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Significance Retinitis pigmentosa GTPase regulator (RPGR) disease variants lead to considerable phenotypic heterogeneity in terms of relative involvement of rod and cone photoreceptors. We have identified a clear progressive shift… Click to show full abstract
Significance Retinitis pigmentosa GTPase regulator (RPGR) disease variants lead to considerable phenotypic heterogeneity in terms of relative involvement of rod and cone photoreceptors. We have identified a clear progressive shift from rod- to cone-dominating phenotypes as the variants move toward the distal end of the gene. Moreover, we find that truncating distal RPGRORF15 variants impair RPGR glutamylation, mediated by TTLL5 enzyme, mirroring the cone-dominated phenotype associated with loss-of-function mutations in TTLL5. The application of RPGR with impaired glutamylation in retinal gene therapy may be less effective in treating RPGR dystrophies.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2022
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