ArticleProceedings of the National Academy of Sciences of the United States of America2016
Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers, 1 of them a synthesis that pooled it.
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Who cites it
74 citing papers in PubMed, 1 synthesis or guideline pooled it, 110 citations in OpenAlex.
- New Insights on the Regulatory Gene Network Disturbed in Central Areolar Choroidal Dystrophy-Beyond Classical Gene Candidates.Frontiers in genetics · 2022Pooled it
- A peripheral subpopulation of retinal pigment epithelium resists oxidative damage through SERPINE3-mediated caspase-1 inhibition.The Journal of clinical investigation · 2026Article
- Defining a Novel RPGR Phenotype of Sector Retinitis Pigmentosa With Cone Dystrophy.Investigative ophthalmology & visual science · 2026Observational
- Insights into retinal disease and non-tubulin glutamylation from a RPGR-TTLL5 complex structure.The Journal of cell biology · 2026Article
- Tubulin glutamylation: a key regulator of flagella, cilia, centrosomes, and disease pathways.Journal of biomedical science · 2026Review
- Tubulin hyperglutamylation induces retinal degeneration by disrupting ciliary architecture and protein trafficking.Zoological research · 2026Article
- RPGRORF15 Mutations Disrupt Lysosomal Lipid Metabolism in Retinal Pigment Epithelium Cells and Cause Retinitis Pigmentosa.Investigative ophthalmology & visual science · 2025Article
- Sub-ciliary localization of CEP290 and effects of its loss in mouse photoreceptors during development.Journal of cell science · 2025Article
- Rescue of ciliogenesis and hyperglutamylation mutant phenotype in AGBL5BMC molecular and cell biology · 2025Article
- Tapetal-like sheen as a key phenotypical feature inAmerican journal of ophthalmology case reports · 2025Article
- Post-Translational Modifications in Cilia and Ciliopathies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Ciliopathy-associated protein, CEP290, is required for ciliary necklace and outer segment membrane formation in retinal photoreceptors.bioRxiv : the preprint server for biology · 2025Article
- Photoreceptor Disc Morphogenesis: Who Are the Conductors of This Highly Metronomic Process?Advances in experimental medicine and biology · 2025Review
- The Challenge of VUS in Inherited Retinal Degeneration: Insight from Functional Studies.Advances in experimental medicine and biology · 2025Review
- Glutamylation imbalance impairs the molecular architecture of the photoreceptor cilium.The EMBO journal · 2024Article
- Structural basis for α-tubulin-specific and modification state-dependent glutamylation.Nature chemical biology · 2024Article
- Gene Therapies in Clinical Development to Treat Retinal Disorders.Molecular diagnosis & therapy · 2024Review
- Article
- Review
- Ciliary tip actin dynamics regulate photoreceptor outer segment integrity.Nature communications · 2024Article
14 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene are a major cause of retinitis pigmentosa, a blinding retinal disease resulting from photoreceptor degeneration. A photoreceptor specific ORF15 variant of RPGR (RPGR(ORF15)), carrying multiple Glu-Gly tandem repeats and a C-terminal basic domain of unknown function, localizes to the connecting cilium where it is thought to regulate cargo trafficking. Here we show that tubulin tyrosine ligase like-5 (TTLL5) glutamylates RPGR(ORF15) in its Glu-Gly-rich repetitive region containing motifs homologous to the α-tubulin C-terminal tail. The RPGR(ORF15) C-terminal basic domain binds to the noncatalytic cofactor interaction domain unique to TTLL5 among TTLL family glutamylases and targets TTLL5 to glutamylate RPGR. Only TTLL5 and not other TTLL family glutamylases interacts with RPGR(ORF15) when expressed transiently in cells. Consistent with this, a Ttll5 mutant mouse displays a complete loss of RPGR glutamylation without marked changes in tubulin glutamylation levels. The Ttll5 mutant mouse develops slow photoreceptor degeneration with early mislocalization of cone opsins, features resembling those of Rpgr-null mice. Moreover TTLL5 disease mutants that cause human retinal dystrophy show impaired glutamylation of RPGR(ORF15) Thus, RPGR(ORF15) is a novel glutamylation substrate, and this posttranslational modification is critical for its function in photoreceptors. Our study uncovers the pathogenic mechanism whereby absence of RPGR(ORF15) glutamylation leads to retinal pathology in patients with TTLL5 gene mutations and connects these two genes into a common disease pathway.
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