An Intronic Mutation in RP2 Causes Semi-Dominant X-Linked Retinitis Pigmentosa

Abstract

Purpose: : A large family with eleven male patients and two affected females, compatible with X-linked Retinitis Pigmentosa (XLRP), was analyzed in search of pathological mutations.

Methods: : Of the two major XLRP genes, RPGR was analyzed by SNP cosegregation whereas RP2 was directly screened for mutations. The pathogenicity of a new variant was assessed in silico, in vivo and in vitro.

Results: : Cosegregation analysis with SNPs closely located to RPGR allowed to discard this gene as the cause of the disease in this family. Direct mutational screening of RP2 showed a putative pathogenic variant in an intronic location. This substitution cosegregated with the disease and was not found in 220 control chromosomes. Direct RT-PCR analysis of the RP2 splicing pattern in blood samples of patients and carrier females showed aberrant splicing, causing a frameshift that introduced a premature STOP codon. Further verification of the pathogenicity of this mutation was obtained by expression of a minigene RP2 construct in cultured cells.

Conclusions: : Interestingly, this mutation in RP2 leads to a wide range of phenotypic traits in carrier females, from completely normal to severe retinal degeneration, thus supporting that RP2 is as likely a candidate to cause semi-dominance in XLRP as RPGR.

Keywords: retinitis • gene/expression • mutations