Close genetic linkage between X-linked retinitis pigmentosa and a restriction fragment length polymorphism identified by recombinant DNA probe L1.28

Abstract

Retinitis pigmentosa (RP) is a group of retinal degeneration characterized by progressive visual field loss, night blindness and pigmentary retinopathy. Its prevalence is in the region of 1-2 in 5,000 of the general population, making it one of the commoner causes of blindness in early and middle life. Although 36-48% of RP patients are isolated cases, the remainder show autosomal dominant, autosomal recessive or X-linked modes of inheritance. The X-linked variety ( XLRP ) is found in 14-22% of RP families in the UK. In the present study, X chromosome-specific recombinant DNA probes which can detect restriction fragment length polymorphisms have been used to localize the XLRP gene(s) to a subregion of the X chromosome using linkage analysis. One of the probes, L1.28, has been shown to be closely linked to XLRP in five kindreds, with 95% confidence limits of 0-15 centimorgans (maximum LOD score of 7.89 at a distance of 3 centimorgans). This suggests that the XLRP locus lies on the proximal part of the short arm of the X chromosome. This probe is potentially useful for carrier detection and early diagnosis in about 40% of cases, provided that genetic heterogeneity can be excluded by analysis of further families.

Mutations ofRPGR in X-linked retinitis pigmentosa (RP3)

“…Although linkage to XLRP was first established in a mixed sample of RP3 and RP2 families by Bhattacharya et al [1984], it took until recently to identify the full range of mutations in the RP3 gene, RPGR . Further mutation analysis of exon ORF15 should finally establish the importance of RPGR in other populations, and settle the question of microheterogeneity at the RP3 locus.…”

“…A milder phenotype is often present in female carriers, probably due to random X-inactivation. Close linkage of XLRP to markers DXS7 [Bhattacharya et al, 1984;Nussbaum et al, 1985] and OTC [Musarella et al, 1988;Chen et al, 1988;Denton et al, 1988;Wirth et al, 1988;Musarella et al, 1989] was found. Subsequent linkage analysis provided evidence for two different loci: RP2 (MIM# 312600) was positioned centromeric of DXS7, while RP3 (MIM# 312610) was telomeric of DXS7 and mapped between DXS1110 and OTC [Musarella et al, 1988;Chen et al, 1989;Musarella et al, 1990;Ott et al, 1990;Dahl et al, 1991].…”

An appraisal of the application of recombinant DNA techniques to chromosome defects

“…The probe L.128 also shows linkage with (0-15cM) retinitis pigmentosa, another serious sexlinked disorder, further demonstrating the usefulness of these techniques (Bhattacharya et al, 1984). More X chromosome specific probes are now available and work on completing an RFLPdefined genetic map of this chromosome is well underway .…”

Identifying Retinal Disease Genes: How Far Have We Come, How Far Do We Have to Go?

“…Identification of RD genes progressed slowly from mapping the first X-linked retinitis pigmentosa (RP) gene in 1984 (Bhattacharya et al 1984) until the early 1990s, as seen in Fig. 1.…”