Affinage

LCA5

Lebercilin · UniProt Q86VQ0

Length
697 aa
Mass
80.6 kDa
Annotated
2026-06-10
20 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Lebercilin (LCA5) is a ciliary scaffold protein that supports intraflagellar transport (IFT)-mediated protein trafficking required for photoreceptor outer segment assembly and maintenance (PMID:17546029, PMID:37071472). It localizes to the connecting cilium of photoreceptors and to the centrioles, microtubules, and primary cilia of cultured cells, and assembles a ciliary interactome linking it to centrosomal and ciliary functions (PMID:17546029). At the bulge region of the outer segment axoneme—a site critical for membrane disc formation—lebercilin co-localizes with RP1 and the IFT proteins IFT81 and IFT88, and its loss reduces RP1 and IFT protein levels and disrupts disc formation (PMID:37071472). Loss-of-function across zebrafish, mouse, and patient-derived retinal organoid models produces a common phenotype: mislocalization of opsins/rhodopsin, cone α-transducin, and IFT and ciliary proteins (IFT88, CEP290), with progressive photoreceptor degeneration (PMID:31348989, PMID:37305852, PMID:39934925). Biochemically, lebercilin dimerizes through coiled-coil segments and binds dynein light chain LC8 via two short linear motifs, with LC8 promoting higher-order oligomerization (PMID:36114230); it also interacts with OFD1, an interaction differentially disrupted by pathogenic OFD1 alleles (PMID:19800048). The retinal degeneration caused by LCA5 loss can be reversed by AAV-mediated gene augmentation within a defined therapeutic window and partially ameliorated by small-molecule treatment (PMID:37071472, PMID:32428231, PMID:39934925).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2007 High

    Established lebercilin as a ciliary/centrosomal protein and defined its physical interactome, framing LCA5 as a candidate scaffold at the photoreceptor connecting cilium.

    Evidence Tandem affinity purification of 24 interactors plus immunofluorescence localization in photoreceptors and cultured cells

    PMID:17546029

    Open questions at the time
    • Functional role of most of the 24 interactors not resolved
    • No demonstration of how localization supports trafficking
  2. 2009 Medium

    Connected lebercilin to OFD1 and showed pathogenic OFD1 alleles differentially disrupt the interaction, linking LCA5 to a broader ciliopathy interaction network.

    Evidence Yeast two-hybrid screen of retinal cDNA and mutant-allele localization in hTERT-RPE1 cells

    PMID:19800048

    Open questions at the time
    • Functional consequence of the LCA5–OFD1 interaction in photoreceptors not tested
    • Interaction mapped in heterologous/yeast systems
  3. 2019 High

    Demonstrated in vivo that lca5 loss impairs IFT-mediated outer segment trafficking, mechanistically tying the gene to opsin and transducin transport.

    Evidence CRISPR/Cas9 zebrafish knockout with ERG, EM, and immunofluorescence for opsin, α-transducin, and IFT88

    PMID:31348989

    Open questions at the time
    • Whether mislocalization is a direct vs. secondary consequence of axonemal breakdown unclear
    • Molecular basis of IFT88 retention not defined
  4. 2020 Medium

    Defined a therapeutic window for AAV gene augmentation, establishing that rescue is possible only before irreversible degeneration.

    Evidence Subretinal AAV8-hLCA5 in Lca5gt/gt mice at three postnatal time points with OCT, ERG, histology

    PMID:32428231

    Open questions at the time
    • Mechanism of late-stage irreversibility not resolved
    • Single model system
  5. 2022 Medium

    Resolved the oligomeric architecture of lebercilin, showing coiled-coil dimerization and LC8-driven higher-order assembly that may underlie scaffold function.

    Evidence Biochemical and biophysical binding assays with motif mutagenesis of the LCA5–LC8 interaction

    PMID:36114230

    Open questions at the time
    • In vivo role of LC8-driven oligomerization in photoreceptors untested
    • Structural data limited to isolated motifs/segments
  6. 2023 High

    Localized lebercilin to the outer segment bulge region with RP1/IFT81/IFT88 and linked its loss to disc malformation, while showing AAV augmentation restores axonemal structure.

    Evidence Retina-specific affinity proteomics, ultrastructure expansion microscopy, loss-of-function mouse, AAV rescue

    PMID:37071472

    Open questions at the time
    • Stoichiometry and assembly order of the bulge complex unknown
    • How lebercilin recruits or stabilizes RP1/IFT proteins not defined
  7. 2023 Medium

    Confirmed in a human isogenic system that a patient nonsense allele abolishes lebercilin and disrupts opsin/rhodopsin trafficking, reversible by gene correction.

    Evidence CRISPR-Cas9 correction of p.Q279* in patient iPSCs and retinal organoid immunofluorescence

    PMID:37305852

    Open questions at the time
    • Single allele/genotype tested
    • Functional photoreceptor readouts beyond localization not assessed
  8. 2025 Medium

    Showed LCA5 loss alters CEP290/IFT88 ciliary distribution and rhodopsin trafficking in human organoids, and identified small molecules that partially correct these defects.

    Evidence LCA5 KO iPSC retinal organoids with IHC, western, transcriptomics, proteomics, and pharmacological rescue (eupatilin, fasudil)

    PMID:39934925

    Open questions at the time
    • Direct molecular targets of the rescuing compounds in this context unclear
    • Durability and in vivo translatability of pharmacological rescue untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How lebercilin's oligomeric scaffold mechanically organizes the bulge-region IFT machinery and selectively governs cargo (opsin, transducin) entry into the outer segment remains unresolved.
  • No structural model of the assembled bulge complex
  • Cargo-selectivity mechanism for outer segment trafficking undefined
  • Connection between LC8-driven oligomerization and IFT function not established in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005929 cilium 3 GO:0005815 microtubule organizing center 1 GO:0005856 cytoskeleton 1
Partners
CEP290DYNLL1IFT81IFT88OFD1RP1

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Lebercilin (LCA5) localizes to the connecting cilia of photoreceptors and to the microtubules, centrioles, and primary cilia of cultured mammalian cells. Using tandem affinity purification, 24 interacting proteins were identified linking lebercilin to centrosomal and ciliary functions. Tandem affinity purification (interactome), subcellular localization by immunofluorescence Nature genetics High 17546029
2009 OFD1 interacts with lebercilin (LCA5) as identified by yeast two-hybrid screen of a retinal cDNA library. X-linked recessive OFD1 mutations reduce but do not eliminate the interaction with lebercilin and do not affect pericentriolar localization, whereas X-linked dominant OFD1 mutations completely abolish binding to lebercilin and eliminate pericentriolar localization of the recombinant protein in hTERT-RPE1 cells. Yeast two-hybrid screen, recombinant protein expression in hTERT-RPE1 cells with immunofluorescence localization, mutation-function analysis American journal of human genetics Medium 19800048
2019 Knockout of lca5 in zebrafish (via CRISPR/Cas9) causes cone-rod dystrophy with progressive photoreceptor degeneration and impaired outer segment protein trafficking: red-cone opsin and cone α-transducin are selectively mislocalized to the inner segment and synaptic terminal, and IFT88 (an intraflagellar transport complex component) is retained in the outer segments, indicating impaired IFT-mediated outer segment protein transport. CRISPR/Cas9 knockout, ERG, histology (HE staining), immunofluorescence, transmission electron microscopy Biochimica et biophysica acta. Molecular basis of disease High 31348989
2023 Lebercilin (LCA5), together with RP1 and IFT proteins IFT81 and IFT88, localizes to the bulge region of the photoreceptor outer segment axoneme, a region crucial for outer segment membrane disc formation. Lebercilin-deficient mice show early axonemal defects at the bulge region and distal outer segment, with reduced levels of RP1 and IFT proteins, disrupting membrane disc formation. AAV-based LCA5 gene augmentation partially restored the bulge region, preserved axoneme structure and membrane disc formation, and promoted photoreceptor survival. Retina-specific affinity proteomics, ultrastructure expansion microscopy (nanoscale resolution), loss-of-function mouse model, AAV gene augmentation rescue JCI insight High 37071472
2022 LCA5 binds dynein light chain LC8 through two short linear motifs. LCA5 itself forms dimers through extensive coiled-coil formation independently of LC8, but LC8 enhances higher-order oligomerization of LCA5 through interplay between coiled-coil segments and both LC8-binding motifs. Biochemical binding assays, structural/biophysical characterization of LCA5–LC8 interaction, mutagenesis of binding motifs Scientific reports Medium 36114230
2023 In LCA5-patient-derived retinal organoids carrying a nonsense mutation (p.Q279*), lebercilin expression is absent and opsin/rhodopsin are mislocalized to the outer nuclear layer. CRISPR-Cas9 correction of the mutation in patient iPSCs restored lebercilin expression and its localization along the ciliary axoneme, and rescued opsin/rhodopsin trafficking. CRISPR-Cas9 single-nucleotide correction in patient iPSCs, differentiation to retinal organoids, immunofluorescence localization Molecular therapy. Methods & clinical development Medium 37305852
2025 Loss of LCA5 in iPSC-derived retinal organoids results in altered localization of CEP290 and IFT88 (extension along the ciliary axoneme), shorter outer segments, and rhodopsin mislocalization to the outer nuclear layer. Treatment with small molecules eupatilin, fasudil, or their combination reduced CEP290 and IFT88 accumulation along cilia, improved rhodopsin trafficking to the outer segment, and reduced rhodopsin mislocalization. LCA5 KO iPSC-derived retinal organoids, immunohistochemistry, western blotting, transcriptomics, proteomics, pharmacological rescue Acta neuropathologica communications Medium 39934925
2020 Subretinal AAV8-hLCA5 gene augmentation delivered to Lca5gt/gt mice at postnatal day 5 or 15, but not day 30, resulted in structural and functional rescue of photoreceptors (preserved outer nuclear layer by OCT, restored ERG responses). This defines a critical therapeutic window before irreversible photoreceptor degeneration. Subretinal AAV gene augmentation in Lca5gt/gt mouse, SD-OCT, ERG, histology, pupillometry; time-course comparison Investigative ophthalmology & visual science Medium 32428231

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. American journal of human genetics 167 19800048
2007 Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis. Nature genetics 153 17546029
2009 Leber congenital amaurosis caused by Lebercilin (LCA5) mutation: retained photoreceptors adjacent to retinal disorganization. Molecular vision 32 19503738
2013 Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations. Human mutation 27 23946133
2003 Progression of phenotype in Leber's congenital amaurosis with a mutation at the LCA5 locus. The British journal of ophthalmology 27 12642313
2019 Knocking out lca5 in zebrafish causes cone-rod dystrophy due to impaired outer segment protein trafficking. Biochimica et biophysica acta. Molecular basis of disease 26 31348989
2023 CRISPR-Cas9 correction of a nonsense mutation in LCA5 rescues lebercilin expression and localization in human retinal organoids. Molecular therapy. Methods & clinical development 21 37305852
2023 Gene augmentation of LCA5-associated Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme. JCI insight 19 37071472
2008 Identification of a novel splice-site mutation in the Lebercilin (LCA5) gene causing Leber congenital amaurosis. Molecular vision 19 18334959
2007 Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II. Human mutation 19 18000884
2013 Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population. Ophthalmology 17 24144451
2020 Treatment Potential for LCA5-Associated Leber Congenital Amaurosis. Investigative ophthalmology & visual science 14 32428231
2011 Identification of a novel LCA5 mutation in a Pakistani family with Leber congenital amaurosis and cataracts. Molecular vision 11 21850168
2016 Next-generation Sequencing Extends the Phenotypic Spectrum for LCA5 Mutations: Novel LCA5 Mutations in Cone Dystrophy. Scientific reports 9 27067258
2025 Small molecule treatment alleviates photoreceptor cilia defects in LCA5-deficient human retinal organoids. Acta neuropathologica communications 7 39934925
2009 LCA5, a rare genetic cause of leber congenital amaurosis in Koreans. Ophthalmic genetics 7 19172513
2005 Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA. Eye (London, England) 6 16082399
2022 The interaction between LC8 and LCA5 reveals a novel oligomerization function of LC8 in the ciliary-centrosome system. Scientific reports 4 36114230
2022 Relative preservation of the extramacular retina in LCA5-associated Leber congenital amaurosis. American journal of ophthalmology case reports 3 35128149
2022 Prenatal detection of pure proximal 6q14.1 microduplication encompassing LCA5 gene: A variant of likely benign. Medicine 0 35713440

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