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

Abstract

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.

Progesterone receptor membrane component 1 (PGRMC1) binds and stabilizes cytochromes P450 through a heme-independent mechanism

“…demonstrated that PGRMC1 binds CYP51A1 and supports cholesterol synthesis in HEK293 cells. Recently, deletion of PGRMC1 was shown to cause X-linked isolated pediatric cataract in humans, and the authors proposed that this is due to disruptions in CYP51A1-dependent cholesterol synthesis in the lens ( 44 ). The fact that Pgrmc1 KO mice are protected from APAP-induced toxicity demonstrates that Pgrmc1 has an in vivo effect on cytochrome P450 activity.…”

“…These proteins do not bind heme, suggesting that additional PGRMC1 functions remain to be discovered. Finally, PGRMC1 was recently identified as the causative mutation in X-linked isolated pediatric cataract ( 44 ). In addition to confirming that defects in CYP51A1 underlie this disease, careful examination of individuals with PGRMC1 mutations may reveal additional phenotypes associated with other cytochromes P450.…”

A Systems Biology Approach for Investigating Significant Biomarkers and Drug Targets Common Among Patients with Gonorrhea, Chlamydia, and Prostate Cancer: A Pilot Study

“…Disease associated with PGRMC1 gene includes pediatric cataract and breast cancer. 33,34 As TFs and miRNAs control gene expression at the transcriptional and posttranscriptional levels, alteration in these biomolecules provides fundamental evidence for gene expression dysregulation. So in this work, we investigated common DEG-TF and DEG-miRNA interactions (Tables 3 and 4).…”

Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity

“…A truncating deletion of PGRMC1 was found in the etiology of developmental cataracts, rationalized by a potential disruption of PGRMC1’s interaction with CYP51A1 and consequently altered cholesterol biosynthesis [ 163 ]. In addition, a His165Arg mutation (located in the cyt b 5 domain of PGRMC1), identified in a heterozygous patient with premature ovarian failure, was shown to interfere with PGRMC1-mediated progesterone’s anti-apoptotic action and abolish binding to CYP7A1, important for the synthesis of bile acid and the regulation of cholesterol levels [ 164 ].…”