{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T17:10:09Z","timestamp":1776791409961,"version":"3.51.2"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000024","name":"CIHR","doi-asserted-by":"publisher","award":["MOP 340328"],"award-info":[{"award-number":["MOP 340328"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Baillie Gifford"},{"name":"Microphthalmia"},{"name":"Anophthalmia"},{"name":"Health Innovation Fund"},{"DOI":"10.13039\/100010053","name":"Oxford Brookes University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010053","id-type":"DOI","asserted-by":"publisher"}]},{"name":"King Salman Center for Disability Research"},{"name":"Researchers Supporting Project","award":["RSP-2020\/181"],"award-info":[{"award-number":["RSP-2020\/181"]}]},{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009874","name":"Universit\u00e9 de Sherbrooke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009874","id-type":"DOI","asserted-by":"publisher"}]},{"name":"La Fondation du Grand D\u00e9fi Pierre Lavoie"},{"name":"La Fondation des \u00c9toiles"},{"name":"Health Innovation Challenge Fund","award":["HICF-1009-003"],"award-info":[{"award-number":["HICF-1009-003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Microphthalmia, coloboma and cataract are part of a spectrum of developmental eye disorders in humans affecting ~12 per 100\u2009000 live births. Currently, variants in over 100 genes are known to underlie these conditions. However, at least 40% of affected individuals remain without a clinical genetic diagnosis, suggesting variants in additional genes may be responsible. Calpain 15 (CAPN15) is an intracellular cysteine protease belonging to the non-classical small optic lobe (SOL) family of calpains, an important class of developmental proteins, as yet uncharacterized in vertebrates. We identified five individuals with microphthalmia and\/or coloboma from four independent families carrying homozygous or compound heterozygous predicted damaging variants in CAPN15. Several individuals had additional phenotypes including growth deficits, developmental delay and hearing loss. We generated Capn15 knockout mice that exhibited similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth. We demonstrate widespread Capn15 expression throughout the brain and central nervous system, strongest during early development, and decreasing postnatally. Together, these findings demonstrate a critical role of CAPN15 in vertebrate developmental eye disorders, and may signify a new developmental pathway.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa198","type":"journal-article","created":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T19:13:36Z","timestamp":1599074016000},"page":"3054-3063","source":"Crossref","is-referenced-by-count":20,"title":["Biallelic variants in the small optic lobe calpain CAPN15 are associated with congenital eye anomalies, deafness and other neurodevelopmental deficits"],"prefix":"10.1093","volume":"29","author":[{"given":"Congyao","family":"Zha","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carole A","family":"Farah","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J","family":"Holt","sequence":"additional","affiliation":[{"name":"Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabiola","family":"Ceroni","sequence":"additional","affiliation":[{"name":"Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lama","family":"Al-Abdi","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh 11564, Saudi Arabia"},{"name":"Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanny","family":"Thuriot","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke J1H 5N4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arif O","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia"},{"name":"Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates"},{"name":"Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine at Case Western University, Cleveland, Ohio 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rana","family":"Helaby","sequence":"additional","affiliation":[{"name":"Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi 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UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola K","family":"Ragge","sequence":"additional","affiliation":[{"name":"Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK"},{"name":"Department of Clinical Genetics, West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women\u2019s and Children\u2019s Foundation Trust, Birmingham B15 2TG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1927-9315","authenticated-orcid":false,"given":"Wayne S","family":"Sossin","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, 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Biol."},{"key":"2020110605012547300_ref23","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"2020110605012547300_ref24","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/gim.2017.239","article-title":"Clinical validity of phenotype-driven analysis software PhenoVar as a diagnostic aid for clinical geneticists in the interpretation of whole-exome sequencing data","volume":"20","author":"Thuriot","year":"2018","journal-title":"Genet. Med."},{"key":"2020110605012547300_ref25","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"2020110605012547300_ref26","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"2020110605012547300_ref27","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nprot.2010.5","article-title":"I-TASSER: a unified platform for automated protein structure and function prediction","volume":"5","author":"Roy","year":"2010","journal-title":"Nat. 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Biol."},{"key":"2020110605012547300_ref31","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1007\/s00335-012-9427-x","article-title":"The international mouse phenotyping consortium: past and future perspectives on mouse phenotyping","volume":"23","author":"Brown","year":"2012","journal-title":"Mamm. Genome"},{"key":"2020110605012547300_ref32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/lm.043745.116","article-title":"A PKM generated by calpain cleavage of a classical PKC is required for activity-dependent intermediate-term facilitation in the presynaptic sensory neuron of Aplysia","volume":"24","author":"Farah","year":"2017","journal-title":"Learn. Mem."},{"key":"2020110605012547300_ref33","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.bbapap.2011.08.005","article-title":"Calpains: an elaborate proteolytic system","volume":"1824","author":"Ono","year":"2012","journal-title":"Biochim. Biophys. 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Biol."},{"key":"2020110605012547300_ref37","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature10163","article-title":"A conditional knockout resource for the genome-wide study of mouse gene function","volume":"474","author":"Skarnes","year":"2011","journal-title":"Nature"},{"key":"2020110605012547300_ref38","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.ajhg.2019.07.005","article-title":"De novo missense variants in FBXW11 cause diverse developmental phenotypes including brain, eye, and digit anomalies","volume":"105","author":"Holt","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"2020110605012547300_ref39","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1007\/s00439-018-1896-x","article-title":"Expanding the phenotype of the X-linked BCOR microphthalmia syndromes","volume":"138","author":"Ragge","year":"2019","journal-title":"Hum. 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