In vivo Functional Analyses of Retinal Function by Multifocal Electroretinography in Unrelated Carriers of XRRP with the Same 2 Basepair Deletion in ORF15 of RPGR (2281_2282 del GG)

Abstract

Abstract: : Purpose: To evaluate in vivo patterns of retinal cell dysfunction/cell death in 3 carriers of X-linked retinitis pigmentosa (XRRP) with identical RPGR mutations from different families (I and II). By comparing the results of these carriers, we will be able to test the hypothesis that patterns of cell death or dysfunction are truly random as dictated by the Lyon hypothesis. Methods: For genotyping, we used dHPLC wave analysis (Transgenomics) and automated sequencing (ABI 9700) of all RPGR exons. For phenotyping, we performed full eye examinations, regular electroretinograms (ERGs) (LKC), multifocal ERGs (Veris), Goldmann visual fields, and digital retinal photography (Nidek) on the 3 subjects; I-1 (age 40), I-2 (age 70), and II-1 (age 50). The stimulus matrix of the mfERG allowed us to record 61 localized cone ERGs from the macular and paramacular regions up to 40° from the central macula. Results: We identified a novel 2 basepair deletion (2281_2282 delGG) in ORF15 of RPGR and found this mutation in 2 separate XRRP families, one from French-Canadian descent (1 carrier), another from British descent (2 carriers), providing the unique opportunity to compare patterns of retinal cell dysfunction in carriers with identical RPGR defects, but with different genetic and environmental backgrounds. mfERG results revealed striking clustered patterns of cone dysfunction (as measured by amplitudes) with interocular, intra-familial, and inter-familial phenotypic variability of the 3 carriers in the 2 pedigrees. The youngest carrier displayed the most severe patterns of dysfunction, the oldest the best preserved. In all 3 carriers, we found non-random clusters of adjacent cone dysfunction. Conclusions: The phenotype of 3 XRRP carriers with a 2281_2282 del GG mutation in ORF15 of RPGR is highly variable and the cone cell dysfunction appears to be non-random. In addition to the primary RPGR defect and lyonization, other factors such as additional genetic and environmental influences appear to play a major role in the resulting phenotype. The mfERG provides an excellent in vivo tool to study patterns of cone dysfunction in the posterior pole of XRRP carriers with known RPGR defects.

Keywords: genetics • retinal degenerations: hereditary • electroretinography: clinical