Novel missense mutations in PRPF6 cause autosomal dominant retinitis pigmentosa with incomplete penetrance and impairment of PRPF6 protein localization within the nucleus

International audience; Purpose : To characterize clinically and genetically two families with autosomal dominant retinitis pigmentosa (adRP) with new causative mutations in PRPF6, a gene described to be associated with this condition in a single study.Methods : A large adRP and sporadic RP cohort was screened for mutations using targeted next-generation sequencing. Clinical investigations included visual acuity and visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging, full-fields and multifocal electroretinogram (ERG) recording. Cellular localization of GFP-tagged wild-type or mutated PRPF6 in HEK293 transfected cells was observed by confocal microscopy.Results : Two heterozygous mutations c.680C>T (p.Thr227Met) and c.514C>T (p.Arg172Trp) in PRPF6 were identified in an adRP family and in a sporadic RP patient, respectively. Both variants segregated with the disease phenotype and were predicted to be pathogenic. An asymptomatic heterozygous carrier of the p.Arg172Trp mutation was also identified. In HEK293 transfected cells, an abnormal accumulation of the two mutated GFP-PRPF6, but not wild-type, within Cajal bodies was observed.Conclusions : We identified two novel causative mutations in PRPF6, responsible for autosomal dominant retinitis pigmentosa with variation of penetrance. Presence of asymptomatic carriers is common among patients with adRP, especially when the cause of the disease is due to a mutation in splicing factors’ genes. The two mutations identified lead to a mislocalization of the PRPF6 protein within the nucleus, which could indicate a possible alteration in the assembly or recycling of the tri-snRNP complex of the spliceosome.