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144750 - a 127kb truncating deletion.pdf (1.76 MB)

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

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journal contribution
posted on 2023-05-20, 23:51 authored by Johanna JonesJohanna Jones, Corbett, MA, Yeaman, E, Zhao, D, Gecz, J, Robert GasperiniRobert Gasperini, Jac CharlesworthJac Charlesworth, Mackey, DA, Elder, JE, Craig, JE, Kathryn BurdonKathryn Burdon
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.


National Health & Medical Research Council


Publication title

European Journal of Human Genetics




Menzies Institute for Medical Research


Nature Publishing Group

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