Comprehensive analysis of the PRPF31 gene in retinitis pigmentosa patients: Four novel Alu ‐mediated copy number variations at the PRPF31 locus

Abstract

Retinitis pigmentosa (RP) is a monogenic disease characterized by irreversible degeneration of the retina. PRPF31, the second most common causative gene of autosomal dominant RP, frequently harbors copy number variations (CNVs), but the underlying mechanism is unclear. In this study, we summarized the phenotypic and genotypic characteristics of 18 RP families (F01−F18) with variants in PRPF31. The prevalence of PRPF31 variants in our cohort of Chinese RP families was 1.7% (18/ 1024). Seventeen different variants in PRPF31 were detected, including eight novel variants. Notably, four novel CNVs encompassing PRPF31, with a proportion of 22.2% (4/18), were validated to harbor gross deletions involving Alu/Alu-mediated rearrangements (AAMRs) in the same orientation. Among a total of 12 CNVs of PRPF31 with breakpoints mapped on nucleotide-resolution, 10 variants (83.3%) were presumably mediated by Alu elements. Furthermore, we described the correlation between the genotypes and phenotypes in PRPF31-related RP. Our findings expand the mutational spectrum of the PRPF31 gene and provide strong evidence that Alu elements of PRPF31 probably contribute to the susceptibility to genomic rearrangement in this locus.

Screening copy number variations in 35 unsolved inherited retinal disease families

“…Alu elements are a type of short interspersed element that accounts for 10% of the total genome content, but in chromosome 19 accounts for 26.3%, with Alu being the richest chromosome (Grover et al 2004). A previous study (Chen et al 2022) also provided strong evidence that Alu elements of PRPF31 probably contributed to the susceptibility to genomic rearrangement in this locus. Herein, we reported several CNVs (exon 1-14 del, exon2-14 del, exon 2-3 del and exon 14 exon del) in PRPF31, consisting with the above points.…”

“…We wonder whether high prevalence is also the reason why CNVs are prone to occurred in these genes. Presently, haploinsufficiency has been suggested to be the main pathological mechanism of PRPF31 ‐associated adRP (Abu-Safieh et al 2006 ; Vithana et al 2003 ; Wheway et al 2020 ), and PRPF31 frequently harbors CNVs (Chen et al 2022 ; Zampaglione et al 2020 ). PRPF31 is located on a region rich in repeat elements, especially in Alu repeats.…”

A novel genomic rearrangement on chr19q13.42 leads to PRPF31‐associated retinitis pigmentosa

“…In the PRPF31 CNV detected in this study, the breakpoints aligned to Alu Y pairs of high identity and a microhomology of 27-bp at breakpoint junctions, suggesting that AAMR which involves a novel Alu-mediated CNV is the putative underlying mechanism of genomic arrangement. 5 Key Laboratory of Endemic and Ethnic Diseases, Ministry…”