Expression of PRPF31 mRNA in patients with autosomal dominant retinitis pigmentosa: a molecular clue for incomplete penetrance?

PURPOSE. To investigate whether the incomplete penetrance phenotype characteristic of adRP families linked to chromosome 19q13.4 (RP11) with mutations in the PRPF31 gene is due to differentially expressed wild-type alleles in symptomatic and asymptomatic individuals. METHODS. Real-time quantitative RT-PCR was performed on RNA from lymphoblastoid cell lines derived from a large adRP family (RP856/AD5) that segregates an 11bp deletion in exon 11 of PRPF31. The mRNA levels from only the wild-type allele of PRPF31 were assayed using a probe designed across the deletion. The Mann–Whitney U test was used to compare the median mRNA copy numbers of the symptomatic with the asymptomatic carriers of the mutant PRPF31 allele. The PRPF31 protein levels from symptomatic and asymptomatic individuals were also assayed by Western blot analysis using an antibody specific to the wild-type PRPF31 protein. RESULTS. The use of cell lines was validated by the observation that cell transformation did not alter PRPF31 expression in the cell lines compared with nucleated blood cells and donor retinas. A significant difference in wild-type PRPF31 mRNA levels was observed between symptomatic and asymptomatic individuals (P 0.001) and was supported by Western blot analysis of the PRPF31 protein. CONCLUSIONS. Partial penetrance in RP11 could be due to the coinheritance of a PRPF31 gene defect and a low-expressed wild-type allele. This study revealed a potential avenue for future therapy in that it appears the moderate overexpression of wild-type PRPF31 may prevent clinical manifestation of the disease. (Invest Ophthalmol Vis Sci. 2003;44:4204 – 4209) DOI:10.1167/iovs.03-0253 R etinitis pigmentosa is a clinically and genetically heterogeneous disorder characterized by progressive degeneration of the peripheral retina leading to night blindness and visual field loss. Clinical manifestations include pigment deposition in the retina and attenuation of retinal blood vessels, with later depigmentation or atrophy of the RPE. ERG abnormalities are recordable in the early stages with attenuation of rod and cone responses. In advanced RP both rod and cone ERG responses are extinguished. 1 With an incidence of approximately 1 in 3500, RP can be inherited as an X-linked, autosomal dominant or autosomal recessive condition. 1