A 127\u2009kb truncating deletion of PGRMC1 is a novel cause of X-linked isolated paediatric cataract

Johanna L Jones,Jozef Gecz,Mark A Corbett,David A Mackey,Elise Yeaman,Duran Zhao,Kathryn P Burdon,Robert J Gasperini,Jac C Charlesworth,James E Elder,Jamie E Craig

doi:10.1038/s41431-021-00889-8

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.

Highlights

IntroductionPaediatric cataracts are known to have genetic basis in up to 25% of cases [3,4,5]
Sequence coverage was at a depth of 30 reads or more for over 80% of the mappable regions in hg19 genome build (Fig. S1)
The progesterone receptor membrane component 1 (PGRMC1) truncating 127 kb deletion is a novel cause of the X-linked isolated paediatric cataracts in this Australian family

Summary

Introduction

Paediatric cataracts are known to have genetic basis in up to 25% of cases [3,4,5]. Paediatric cataract is typically a highly penetrant monogenic disease; autosomal dominant, autosomal recessive and X-linked inheritance patterns have all been reported [6]. At least 52 genes and loci have been reported to cause isolated paediatric cataract [7] with two of these located on the X chromosome. Other X-linked syndromic paediatric cataract genes include ARSE (MIM: 300180), BCOR (MIM: 300485), NDP (MIM: 300658), EBP (MIM: 300205), UBE2A (MIM: 312180), OCRL (MIM: 300535) and loci causing: diffuse leiomyomatosis with Alport syndrome (DL-ATS [MIM: 308940]), contiguous ABCD1/ DXS1375E deletion syndrome (CADDS [MIM: 300475]) and CASM syndrome (MIM: 300619). We describe the identification of the causative variant in this family

Methods

Results

Conclusion