期刊
OPHTHALMOLOGY RETINA
卷 4, 期 5, 页码 510-520出版社
ELSEVIER INC
DOI: 10.1016/j.oret.2019.11.010
关键词
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资金
- National Institutes of Health, Bethesda, Maryland [2K12EY022299-06, EY007142, EY09076]
- Department of Ophthalmology
- University of Michigan, Ann Arbor, Michigan
- William Stamps Farish Fund, Houston, Texas
- Foundation Fighting Blindness, Columbia, Maryland
Purpose: X-linked retinitis pigmentosa can manifest in female carriers with widely variable severity, whereas others remain unaffected. The contribution of X-chromosome inactivation (XCI) to phenotypic variation has been postulated but not demonstrated. Furthermore, the impact of genotype and genetic modifiers has been demonstrated in affected males but has not been well established in female carriers. The purpose of this study was to describe the scope of clinical phenotype in female carriers with mutations in RPGR and quantify the contribution of genotype, genetic modifiers, and XCI to phenotypic severity. Design: Cohort study. Participants: Seventy-seven female carriers with RPGR mutations from 41 pedigrees. Methods: Coding single nucleotide polymorphisms were sequenced in candidate genetic modifier genes encoding known RPGR-interacting proteins. X-chromosome inactivation ratios were determined in genomic DNA isolated from blood (n = 42) and saliva (n = 20) using methylation status of X-linked polymorphic repeats. These genetic data were compared with disease severity based on quantitative clinical parameters. Main Outcome Measures: Visual acuity, Humphrey visual field (HVF) results, full-field electroretinography results, and dark adaptation. Results: Most individuals at all ages were mildly affected or unaffected, whereas those who progressed to moderate or severe vision loss were older than 30 years. RPGR genotype was not associated with clinical severity. The D1264N variant in RPGRIP1L was associated with more severe disease. Skewed XCI toward inactivation of the normal RPGR allele was associated with more severe disease. The XCI ratio in both blood and saliva was a predictor of visual function as measured by HVF diameter, rod amplitude, flicker amplitude, and flicker implicit time. For carriers with extreme XCI skewing of 80:20 or more, 57% were affected severely compared with 8% for those with XCI of less than 80:20 (P = 0.002). Conclusions: Female carriers with mutations in RPGR demonstrate widely variable clinical severity. X-chromosome inactivation ratios correlate with clinical severity and may serve as a predictor of clinically significant disease. Because RPGR gene therapy trials are underway, a future imperative exists to determine which carriers require intervention and when to intervene. X-chromosome inactivation analysis may be useful for identifying candidates for early intervention. (C) 2019 by the American Academy of Ophthalmology
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