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PA Sieving, YK Demirci, J Liu, EL Bingham, H Stringham, LE Kakuk, M Boehnke, MB Gorin, JE Richards, R Ayyagari; X-Linked Macular Degeneration Associated with a RPGR Nonsense Mutation Causing Premature Termination . Invest. Ophthalmol. Vis. Sci. 2002;43(13):803.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To identify the gene associated with the disease in a large pedigree with a predominant phenotype of X linked macular degeneration. Methods: Clinical characterization was carried out by standard ophthalmic examination including fundus photography, fluroscein angiography Ganzfeld electroretinography (ERG), Goldmann perimertry, and color vision tests. Linkage and haplotype analyses were carried out using microsatellite markers. Mutation analysis was conducted by sequencing all exons plus limited flanking intronic sequence. Results: Eleven out of 12 affected males had predominant macular atrophy with loss of visual acuity and minor or no peripheral visual field impairment. The prepositus had normal ERG response wave-form and amplitude for dark- and light- adapted states and for 30 Hz flicker with only macular atrophy evident. One individual showed macular degeneration plus extensive peripheral RPE and choricapillaris loss that mimics retinitis pigmentosa (RP). Linkage and haplotype analysis localized the disease to a 15 cM interval at Xp21.3-11.4. The critical interval in this family encompasses the locus for Cone Dystrophy 1(COD1), nyctalopin (NYX):Congenital Stationary Night Blindness and RP3: retinitis pigmentosa GTPas regulator (RPGR) genes. Sequence analysis excluded the NYX gene with no disease causing mutations identified. A nonsense mutation segregating with the disease was detected in the RPGR gene and predicts the premature truncation of the protein product. Conclusion: We have identified an RPGR nonsense mutation segregating with X-linked macular degeneration. This expands the phenotype associated with RPGR. The macular degeneration in our patients suggests a role for RPGR protein in cone cellular function consistent with the cone semi-selective dysfunction in RPGR knock out mice.
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