A 127 kb truncating deletion of PGRMC1 is a novel cause of X-linked isolated paediatric cataract
| Autor: | Jozef Gecz, Kathryn P. Burdon, Mark A. Corbett, Johanna L. Jones, James E. Elder, David A. Mackey, Duran Zhao, Robert Gasperini, Elise J. Yeaman, Jac Charlesworth, Jamie E Craig |
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| Rok vydání: | 2020 |
| Předmět: |
Male
genetic structures Biology Cataract Article 03 medical and health sciences Exon Sterol 14-Demethylase 0302 clinical medicine Progesterone receptor Genetics Animals Humans Child PGRMC1 Gene Zebrafish Genetics (clinical) 030304 developmental biology 0303 health sciences Gene knockdown RNA Membrane Proteins biology.organism_classification eye diseases Pedigree Genetic linkage study 030220 oncology & carcinogenesis Next-generation sequencing sense organs Receptors Progesterone PGRMC1 Gene Gene Deletion Protein Binding |
| Zdroj: | European Journal of Human Genetics |
| ISSN: | 1476-5438 1183-7322 |
| Popis: | Inherited 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. |
| Databáze: | OpenAIRE |
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