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S. P. Daiger, L. S. Sullivan, A. I. Gire, C. J. Spellicy, D. G. Birch, D. Hughbanks-Wheaton, J. R. Heckenlively, S. J. Bowne; Prevalence of Mutations in TOPORS Causing Autosomal Dominant Retinitis Pigmentosa (adRP). Invest. Ophthalmol. Vis. Sci. 2008;49(13):3282.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the frequency of mutations in the TOPORS gene causing autosomal dominant retinitis pigmentosa (adRP) in a well-characterized cohort of families. TOPORS is the topoisomerase I-binding arginine/serine rich protein gene on human chromosome 9p21.1. Mutations in TOPORS cause the RP31 form of adRP previously mapped to this location.
Affected members of adRP families without known mutations in other RP genes were screened for mutations in TOPORS by DNA sequencing and subsequently tested for large deletions or rearrangements by multiplex ligation probe amplification (MLPA) analysis. The families selected for testing (N = 89) were from a cohort of 215 screened previously for mutations in all adRP genes known to cause an appreciable fraction of cases (Sullivan et al., Invest. Ophthalmol. Vis. Sci., 47:3052-3064, 2006). All families included in the cohort were diagnosed with adRP by a knowledgeable clinical expert and were composed of either 1.) three or more affected generations with multiple affected females or 2.) two or more affected generations with male-to-male transmission. Sequencing included the three known coding exons of TOPORS and intron-exon junctions. MLPA probe pairs were designed to interrogate each of the eight sequences amplified for PCR-based sequencing.
Two novel TOPORS mutations, p.Glu808X (c.G2422T) and p.Arg857Glyfs9X (c.2569delA), were detected in two adRP families. The first mutation segregates with disease in 8 affected family members. No additional family members were available for testing segregation of the second mutation, but the mutation causes a frame shift and premature termination and is most likely pathogenic. Two additional novel, benign variants were also observed, p.Pro20Ser (c.C58T) and p.Thr782Ala (c.A2344G). No large deletions or complex rearrangements were detected.
Mutations in the TOPORS gene account for 1% of adRP families in this cohort, largely Americans of European origin. Together with earlier studies in this cohort, mutations in TOPORS and 11 additional genes, CRX, IMPDH1, NR2E3, PRPF3, PRPF8, PRPF31, RDS, RDS-ROM1, RHO, RP1, and RPGR, account for 60% of families with dominant retinitis pigmentosa.
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