Spectrum of Mutations in the RPGR Gene That Are Identified in 20% of Families with X-Linked Retinitis Pigmentosa

Abstract

The RPGR (retinitis pigmentosa GTPase regulator) gene for RP3, the most frequent genetic subtype of X-linked retinitis pigmentosa (XLRP), has been shown to be mutated in 10%-15% of European XLRP patients. We have examined the RPGR gene for mutations in a cohort of 80 affected males from apparently unrelated XLRP families, by direct sequencing of the PCR-amplified products from the genomic DNA. Fifteen different putative disease-causing mutations were identified in 17 of the 80 families; these include four nonsense mutations, one missense mutation, six microdeletions, and four intronic-sequence substitutions resulting in splice defects. Most of the mutations were detected in the conserved N-terminal region of the RPGR protein, containing tandem repeats homologous to those present in the RCC-1 protein (a guanine nucleotide-exchange factor for Ran-GTPase). Our results indicate that mutations either in as yet uncharacterized sequences of the RPGR gene or in another gene located in its vicinity may be a more frequent cause of XLRP. The reported studies will be beneficial in establishing genotype-phenotype correlations and should lead to further investigations seeking to understand the mechanism of disease pathogenesis.

Mutation analysis of the RPGR gene reveals novel mutations in south European patients with X-linked retinitis pigmentosa

“…This consequence is a protein with a small 'charged domain'. 12 These three mutations were absent in 70 XLRP and 120 control chromosomes, indicating that they are not simply frequent variant alleles in these populations.…”

“…12 Most mutations fall in exons encoding RCC1 repeats, the characteristic domain of the amino-terminal region of RPGR putative protein. It is conceivable that RPGR is not responsible for most cases of XLRP linked to this region and that another RP novel gene(s) remains unidentified.…”

“…10,13 To date 29 different RPGR mutations have been identified. [10][11][12][13][14][15] Most mutations identified in European families have been different from those identified in the United States. To extend the information about the range, type, and frequency of RPGR mutations in different populations, the goal of the present study was to investigate southern European patients with XLRP.…”

A retinitis pigmentosa GTPase regulator (RPGR)- deficient mouse model for X-linked retinitis pigmentosa (RP3)

“…Among the latter is the X-linked locus RP3 (OMIM 312610), which accounts for the majority of X-linked RP families by linkage studies. The retinal disease associated with RP3 appears to have an early age of onset (1) and exhibits early involvement of both cones and rods (2)(3)(4)(5)(6)(7). This is in contrast with other types of RP in which rods are primarily affected followed by a secondary degeneration of cones.…”

Ten novel ORF15 mutations confirm mutational hot spot in theRPGR gene in European patients with X-linked retinitis pigmentosa

“…The two major loci, RP2 on Xp11.23 [MIM# 312600, Thiselton et al, 1996] and RP3 on Xp21.1 [MIM# 312610, Musarella et al, 1990] account for 20-25% and 70% of cases, respectively [Teague et al, 1994;Ott et al, 1990]. Although the disease genes from both genetic intervals have been isolated [RP2 by Schwahn et al, 1998 and RPGR by Meindl et al, 1996;Roepman et al, 1996], XLRP cases linked to the RP3 locus have perplexed investigators in the past, since only 20% of patients had mutations identified in the RPGR gene [Buraczynska et al, 1997;Miano et al, 1999;Zito et al, 1999;Sharon et al, 2000]. This raised the suspicion that some mutational hot spots remained to be identified and in 2000, Vervoort et al described a new RPGR exon, called ORF15, in which they identified mutations in 60% of XLRP patients .…”