Mutation Screening of RPGR in Male Patients With X-Linked or Isolated Forms of Retinitis Pigmentosa or Cone-Rod Dystrophy

Abstract

Abstract: : Purpose: Mutations in the RPGR (retinitis pigmentosa GTPase regulator) gene isolated from RP3 region (Xp21.1) have been reported to be responsible for up to 70% of X-linked (XL) retinitis pigmentosa (RP) families. RPGR exon ORF15 mutations have also been shown to cause XL-atrophic macular degeneration and COD1 type XL-cone-rod dystrophy (CRD). This study is intended to determine the spectrum and frequency of RPGR mutations in our male patients with XL or isolated forms of RP or CRD. Methods: RPGR exons 1-14 and exon ORF15 were screened for mutations by direct PCR sequencing of samples from 5 XLRP and 11 XL-CRD families and a total of 24 male patients with isolated forms of either RP or CRD. Unlike previous reports that primarily screened isolated RP cases with severe phenotypes, we evaluated all available isolated RP males to avoid an ascertainment bias. Results: Mutations were found in 2 XLRP samples (IVS1+1G>A and ORF15+483_484delGA) and in 2 isolated RP samples (213G>A and 1404C>T). Analyses of additional samples are underway. The 213G>A (G52R) is a novel missense mutation, which would also be predicted to disrupt normal splicing and was not detected in 100 control chromosomes. The 1404C>T (R449X) mutation was found in an affected male whose mother had both normal alleles, thus representing a de novo mutation. Despite a sampling bias created by our previous efforts to recruit COD1 families, more than half of our XL-CRD families have not been mapped to COD1 region and/or lack RPGR mutations, supporting the importance of genetic heterogeneity. No RPGR mutations were detected in any isolated CRD cases. Conclusions: Our data supports the involvement of RPGR in isolated RP. The determination of the mode of inheritance by molecular testing has major implications for genetic counseling. The comparison of phenotypes of RPGR mutation-positive patients versus negatives may provide indicators for prediction of the isolated cases at high-risk for RPGR mutations. A larger cohort will be necessary to clearly establish any correlation of phenotype with RPGR mutations. However, the phenotypes of our isolated cases with RPGR mutation are consistent with the early onset, severe RP previously reported in RP3 families.

Keywords: retinal degenerations: hereditary • mutations • genetics