Determinants of Disease Penetrance in PRPF31-Associated Retinopathy

Abstract

Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in PRPF31, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between CNOT3 polymorphism, MSR1 repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized PRPF31 and CNOT3 expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C>T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy MSR1 repeat in the PRPF31 promoter, while 3/5 NPCs carried a 4-copy MSR1 repeat. The CNOT3 rs4806718 genotype did not correlate with disease penetrance. PRFP31 expression declined with age in adult cadaveric retina. PRPF31 and CNOT3 expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy MSR1 repeat, but not with CNOT3 polymorphisms.

Genetic treatment for autosomal dominant inherited retinal dystrophies: approaches, challenges and targeted genotypes

“…66 PRPF31 non-penetrance has been associated with the co-inheritance of a 4-copy MSR1 repeat, with the complete underlying basis of variable expressivity remaining unclear. 67 Genotype-phenotype correlations have been investigated, with an earlier age of onset observed in those with null versus missense variants. 11 An exponential yearly decline in kinetic visual field, cone ERG responses, and EZ area, has been reported.…”

Characterising splicing defects of ABCA4 variants within exons 13–50 in patient-derived fibroblasts

“…All cells were maintained at 37 • C in a 5% CO 2 /95% air atmosphere. Human retinal samples were obtained from a donor at the age of 28 and RNA extraction was performed as previously described (McLenachan et al, 2021).…”

Unique transcriptomes of sensory and non-sensory neurons: insights from Splicing Regulatory States

“…Malfunctioning of these genes seems to be tolerated in most human tissues yet they are pathogenic in the retina, where photoreceptors are affected and degenerate. Although it remains unclear why mutations in core SFs affect only this cell type, and even though these are not always fully penetrant (e.g., due to differences in the Transcriptional Regulatory State (Rose et al, 2016 ; McLenachan et al, 2021 )), it seems obvious that the explanation largely lies in the interplays within its unique SRS. A similar scenario can be envisioned for other sensory cells.…”