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E. Pomares, M. Riera, J. Castro-Navarro, Á. Andrés-Gutiérrez, R. Gonzàlez-Duarte, G. Marfany; An Intronic Mutation in RP2 Causes Semi-Dominant X-Linked Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2299.
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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.
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.
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.
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.
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