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TL McGee, EL Berson, TP Dryja; Identification Of Novel Mutations In The PRPF31 Gene (RP11) In Patients With Autosomal Dominant Retinitis Pigmentosa With Reduced Penetrance . Invest. Ophthalmol. Vis. Sci. 2002;43(13):792.
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Purpose: Pathogenic mutations in the PRPF31 gene, a homologue of the yeast pre-mRNA splicing gene PRP31, were recently reported to segregate with RP11 (chromosome 19q13.4), a form of autosomal dominant retinitis pigmentosa (RP) (Vithana et al. Molecular Cell 8: p375, 2001). RP11 is unique because many carriers of a mutant RP11 allele are unaffected. There is indirect evidence that the reduced penetrance is due to isoalleles (i.e., one or more polymorphisms that are ordinarily wild-type) at the same or a closely linked locus. To date, the postulated isoalleles have not been identified. The purpose of this study is to screen the PRPF31 gene in three additional families with RP11-linked retinitis pigmentosa in an effort to identify both the primary RP11 mutation and the isoalleles. Methods: The promoter region and the exons of the PRPF31 gene and the TFPT gene (located immediately upstream of PRPF31) are being sequenced in an affected patient and an unaffected obligate carrier from each of 3 separate families with dominant RP previously shown to be linked to RP11 (McGee et al. Am J Hum Genet 61: p1059, 1997). Results: Novel pathogenic mutations were identified in two of the RP11-linked families. One mutation is a 34-bp deletion, Arg293(34-bp del), in exon 9, and the other mutation affects the splice acceptor site of intron 8 (IVS8 -2 A≷G). These mutations were present in both the affected patient and unaffected carrier from the respective families. The mutation in the third family has yet to be identified. Two intronic sequence variants have been identified that correlate with penetrance in the small number of patients analyzed to date. Conclusion: We report novel mutations in 2 out of 3 RP11-linked families. These are null alleles and are likely to represent the primary pathogenic mutations in these families. Whether the two isoalleles we also identified specify penetrance is under investigation.
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