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By whole exome sequencing of affected members from 11 multiplex families of European ancestry, we identified 23 rare, heterozygous, potentially pathogenic variants in 8 genes. These include nonsynonymous single amino acid substitutions in HSPG2, EML6 and CENPF in two families each, and in NBEAL2, LRP1B, PIK3CG and MRGPRD in three families each; ITGAX had nonsynonymous single amino acid substitutions in two families and an indel with a base substitution producing a nonsense allele in the third family. Only HSPG2, EML6 and CENPF have been associated with ocular phenotypes previously. With the exception of MRGPRD and ITGAX, we detected the transcript and encoded protein of the remaining genes in the cornea and corneal cell cultures. Cultured stromal cells showed cytoplasmic punctate staining of NBEAL2, staining of the fibrillar cytoskeletal network by EML6, while CENPF localized to the basal body of primary cilia. We inhibited the expression of HSPG2, EML6, NBEAL2 and CENPF in stromal cell cultures and assayed for the expression of COL1A1 as a readout of corneal matrix production. An upregulation in COL1A1 after siRNA inhibition indicated their functional link to stromal cell biology. For ITGAX, encoding a leukocyte integrin, we assayed its level in the sera of 3 affected families compared with 10 unrelated controls to detect an increase in all affecteds. Our study identified genes that regulate the cytoskeleton, protein trafficking and secretion, barrier tissue function and response to injury and inflammation, as being relevant to keratoconus.<\/jats:p>","DOI":"10.1093\/hmg\/ddab075","type":"journal-article","created":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T04:15:19Z","timestamp":1615349719000},"page":"658-671","source":"Crossref","is-referenced-by-count":28,"title":["Pathogenic alleles in microtubule, secretory granule and extracellular matrix-related genes in familial keratoconus"],"prefix":"10.1093","volume":"30","author":[{"given":"Vishal","family":"Shinde","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nara","family":"Sobreira","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth S","family":"Wohler","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Maiti","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuliana","family":"Silvestri","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Belfast Health and Social Care Trust, Belfast BT12 6BA UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"George","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Belfast Health and Social Care Trust, Belfast BT12 6BA UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Belfast Health and Social Care Trust, Belfast BT12 6BA UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aravinda","family":"Chakravarti","sequence":"additional","affiliation":[{"name":"Center for Human Genetics and Genomics, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin E","family":"Willoughby","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Belfast Health and Social Care Trust, Belfast BT12 6BA UK"},{"name":"Genomic Medicine, Biomedical Sciences Research Institute, Ulster University, Coleraine BT52 1SA, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shukti","family":"Chakravarti","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,3,17]]},"reference":[{"key":"2022022408484772400_ref1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/cxo.12047","article-title":"Recent advances in corneal transplantation for keratoconus","volume":"96","author":"Cassidy","year":"2013","journal-title":"Clin. 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