Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa


The gene RPGR was previously identified in the RP3 region of Xp21.1 and shown to be mutated in 10–20% of patients with the progressive retinal degeneration X-linked retinitis pigmentosa1,2 (XLRP). The mutations predominantly affected a domain homologous to RCC1, a guanine nucleotide exchange factor for the small GTPase Ran, although they were present in fewer than the 70–75% of XLRP patients predicted from linkage studies3,4,5,6. Mutations in the RP2 locus at Xp11.3 were found in a further 10–20% of XLRP patients, as predicted from linkage studies6,7,8. Because the mutations in the remainder of the XLRP patients may reside in undiscovered exons of RPGR, we sequenced a 172-kb region containing the entire gene. Analysis of the sequence disclosed a new 3′ terminal exon that was mutated in 60% of XLRP patients examined. This exon encodes 567 amino acids, with a repetitive domain rich in glutamic acid residues. The sequence is conserved in the mouse, bovine and Fugu rubripes genes. It is preferentially expressed in mouse and bovine retina, further supporting its importance for retinal function. Our results suggest that mutations in RPGR are the only cause of RP3 type XLRP and account for the disease in over 70% of XLRP patients and an estimated 11% of all retinitis pigmentosa patients.

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Figure 1: Alternative splicing of human RPGR.
Figure 2: Mutation analysis of RPGR exon ORF15 in XLRP patients.
Figure 3: Conservation of predicted RPGR exon ORF15 protein.
Figure 4: Expression of exons ORF15 and ORF14/15 in mouse and bovine tissues.

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We thank M. Boulton and V. Smith for human retinas; J. Kenyon for the mouse PAC clones; M. Warren and L. Sawyer for comments; the Sequencing Unit Core of Area di Ricerca di Napoli, CNR, for cosmid sequencing; and M. D'Urso for support. We acknowledge the generous support of The Foundation Fighting Blindness, the British Retinitis Pigmentosa Society, Guide Dogs for the Blind Association and the UK Medical Research Council. A.C. was supported by Telethon, Italy grant E1093.

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Correspondence to Alan F. Wright.

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Vervoort, R., Lennon, A., Bird, A. et al. Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa. Nat Genet 25, 462–466 (2000).

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