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1083\/jcb.143.3.815","article-title":"Targeted Ablation of Connexin50 in Mice Results in Microphthalmia and Zonular Pulverulent Cataracts","volume":"143","author":"White","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.bbamem.2017.05.016","article-title":"Gap junction gene and protein families: Connexins, innexins, and pannexins","volume":"1860","author":"Beyer","year":"2018","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/BF01868674","article-title":"Expression of the gap junction protein connexin43 in embryonic chick lens: Molecular cloning, ultrastructural localization, and post-translational phosphorylation","volume":"116","author":"Musil","year":"1990","journal-title":"J. Membr. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1242\/dev.114.1.203","article-title":"Spatial and temporal patterns of distribution of the gap junction protein connexin43 during mouse gastrulation and organogenesis","volume":"114","author":"Yancey","year":"1992","journal-title":"Development"},{"key":"ref_22","doi-asserted-by":"crossref","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":"ref_23","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1113\/jphysiol.2006.113837","article-title":"Role of the N-terminus in permeability of chicken connexin45.6 gap junctional channels","volume":"576","author":"Dong","year":"2006","journal-title":"J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nature07869","article-title":"Structure of the connexin 26 gap junction channel at 3.5 \u00c5 resolution","volume":"458","author":"Maeda","year":"2009","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/368348a0","article-title":"Opposite voltage gating polarities of two closely related onnexins","volume":"368","author":"Verselis","year":"1994","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1085\/jgp.114.3.339","article-title":"Molecular determinants of electrical rectification of single channel conductance in gap junctions formed by connexins 26 and 32","volume":"114","author":"Oh","year":"1999","journal-title":"J. Gen. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1006\/abbi.2000.1989","article-title":"Structure of the amino terminus of a gap junction protein","volume":"381","author":"Purnick","year":"2000","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1086\/301762","article-title":"A Missense Mutation in the Human Connexin50 Gene (GJA8) Underlies Autosomal Dominant \u201cZonular Pulverulent\u201d Cataract, on Chromosome 1q","volume":"62","author":"Shiels","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"C1443","DOI":"10.1152\/ajpcell.1999.276.6.C1443","article-title":"Molecular mechanism underlying a Cx50-linked congenital cataract","volume":"276","author":"Pal","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_30","first-page":"1171","article-title":"A mutation in GJA8 (p.P88Q) is associated with \u201cballoon-like\u201d cataract with Y-sutural opacities in a family of Indian origin","volume":"14","author":"Vanita","year":"2008","journal-title":"Mol. Vis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4121","DOI":"10.1038\/srep04121","article-title":"Identification of a novel GJA8 (Cx50) point mutation causes human dominant congenital cataracts","volume":"4","author":"Ge","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","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":"ref_33","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1086\/302383","article-title":"Connexin46 mutations in autosomal dominant congenital cataract","volume":"64","author":"Mackay","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_34","first-page":"789","article-title":"A novel insertional mutation in the connexin 46 (gap junction \u03b13) gene associated with autosomal dominant congenital cataract in a Chinese family","volume":"19","author":"Zhou","year":"2013","journal-title":"Mol. Vis."},{"key":"ref_35","first-page":"684","article-title":"A novel frameshift mutation in CX46 associated with hereditary dominant cataracts in a Chinese family","volume":"10","author":"Cui","year":"2017","journal-title":"Int. J. Ophthalmol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Li, S., Zhang, J., Cao, Y., You, Y., and Zhao, X. (2019). Novel mutations identified in Chinese families with autosomal dominant congenital cataracts by targeted next-generation sequencing. BMC Med. Genet., 20.","DOI":"10.1186\/s12881-019-0933-5"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3752","DOI":"10.1523\/JNEUROSCI.19-10-03752.1999","article-title":"Altered formation of hemichannels and gap junction channels caused by C-terminal connexin-32 mutations","volume":"19","author":"Castro","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9077","DOI":"10.1523\/JNEUROSCI.17-23-09077.1997","article-title":"Altered Trafficking of Mutant Connexin32","volume":"17","author":"Walcott","year":"1997","journal-title":"J. Neurosci."},{"key":"ref_39","first-page":"846","article-title":"Novel mutations in GJA3 associated with autosomal dominant congenital cataract in the Indian population","volume":"11","author":"Devi","year":"2005","journal-title":"Mol. Vis."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Moln\u00e1r, J., Szak\u00e1cs, G., and Tusn\u00e1dy, G.E. (2016). Characterization of Disease-Associated Mutations in Human Transmembrane Proteins. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151760"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.exer.2016.06.011","article-title":"Mutations and mechanisms in congenital and age-related cataracts","volume":"156","author":"Shiels","year":"2017","journal-title":"Exp. Eye Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/5\/512\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:25:58Z","timestamp":1760174758000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/5\/512"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,6]]},"references-count":41,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["genes11050512"],"URL":"https:\/\/doi.org\/10.3390\/genes11050512","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,6]]}}}