Mapping the RP2 locus for X-linked retinitis pigmentosa on proximal Xp: a genetically defined 5-cM critical region and exclusion of candidate genes by physical mapping.

Abstract

Genetic linkage studies have implicated at least two loci for X-linked retinitis pigmentosa (XLRP) on proximal Xp. We now report a defined genetic localization for the RP2 locus to a 5-cM interval in Xp11. 3-11.23. Haplotype analysis of polymorphic markers in recombinant individuals from two XLRP families has enabled us to identify DXS8083 and DXS6616 as the new distal and proximal flanking markers for RP2. Using STS-content and YAC end-clone mapping, an -1.2 Mb YAC contig has been established encompassing the proximal RP2 boundary and extending from TIMP1 to DXSI240 in Xpll.23. Several ESTs have been positioned and ordered on this contig, one of which is novel to the region, identified by sequence data-base match to a physically mapped YAC insert terminal STS. Integration of the genetic and physical data has placed four retinally expressed genes proximal to DXS6616, and thereby excluded them from a causitive role in RP2. This work now provides a much needed focus for positional cloning approaches to isolation of the defective gene.Retinitis pigmentosa (RP) is a group of hereditary progressive retinal degenerations characterized by night blindness, visual field impairment, and degenerative pigmentary changes in the retina. RP exists as autosomal dominant, autosomal recessive, and X-linked forms and displays considerable genetic heterogeneity with at least 15 distinct loci so far assigned to human chromosomes (for review, see Dryja et al. 1995). X-linked retinitis pigmentosa (XLRP) is the most severe clinical form, accounting for 7-30% of all cases, depending on the population studied, with an incidence of-1:20,000 (Jay 1982;Heckenlively 1983). Male XLRP patients generally develop concentric visual field loss before the 20th year of life leading to severe visual handicap by the age 6Corresponding author. E-MAIL ahardcas@hgmp.mrc.ac.uk; FAX 44-171-608-6863.of 40 (Bird 1975). Female carriers show variable symptoms of the disease on ophthalmological testing, with visual impairment usually beginning in middle age, although absence of ocular abnormalities does not exclude the carrier state (Arden et al. 1983).In the absence of functional clues as to the pathophysiology of XLRP, positional cloning strategies have been adopted to isolate the defective genes. Following the first genetic linkage of an RP gene (designated RP2) to Xp11.3 in a panel of British families (Bhattacharya et al. 1984), subsequent genetic analyses have indicated the existence of at least three other XLRP loci (RP3, RP6, and RP15) located more distally on Xp (Musarella et al. 1990;Ott et al. 1990;Teague et al. 1994;McGuire et al. 1995) and the fact that the disease in some families maps to none of these locations suggests the possibility of even more XLRP loci (Aldred et al. 1994). As evidence for RP6 is to date only statistical (Ottet al. 1990), and RP15 has been demonstrated in only one family (which is THISELTON ET AL.reported as a cone-rod degeneration; McGuire et al. 1995), the majority of XLRP families fall into the categories of RP2 or RP3...

DNA sequence comparison of human and mouse retinitis pigmentosa GTPase regulator (RPGR) identifies tissue-specific exons and putative regulatory elements

“…Two disease loci on the short arm of the human X chromosome, designated RP2 and RP3, have been identified by genetic linkage studies (Bhattacharya et al 1984;Musarella et al 1990;Ott et al 1990;Thiselton et al 1996), and the corresponding genes have been isolated by positional cloning (Meindl et al 1996;Roepman et al 1996aRoepman et al , 1996bSchwahn et al 1998). RP3 is due to mutations in the gene encoding the retinitis pigmentosa GTPase regulator (RPGR), residing in Xp21.1.…”

Positional cloning of the gene for X-linked retinitis pigmentosa 2

“…8). To study this region in more detail, we established a YAC contig and screened 26 unrelated patients with XLRP for submicroscopic chromosomal rearrangements using the YRH technique.…”

Complete congenital stationary night blindness maps on Xp11.4 in a Sardinian family

“…A second key recombination is present in the unaffected male V:18, locating the CSNBX locus distal to marker DXS6810 (Figure 2). This locus is therefore distinct from the RP3 locus, which mapped distally to marker DXS1110, 11 and from the RP2 locus, which mapped proximally to MAOB 17,18 (Figure 1).…”