Dominant X-linked RP is Frequently Accounted for by Truncating Mutations in the Exon ORF15 of the RPGR Gene

Abstract

Abstract: : Purpose:To determine whether dominant X-linked retinitis pigmentosa (DXLRP), a condition previously described as different from the recessive X-linked RP (RP3), are due to mutations in the retinitis pigmentosa GTPase-regulator (RPGR) gene. Methods:The RPGR gene was screened for mutations in fourteen X-linked RP families with severe expression in carrier females. Results:Direct sequencing of the RPGR gene in affected patients allowed the identification of eight different null mutations in 9/14 families. All mutations were found to lie in the ORF15 exon. The segregation of the mutation with the disease was confirmed in all nine families. Interestingly, in two of these families, the mutation was found in an asymptomatic potential carrier. On the other hand, in-frame deletions or duplications reported earlier as polymorphism were identified in 2/5 families with no mutation and direct sequencing of the RPGR exon ORF15 failed to detect any base change in the three remaining families. Nevertheless, linkage analyses confirmed the localisation of the gene in all families at the RP3 locus, suggesting that in these last 5 families the disease might be caused by a mutation located in an unexplored region of the RPGR gene such as the promotor or the introns. Conclusion:In conclusion, we report here on the identification of null RPGR alleles in patients affected with DXLRP. It is worth noting that in this retinal dystrophy, both males and females display minimal inclusion criteria for RP. Although, the age at onset of the disease in females is delayed compared to males (20-40 years versus 10-20 years, respectively) the visual impairment, the fundus alteration and the visual field reduction can be as severe in heterozygous females as in hemizygous males. In these females who’s ERG is non-recordable, no preferential X-inactivation was observed. It would be extremely interesting to know the exact phenotype of females harbouring truncating mutations in the RPGR exon ORF15 in the XLRP families recently reported. Indeed, if some of the women were more severely affected than what is usually described for carrier females in recessive X-linked RP (ie tapetal-like reflex or peripheral pigmentary deposits in the fundus) we would have to consider RP3 as an incomplete dominant X-linked disease such as it is now reported for ornithine transcarbamylase deficiency.

Keywords: 562 retinal degenerations: hereditary • 335 candidate gene analysis • 457 linkage analysis