Genetic analysis of the X-linked retinitis pigmentosa locus RP3

Purpose. To determine the precise location of the X-linked retinitis pigmentosa (XLRP) locus RP3 by genetic linkage studies. Methods. Sixteen polymorphic markers spanning the proximal region of the X chromosome, from p21.1 to q13, have been used in four large and ≈20 nuclear XLRP families. DNA from >50 patients representing independent families was analyzed with 6-8 markers in the RP3 region for allele comparison. Results. All four large families and several of the nuclear families have been determined to carry the RP3 mutation, as shown by the co-segregation of the disease locus with markers from the RP3 critical region. One family shows recombination with RP3 markers; however, additional studies are necessary to determine the segregation with another XLRP locus. One of the RP3 families shows a recombination localized within 100 kb outside the BB deletion, currently considered the distal boundary of the RP3 gene. No significant allelic preference has been detected so far with three polymorphic markers near the BB deletion. Conclusions. Our results demonstrate that the genetic defect in most U.S. XLRP patients is at the RP3 locus. However, many families remain genetically uncharacterized because of the proximity of the XLRP loci, which are clustered at Xp21.3-p11.23. A meiotic recombination in one large family shows that the RP3 mutation lies outside of the BB deletion, thereby redefining the location of this gene. Preliminary results do not show a linkage disequilibrium of the markers close to the BB deletion with the disease locus. We are now collecting blood/DNA samples from an additional ≈100 families for further genetic studies to refine the location of the RP3 gene.