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A. T. Fahim, L. S. Sullivan, S. J. Bowne, D. G. Birch, D. K. Wheaton, K. Clark, S. P. Daiger; Polymorphic Variation in RPGRIP1 and RPGRIP1L as Potential Modifiers of X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1658.
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To identify common SNPs and protein haplotypes of RPGRIP1 (RPGR interacting protein 1) and RPGRIP1L (RPGRIP1-like) and determine whether these variants are associated with clinical affectation in females, or phenotypic severity in males, with X-linked retinitis pigmentosa (RP) caused by mutations in RPGR. The clinical consequences of RPGR mutations are highly varied, even among individuals with the same mutation: males demonstrate a wide range of phenotypic severity and symptoms in female carriers range from no clinical consequences to severe RP. Genetic modifiers may contribute to this striking clinical diversity. RPGRIP1 and RPGRIP1L are promising candidates for genes modifying RPGR mutations because a.) mutations in RPGRIP1 and RPGRIP1L each cause retinal diseases, b.) RPGRIP1 and RPGRIP1L interact with RPGR and all 3 proteins localize to the photoreceptor cilium and c.) recent evidence suggests that polymorphic variation at the RPGRIP1L locus may modify the retinal phenotype in several syndromic ciliopathies (Khanna et al. Nat Genet 41:739, 2009).
Common protein haplotypes of RPGRIP1 and RPGRIP1L were identified by sequencing coding SNPs in human-murine hybrid cell lines that are monochromosomic for human chromosome 14 and 16, respectively. Each SNP was sequenced in at least 100 cell lines, including 32-38 lines derived from each of three ethnicities, African-American, European-American and Mexican-American. Thirty-six families with known RPGR mutations are currently included in the study, including 161 affected males and 224 known or obligate female carriers. We are ascertaining all available individuals with RPGR mutations in each family, conducting standardized clinical examinations, and genotyping SNPs in RPGRIP1 and RPGRIP1L.
Far more variation was found in RPGRIP1 than in RPGRIP1L (14 vs. 5 polymorphic protein haplotypes, respectively). The most common RPGRIP1 haplotype has a frequency of 41% across all ethnicities compared to 85% for the most common RPGRIP1L haplotype. A wide range of clinical consequences of RPGR mutations in males and in females has been observed both within and between enrolled families.
RPGRIP1 and RPGRIP1L demonstrate substantial polymorphic variation in protein primary structure, and linkage and association testing will determine whether these haplotypes have clinical consequences in patients with RPGR mutations.
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