A 127 kb truncating deletion of PGRMC1 is a novel cause of X-linked isolated paediatric cataract

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dc.contributor.authorJones, J.L.
dc.contributor.authorCorbett, M.A.
dc.contributor.authorYeaman, E.
dc.contributor.authorZhao, D.
dc.contributor.authorGecz, J.
dc.contributor.authorGasperini, R.J.
dc.contributor.authorCharlesworth, J.C.
dc.contributor.authorMackey, D.A.
dc.contributor.authorElder, J.E.
dc.contributor.authorCraig, J.E.
dc.contributor.authorBurdon, K.P.
dc.date.issued2021
dc.description.abstractInherited paediatric cataract is a rare Mendelian disease that results in visual impairment or blindness due to a clouding of the eye's crystalline lens. Here we report an Australian family with isolated paediatric cataract, which we had previously mapped to Xq24. Linkage at Xq24-25 (LOD = 2.53) was confirmed, and the region refined with a denser marker map. In addition, two autosomal regions with suggestive evidence of linkage were observed. A segregating 127 kb deletion (chrX:g.118373226_118500408del) in the Xq24-25 linkage region was identified from whole-genome sequencing data. This deletion completely removed a commonly deleted long non-coding RNA gene LOC101928336 and truncated the protein coding progesterone receptor membrane component 1 (PGRMC1) gene following exon 1. A literature search revealed a report of two unrelated males with non-syndromic intellectual disability, as well as congenital cataract, who had contiguous gene deletions that accounted for their intellectual disability but also disrupted the PGRMC1 gene. A morpholino-induced pgrmc1 knockdown in a zebrafish model produced significant cataract formation, supporting a role for PGRMC1 in lens development and cataract formation. We hypothesise that the loss of PGRMC1 causes cataract through disrupted PGRMC1-CYP51A1 protein-protein interactions and altered cholesterol biosynthesis. The cause of paediatric cataract in this family is the truncating deletion of PGRMC1, which we report as a novel cataract gene.
dc.description.statementofresponsibilityJohanna L. Jones, Mark A. Corbett, Elise Yeaman, Duran Zhao, Jozef Gecz, Robert J. Gasperini, Jac C. Charlesworth, David A. Mackey, James E. Elder, Jamie E. Craig, Kathryn P. Burdon
dc.identifier.citationEuropean Journal of Human Genetics, 2021; 29(8):1206-1215
dc.identifier.doi10.1038/s41431-021-00889-8
dc.identifier.issn1018-4813
dc.identifier.issn1476-5438
dc.identifier.orcidCorbett, M.A. [0000-0001-9298-3072]
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.urihttp://hdl.handle.net/2440/130508
dc.language.isoen
dc.publisherSpringer Nature
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1185477
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1116360
dc.rights© The Author(s) 2021. This article is published with open access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.
dc.source.urihttps://doi.org/10.1038/s41431-021-00889-8
dc.subjectAnimals
dc.subjectZebrafish
dc.subjectHumans
dc.subjectCataract
dc.subjectMembrane Proteins
dc.subjectReceptors, Progesterone
dc.subjectPedigree
dc.subjectGene Deletion
dc.subjectProtein Binding
dc.subjectChild
dc.subjectMale
dc.subjectSterol 14-Demethylase
dc.titleA 127 kb truncating deletion of PGRMC1 is a novel cause of X-linked isolated paediatric cataract
dc.typeJournal article
pubs.publication-statusPublished

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