Prpf31 Knock-In Mouse as a Model of Retinitis Pigmentosa 11

Abstract

Purpose: : Pre-mRNA processing factor 31 (PRPF31) is a ubiquitous protein, needed for the assembly of the pre-mRNA splicing machinery. It has been shown that mutations in this gene cause autosomal dominant retinitis pigmentosa 11 (RP11), which is characterised by rod-cell degeneration. Interestingly, mutations in this ubiquitously expressed gene do not lead to other phenotypes than retinal malfunction. Furthermore, the dominant inheritance pattern has shown incomplete penetrance which poses interesting questions about the disease mechanism of RP11.

Methods: : In order to characterise the specificity of PRPF31 function in the rod cells, an animal model has been generated. This is a knock-in (KI) mouse carrying a point mutation A216P, which has been previously identified in RP11 patients. Retinal degeneration in Prpf31^A216P/+ mice was monitored by electroretinography (ERG) and histology. The level of Prpf31 expression in Prpf31^A216P/+ mice and different mouse strains was investigated with real time quantitative PCR.

Results: : Generation of the mouse model will be presented as well as results of retinal function and morphology. Up to 18 months of age, no degenerative phenotype was found in Prpf31^A216P/+ mice. A216P mutation of PRPF31 in homozygous state was found to be lethal and there were no Prpf31^A216P/A216P embryos found at E10. These results imply that A216P mutation affects Prpf31 protein function and that there is no compensation effect from other proteins. Quantitative PCR experiments have demonstrated a differential expression of the Prpf31 gene in various mouse strains, where Prpf31^A216P/+ mice expressed 24% more than the lowest expressing strain C57BL/6J.

Conclusions: : This work suggests that similarly to partial penetrance in RP11 patients, lack of retinal phenotype in Prpf31^A216P/+ mice might be caused by a highly expressing Prpf31 allele.

Keywords: retinitis