An Additional Locus for Autosomal Dominant Retinitis Pigmentosa (RP) on Chromosome 7p

Abstract

Abstract: : Purpose: To map the locus of a dominantly inherited retinitis pigmentosa (RP) occurring in a 3–generation Swiss family Methods: Twenty–three members of a 3–generation Swiss family were assessed because of juvenile onset hemeralopia. Complete ophthalmic examination, including visual fundus ophthalmoscopy, visual field and ERG, was performed in all members. Blood for DNA extraction was obtained after informed consent. Linkage analysis was first performed with microsatellite markers located in the proximity of known RP genes. Subsequently, a whole genome–wide screen was done using di–nucleotide repeats from the ABI Prism Linkage Mapping Set–MD10. Linkage analysis was performed with MLINK and all the exons of the candidate gene PAP1 (RP9) were directly sequenced after PCR amplification. Results: Thirteen affected and 10 non–affected individuals were examined. Hemeralopia was the first symptom with an age of onset ranging from 1st to 5th decade of life. The disease progression is dependent on the variable severity of the atrophic maculopathy. Subcapsular cataract is an early feature requiring cataract surgery by the 5th decade of life. The fundus phenotype was characterized in most cases by a clumped pigmented retinopathy, associated in the late stages with a non–geographic form of central and/or a numular midperipheral chorioretinal atrophy. Reduction of the scotopic b wave was more pronounced than the photopic b wave with extinct scotopic ERG by the 4th decade in some patients.Linkage analysis with markers flanking known adRP excluded all known loci. Genome–wide analysis revealed a lod score of 3.08 and 2.53 at theta = 0 for markers D7S484 and D7S510 respectively. Mutation analysis of the PAP1 (RP9) gene did not reveal any mutation. Conclusions: We report the linkage of a new autosomal dominant RP locus to chromosome 7q, in an interval close to but different from that of RP9. Haplotype analysis revealed a 4–cM common inherited DNA fragment bound by markers D6S656 and D7S2428 defining a 11 cM region. Mutation analysis of various candidate genes with expression in the eye is currently underway.

Keywords: retinitis • gene mapping • linkage analysis