Determinants of Disease Penetrance in PRPF31-Associated Retinopathy

Abstract

Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in <i>PRPF31</i>, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between <i>CNOT3</i> polymorphism, <i>MSR1</i> repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized <i>PRPF31</i> and <i>CNOT3</i> 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 <i>MSR1</i> repeat in the <i>PRPF31</i> promoter, while 3/5 NPCs carried a 4-copy <i>MSR1</i> repeat. The <i>CNOT3</i> rs4806718 genotype did not correlate with disease penetrance. <i>PRFP31</i> expression declined with age in adult cadaveric retina. <i>PRPF31</i> and <i>CNOT3</i> 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 <i>MSR1</i> repeat, but not with <i>CNOT3</i> polymorphisms.