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R. Koenekoop, I. Lopez, M. Fossarello, D. Mansfield, A. Wright; RPGRIP1 mutations in juvenile retinitis pigmentosa: a linkage and mutation study. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4727.
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Purpose: One of the six LCA genes, RPGRIP1 (the retinitis pigmentosa GTPase interacting protein), resides on 14q11 and encodes a protein involved in anchoring the connecting cilium in photoreceptors. We tested the hypothesis that juvenile retinitis pigmentosa (juv RP) can be caused by mutations in RPGRIP1. Methods: Five out of eleven small Sardinian families with juv RP that linked to 14q11, and five sporadic French Canadian juv RP patients participated in this study and underwent mutation screening by PCR using intronic primers for all 24 RPGRIP1 exons, dHPLC wave analysis (Transgenomics), automated sequencing (ABI, Perkin Elmer), and restriction enzyme confirmation. Controls were 100 culturally matched normals. Linkage analysis was performed following a whole genome scan using 195 microsatellite markers, and LOD scores were calculated. Full eye examinations were done. Results: In 2/5 French Canadian families with juv RP, we found important sequence changes. In family I, we found the compound heterozygous P882S/D1114G mutations, in a child with normal visual function at birth, no nystagmus, who progressed to 20/100 vision at age 18 (with high myopia), a 60 ° visual field, a pigmentary retinopathy, and a non–detectable ERG. In family II, we found a heterozygous IVS 22 –3 del TT mutation, in a patient with normal vision at birth, but with rapidly declining vision to HM, severe myopia, and retinal degeneration. The maximum LOD score under a heterogeneity model in the Sardinian families was 2.05. Mutation screening revealed a highly conserved homozygous A547S change, that was recently reported as a mutation in 3 Pakistani families with recessive cone–rod dystrophy.1 We also found this change in up to 20% of normal controls. Conclusions: RPGRIP1 mutations may be a rare cause of juv. RP, as we found three significant mutations in our French Canadian patients. The Sardinian juv RP families that link to 14q11 do not appear to harbor mutations in RPGRIP1, and the A547S change appears to be a common polymorphism. Mutations outside of our studied RPGRIP1 exons (intronic or promotor regions) or a second retinal gene close to RPGRIP1 in the 14q11 region may explain our linkage results. 1 Hameed et al. J Med Genet 2003; 0 : 616–619.
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