Mutations in X-Linked RPGR in Families With Apparent Autosomal Dominant Retinitis Pigmentosa (adRP)

Abstract

Abstract: : Purpose: Mutations in RPGR are the most frequent cause of X-linked retinitis pigmentosa (xlRP). Studies have shown that females with RPGR mutations often exhibit symptoms of retinal degeneration more typical of a mildly affected individual than of a carrier. This phenomenon is especially true of mutations located in the ORF15 region of RPGR and can cause pedigrees of families with xlRP to give the appearance of an autosomal dominant pattern of inheritance. The goal of this study was to examine several "autosomal dominant" RP families to see if they are actually X- linked in inheritance due to mutations in ORF 15 of RPGR. Methods: We have collected DNAs from individuals from more than 450 "adRP" pedigrees. These pedigrees were evaluated to select families for this study using the following criteria: i) clear cut diagnosis of RP; ii) the presence of affected females; iii) at least 3 affected generations; iv) no male-to male transmission; and v) no mutations in rhodopsin, peripherin/RDS, RP1 or IMPDH1. One proband from each of 20 families identified using these criteria was analyzed for mutations in RPGR ORF15 by automated sequencing. We also tested members of an apparent adRP family whose disease was mapped previously to the X chromosome (unpublished). Results: Sequence analysis of the 20 families selected for this study identified an ORF15+587delA mutation that segregates with disease in one family. Analysis of the adRP family whose disease was linked to the X chromosome identified a novel 2bp deletion, ORF15+764_765delAG, which also segregates with disease. Conclusions: Our analysis identified two apparent "adRP" families with mutations in RPGR. This suggests that X- linked mutations in RPGR will be a significant cause of RP that appears to have an autosomal dominant mode of inheritance. However, it is important to note, that clinical examinations of multiple family members can help define a mode of inheritance since females in X-linked families have milder disease than affected males.

Keywords: genetics • retina • photoreceptors