{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T21:49:32Z","timestamp":1759960172978,"version":"3.37.3"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:00:00Z","timestamp":1615248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"UGC-Kothari fellowship","award":["F.4-2\/2006 (BSR)\/BL\/17-18\/0280"],"award-info":[{"award-number":["F.4-2\/2006 (BSR)\/BL\/17-18\/0280"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Isolated Microspherophakia (MSP) is an autosomal recessive disorder characterized by a smaller than normal spherical lens. Till date, LTBP2 is the only gene shown to cause MSP. We used homozygosity mapping and whole-exome sequencing and identified a homozygous mutation, c.1148C\u2009&amp;gt;\u2009T (p.Pro383Leu), in the WDR8 (or WRAP73) gene in two Indian MSP families. In vitro experiments showed that the missense mutation renders the protein unstable. WDR8 is a centriolar protein that has important roles in centrosomal assembly, spindle pole formation and ciliogenesis. Co-immunoprecipitation experiments from HeLa cells indicated that the mutation interferes with the interaction of WDR8 with its binding partners. In zebrafish, both morpholino-mediated knockdown and CRISPR\/Cas knockout of wdr8 resulted in decreased eye and lens size. The lack of wdr8 affected cell cycle progression in the retinal cells, causing a reduction in cell numbers in the retina and lens. The reduction in eye size and the cell cycle defects were rescued by exogenous expression of the human wild-type WDR8. However, the human mutant WDR8 (p.Pro383Leu) was unable to rescue the eye defects, indicating that the missense mutation abrogates WDR8 protein function. Thus, our zebrafish results suggested that WDR8 is the causative gene for MSP in these Indian families.<\/jats:p>","DOI":"10.1093\/hmg\/ddab061","type":"journal-article","created":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T20:10:37Z","timestamp":1614197437000},"page":"467-484","source":"Crossref","is-referenced-by-count":3,"title":["Exome sequencing and functional studies in zebrafish identify <i>WDR8<\/i> as the causative gene for isolated Microspherophakia in Indian families"],"prefix":"10.1093","volume":"30","author":[{"given":"M","family":"Madhangi","sequence":"first","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debanjan","family":"Dutta","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sautan","family":"Show","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vishwanath K","family":"Bhat","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad I","family":"Rather","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ankana","family":"Tiwari","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nivedita","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maheswara R","family":"Duvvari","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gowri J","family":"Murthy","sequence":"additional","affiliation":[{"name":"Prabha Eye Clinic and Research Centre, Bangalore 560070, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arun","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0616-5995","authenticated-orcid":false,"given":"Upendra","family":"Nongthomba","sequence":"additional","affiliation":[{"name":"Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"2021050614184970200_ref1","first-page":"248","article-title":"Abnorme Kleinheit und Kugelgestalt der Linse beizwei Geschwisterpaaren","volume":"80","author":"Fleischer","year":"1916","journal-title":"Arch. Augenheilk."},{"key":"2021050614184970200_ref2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s00439-010-0858-8","article-title":"A homozygous mutation in LTBP2 causes isolated microspherophakia","volume":"128","author":"Kumar","year":"2010","journal-title":"Hum. Genet."},{"key":"2021050614184970200_ref3","first-page":"684","article-title":"The eye in the Marfan syndrome","volume":"79","author":"Maumenee","year":"1981","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"2021050614184970200_ref4","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1136\/bjo.74.10.631","article-title":"Histology of the lens in the Weill-Marchesani syndrome","volume":"74","author":"Fujiwara","year":"1990","journal-title":"Br. J. Ophthalmol."},{"key":"2021050614184970200_ref5","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1002\/ajmg.a.20289","article-title":"Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome","volume":"123A","author":"Faivre","year":"2003","journal-title":"Am. J. Med. Genet."},{"key":"2021050614184970200_ref6","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/j.1442-9071.1995.tb00160.x","article-title":"Ultrasound biomicroscopic features of spherophakia","volume":"23","author":"Macken","year":"1995","journal-title":"Aust. NZ. J. Ophthalmol."},{"key":"2021050614184970200_ref7","doi-asserted-by":"crossref","first-page":"516490","DOI":"10.1155\/2013\/516490","article-title":"Isolated spherophakia and glaucoma","volume":"2013","author":"Pikkel","year":"2013","journal-title":"Case Rep. Med."},{"key":"2021050614184970200_ref8","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/352337a0","article-title":"Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene","volume":"352","author":"Dietz","year":"1991","journal-title":"Nature"},{"key":"2021050614184970200_ref9","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1136\/jmg.40.1.34","article-title":"In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome","volume":"40","author":"Faivre","year":"2003","journal-title":"J. Med. Genet."},{"key":"2021050614184970200_ref10","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1086\/425231","article-title":"ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome","volume":"75","author":"Dagoneau","year":"2004","journal-title":"Am. J. Hum. 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Rep."},{"key":"2021050614184970200_ref46","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilising the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."},{"key":"2021050614184970200_ref47","first-page":"10.25.1","article-title":"Preparation of proteins and peptides for mass spectrometry analysis in a bottom-up proteomics workflow","volume":"90","author":"Gundry","year":"2009","journal-title":"Curr. Protoc. Mol. Biol."},{"key":"2021050614184970200_ref48","volume-title":"The Zebrafish Book. 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