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Despite the discovery of a growing number of genes associated with this disease, the molecular mechanisms of photoreceptor cell degeneration of most LCA subtypes remain poorly understood. Here, using retina-specific affinity proteomics combined with ultrastructure expansion microscopy, we reveal the structural and molecular defects underlying LCA type 5 (LCA5) with nanoscale resolution. We show that\n                    <jats:italic>LCA5<\/jats:italic>\n                    -encoded lebercilin, together with retinitis pigmentosa 1 protein (RP1) and the intraflagellar transport (IFT) proteins IFT81 and IFT88, localized at the bulge region of the photoreceptor outer segment (OS), a region crucial for OS membrane disc formation. Next, we demonstrate that mutant mice deficient in lebercilin exhibited early axonemal defects at the bulge region and the distal OS, accompanied by reduced levels of RP1 and IFT proteins, affecting membrane disc formation and presumably leading to photoreceptor death. Finally, adeno-associated virus\u2013based\n                    <jats:italic>LCA5<\/jats:italic>\n                    gene augmentation partially restored the bulge region, preserved OS axoneme structure and membrane disc formation, and resulted in photoreceptor cell survival. Our approach thus provides a next level of assessment of retinal (gene) therapy efficacy at the molecular level.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.169162","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T12:01:46Z","timestamp":1681819306000},"source":"Crossref","is-referenced-by-count":30,"title":["Gene augmentation of LCA5-associated Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme"],"prefix":"10.1172","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2852-8478","authenticated-orcid":true,"given":"Siebren","family":"Faber","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Mercey","sequence":"additional","affiliation":[{"name":"Department of Molecular and 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Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"May-Simera","sequence":"additional","affiliation":[{"name":"Cilia Cell Biology, Institute of Molecular Physiology, Johannes-Gutenberg University, Mainz, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Ueffing","sequence":"additional","affiliation":[{"name":"Division of Experimental Ophthalmology and Medical Proteome Center, Institute for Ophthalmic Research, Eberhard Karls University T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob W.J.","family":"Collin","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 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