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L.S. Sullivan, S.J. Bowne, C.R. Seaman, D.G. Birch, D.H. Wheaton, R.A. Lewis, S.H. Blanton, S.P. Daiger; Identification of a Large Insertion/Deletion in the PRPF31 Gene in a Family with adRP . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1704.
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© ARVO (1962-2015); The Authors (2016-present)
To identify the cause of disease in a large 5–generation family with autosomal dominant retinitis pigmentosa. The presence of several non–penetrant individuals suggested the PRPF31 gene as a likely candidate but X–linked transmission was also considered, given the pedigree structure.
Each of the known adRP genes (CA4, FSCN2, IMPDH1, NRL, PRPF3, PRPF8, PRPF31, RDS, RHO, ROM1, RP1, RP9) was screened by DNA sequencing. Linkage testing with polymorphic STR markers at each adRP locus and markers for XlRP loci was performed and LOD scores calculated. SNPs in and around the PRPF31 gene were amplified and sequenced. MLPA (multiplex ligation–dependent probe amplification) and additional family testing confirmed positive results.
No disease–causing mutations were identified by DNA sequencing of the 12 adRP genes. All adRP and XlRP loci were excluded by linkage testing except PRPF31 which yielded LOD scores >3.0. Sequencing of numerous SNPs in the PRPF31 region in several family members produced inconsistent results, suggesting that some part of the PRPF31 gene was deleted.
A complex mutation consisting of the deletion of 149 bp at the exon 1/intron 1 junction and the insertion of 640 bp of genomic DNA at the same site appears to be the cause of disease in this family. The mutation is found in all affected family members tested, as well as in obligate carriers who show no sign of disease. The mutation is likely to prevent the splicing of non–coding exon 1 to exon 2, resulting in a null allele.
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