LCA5-Related Retinopathy

Mendelian MONDO:0100445 Pathograph 7 Show in embeddings browser Ophthalmological Disease Retinal Dystrophy Inherited retinal dystrophy Ciliopathy

LCA5-related retinopathy (Leber congenital amaurosis 5, LCA5) is a severe, early-onset autosomal recessive inherited retinal ciliopathy caused by biallelic loss-of-function variants in LCA5, which encodes the ciliary protein lebercilin. Lebercilin localizes, together with retinitis pigmentosa 1 protein (RP1) and the intraflagellar transport (IFT) proteins IFT81 and IFT88, to the "bulge region" of the photoreceptor connecting-cilium axoneme -- a site distal to the CEP290 transition zone that is required for outer-segment membrane disc formation. Loss of lebercilin destabilizes this region, reduces RP1 and IFT protein levels, and disrupts intraflagellar cargo delivery, impairing outer-segment disc formation and causing progressive photoreceptor degeneration. LCA5-related retinopathy presents in infancy with severe visual impairment, nystagmus, and hyperopia. Natural-history imaging shows a distinctive dissociation of retinal structure and function: central photoreceptors and retinal pigment epithelium can remain relatively preserved despite profound vision loss, while more peripheral retina shows laminar disorganization -- a structural window that AAV8-based lebercilin gene-augmentation therapy (OPGx-001 / OPGx-LCA5) has targeted, with an ongoing phase 1b/2a/3 trial reporting sustained cone-mediated vision gains without serious adverse events.

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1
Mappings
1
Inheritance
3
Pathophys.
5
Phenotypes
7
Pathograph
1
Genes
3
Medical Actions
1
Trials
1
Models
1
References
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
🔗

Mappings

MONDO
MONDO:0011473 Leber congenital amaurosis 5 Not Yet Curated
skos:narrowMatch MONDO
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
LCA5-related retinopathy is caused by biallelic (homozygous or compound heterozygous) pathogenic LCA5 variants.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:17546029 SUPPORT Human Clinical
"We detected homozygous nonsense and frameshift mutations in LCA5 in five families affected with LCA."
Homozygous LCA5 genotypes identified by homozygosity mapping across five independent families establish autosomal recessive inheritance.
PMID:18334959 SUPPORT Human Clinical
"Here we present a homozygosity mapping analysis in a consanguineous sibship that led to the identification of a mutation in the recently discovered LCA5 gene."
Independent confirmation via homozygosity mapping in a consanguineous sibship with two affected siblings, the classic pedigree pattern of autosomal recessive inheritance.
⚙

Pathophysiology

3
Lebercilin Loss and Bulge Region Ciliary Axoneme Disruption
LCA5 encodes lebercilin, a ciliary protein that localizes, together with retinitis pigmentosa 1 protein (RP1) and the intraflagellar transport (IFT) proteins IFT81 and IFT88, to the "bulge region" of the photoreceptor outer-segment connecting-cilium axoneme -- a site distal to the CEP290 transition zone that is required for outer-segment membrane disc formation. Biallelic loss-of-function LCA5 variants (nonsense, frameshift, or splicing-disrupting) abolish lebercilin function and destabilize this bulge region.
photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
LCA5 hgnc:31923 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased LCA5 (hgnc:31923). hgnc:31923 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED
cilium assembly GO:0060271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Lca5 gene-trap (Lca5gt/gt) mouse Mouse rescues AAV-mediated LCA5 gene augmentation in HOM mice partially rescues the bulge-region axonemal defect caused by lebercilin loss.
Downstream
Impaired IFT Cargo Delivery and Outer Segment Disc Formation Failure Loss of lebercilin destabilizes the bulge region, reducing RP1 and IFT protein levels and disrupting delivery of outer-segment-building cargo along the distal axoneme.
Show evidence (2 references)
PMID:17546029 SUPPORT Human Clinical
"Lebercilin localizes to the connecting cilia of photoreceptors and to the microtubules, centrioles and primary cilia of cultured mammalian cells."
Establishes lebercilin as a ciliary protein localizing to the photoreceptor connecting cilium, the structural basis for its role in ciliary axoneme organization.
PMID:37071472 SUPPORT Model Organism
"We show that LCA5-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."
Precisely localizes lebercilin, RP1, and IFT81/IFT88 to the bulge region of the photoreceptor outer-segment axoneme, the structural node required for outer-segment disc formation.
Impaired IFT Cargo Delivery and Outer Segment Disc Formation Failure
With the bulge region destabilized, intraflagellar transport of outer-segment membrane and phototransduction cargo along the distal connecting-cilium axoneme fails, preventing normal outer-segment disc morphogenesis and renewal.
photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
intraciliary transport GO:0042073 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased intraciliary transport (GO:0042073). GO:0042073 is a biological process from the Gene Ontology. ↓ DECREASED protein localization to cilium GO:0061512 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to cilium (GO:0061512). GO:0061512 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Photoreceptor Outer Segment Degeneration Failure of outer-segment disc formation and maintenance leads to progressive photoreceptor degeneration.
Show evidence (1 reference)
PMID:37071472 SUPPORT Model Organism
"adeno-associated virus–based LCA5 gene augmentation partially restored the bulge region, preserved OS axoneme structure and membrane disc formation, and resulted in photoreceptor cell survival."
Restoring lebercilin via gene augmentation rescues bulge-region structure, axoneme integrity, and disc formation, confirming that disc-formation failure is the mechanistic consequence of impaired IFT cargo delivery when lebercilin is absent.
Photoreceptor Outer Segment Degeneration
Progressive rod and cone photoreceptor degeneration produces severe congenital visual impairment with a paradoxical dissociation of retinal structure and function: central (foveal) photoreceptors and retinal pigment epithelium can remain relatively retained on imaging despite profound visual loss, while more peripheral retina shows laminar disorganization -- a structural window that gene-augmentation therapy has targeted.
photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology. retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology. retinal cone cell CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
photoreceptor cell maintenance GO:0045494 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased photoreceptor cell maintenance (GO:0045494). GO:0045494 is a biological process from the Gene Ontology. ↓ DECREASED
retina UBERON:0000966 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in retina (UBERON:0000966). UBERON:0000966 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Lca5 gene-trap (Lca5gt/gt) mouse Mouse recapitulates The Lca5gt/gt mouse fully recapitulates the early-onset, progressive photoreceptor degeneration of human LCA5-related retinopathy.
Show evidence (2 references)
PMID:19503738 SUPPORT Human Clinical
"With increasing eccentricity, there was retinal laminar disorganization."
Directly documents progressive structural disorganization with increasing retinal eccentricity outside the fovea in LCA5 patients.
PMID:19503738 SUPPORT Human Clinical
"LCA5 patients had evidence of retained photoreceptors mainly in the central retina. Retinal remodeling was present in pericentral regions in both patients."
Establishes the central-preservation-with-peripheral-remodeling pattern that defines the structure-function dissociation and therapeutic window in LCA5.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for LCA5-Related Retinopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Eye 4
Undetectable electroretinogram VERY_FREQUENT HP:0000550 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Undetectable electroretinogram (HP:0000550). HP:0000550 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10615133 SUPPORT Human Clinical
"Individuals affected with LCA are diagnosed at birth or in the first few months of life with severely impaired vision or blindness, nystagmus and an abnormal or flat electroretinogram (ERG)."
This original LCA gene-discovery paper establishes the abnormal or flat ERG as a defining diagnostic feature of LCA, of which LCA5 is a genetic subtype.
Nystagmus VERY_FREQUENT HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19503738 SUPPORT Human Clinical
"Both LCA5 patients had light perception vision only, hyperopia, and nystagmus."
Documents nystagmus alongside severe visual impairment and hyperopia in two independent LCA5 patients.
Hyperopia FREQUENT Hypermetropia HP:0000540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperopia, annotated with Hypermetropia (HP:0000540). HP:0000540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19503738 SUPPORT Human Clinical
"Both LCA5 patients had light perception vision only, hyperopia, and nystagmus."
Documents hyperopia alongside severe visual impairment and nystagmus in two independent LCA5 patients.
Pigmentary retinopathy FREQUENT HP:0000580 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pigmentary retinopathy (HP:0000580). HP:0000580 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19503738 SUPPORT Human Clinical
"P1 showed a prominent central island of retinal pigment epithelium (RPE) surrounded by alternating elliptical-appearing areas of decreased and increased pigmentation."
Directly documents the characteristic pigmentary fundus pattern in LCA5-related retinopathy.
Other 1
Severe congenital visual impairment VERY_FREQUENT Congenital blindness HP:0007875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe visual impairment, annotated with Congenital blindness (HP:0007875), qualified as congenital onset. HP:0007875 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:17546029 SUPPORT Human Clinical
"Leber congenital amaurosis (LCA) causes blindness or severe visual impairment at or within a few months of birth."
Establishes severe early-onset vision loss as the defining clinical feature, from the original LCA5 gene-discovery paper.
🧬

Genetic Associations

1
LCA5 (Causative)
Gene: LCA5 hgnc:31923 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LCA5 (hgnc:31923). hgnc:31923 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:17546029 SUPPORT Human Clinical
"In a sixth family, the LCA5 transcript was completely absent."
Documents a complete loss-of-transcript LCA5 genotype as an additional independent disease-causing mechanism beyond point mutations.
PMID:18334959 SUPPORT Human Clinical
"A c.955G>A missense mutation in the last base of exon 6 causing disruption of the splice donor site was identified in both the affected sibs."
Documents a splice-disrupting LCA5 variant as an independent disease-causing mechanism, illustrating the allelic spectrum beyond nonsense/frameshift variants.
💊

Medical Actions

3
OPGx-001 / OPGx-LCA5 AAV8 Gene Augmentation Therapy
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
A recombinant adeno-associated virus serotype 8 (AAV8) vector carrying native human LCA5 cDNA (OPGx-001, now advancing as OPGx-LCA5), administered by subretinal injection. In an ongoing phase 1b/2a/3 dose-escalation trial (NCT05616793), the first three treated adults with LCA5-associated LCA had no serious treatment-related adverse events and showed improvements in cone-mediated vision detectable at 1 month and sustained for at least 12 months, with visual acuity returning to baseline or improving in all treated eyes. Mouse preclinical data show that gene augmentation restores bulge-region axoneme structure and outer-segment disc formation.
Mechanism Target:
RESTORES Lebercilin Loss and Bulge Region Ciliary Axoneme Disruption — AAV8-delivered LCA5 cDNA restores lebercilin expression, repairing the bulge-region axoneme defect at its molecular source.
Show evidence (1 reference)
PMID:37071472 SUPPORT Model Organism
"adeno-associated virus–based LCA5 gene augmentation partially restored the bulge region, preserved OS axoneme structure and membrane disc formation, and resulted in photoreceptor cell survival."
Mouse preclinical data directly demonstrate that LCA5 gene augmentation restores the bulge-region axoneme defect, the molecular mechanism target of this treatment.
Show evidence (5 references)
PMID:40598770 SUPPORT Human Clinical
"We assessed the preliminary safety of a recombinant adeno-associated virus serotype 8 vector carrying the native human LCA5 cDNA (OPGx-001) in LCA5-associated Leber congenital amaurosis (LCA5-LCA), a congenital blindness."
Defines the therapy (AAV8-delivered LCA5 cDNA) and its target population.
PMID:40598770 SUPPORT Human Clinical
"There were no serious adverse events related to OPGx-001 or the procedure."
Establishes the favorable safety profile in the first-in-human trial.
PMID:40598770 SUPPORT Human Clinical
"Chromatic full-field stimulus testing showed improvements in cone-mediated vision averaging ∼1 log10 unit."
Quantifies the cone-mediated visual function improvement, the trial's key efficacy signal.
+ 2 more references
Low-vision supportive care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Outside of clinical trials, management consists of low-vision support and routine ophthalmological monitoring, with early referral for LCA5 gene-therapy trial eligibility once biallelic LCA5 variants are molecularly confirmed.
Genetic counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling is indicated given the autosomal recessive inheritance pattern of LCA5-related retinopathy.
Show evidence (1 reference)
PMID:18334959 SUPPORT Human Clinical
"Here we present a homozygosity mapping analysis in a consanguineous sibship that led to the identification of a mutation in the recently discovered LCA5 gene."
Consanguineous-family transmission underlies the recessive-inheritance basis for genetic counseling.
🔬

Diagnosis

3
Electroretinography
Full-field ERG is the defining electrophysiological test for LCA5-related retinopathy: it is abnormal or non-recordable (flat) in essentially all affected individuals from birth or the first few months of life, directly measuring the near-total loss of functional rod and cone photoreceptor signaling.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Results: An abnormal or flat ERG is present alongside severely impaired vision or blindness and nystagmus from early infancy.
Show evidence (1 reference)
PMID:10615133 SUPPORT Human Clinical
"Individuals affected with LCA are diagnosed at birth or in the first few months of life with severely impaired vision or blindness, nystagmus and an abnormal or flat electroretinogram (ERG)."
This original LCA gene-discovery paper establishes the abnormal or flat ERG as a defining diagnostic feature of LCA, of which LCA5 is a genetic subtype.
Molecular genetic testing
Sequencing of LCA5 confirms the molecular diagnosis by identifying biallelic (homozygous or compound heterozygous) loss-of-function variants, which is required to establish eligibility for AAV8 lebercilin gene-augmentation clinical trials.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Results: Homozygous or compound-heterozygous nonsense, frameshift, or splice-disrupting LCA5 variants confirm the diagnosis.
Show evidence (1 reference)
PMID:17546029 SUPPORT Human Clinical
"We detected homozygous nonsense and frameshift mutations in LCA5 in five families affected with LCA."
Homozygosity mapping across five independent families establishes the molecular genotype-confirmation approach used to diagnose LCA5-related retinopathy.
Multimodal retinal imaging
Optical coherence tomography and other multimodal retinal imaging assess the distinctive dissociation of retinal structure and function in LCA5, identifying central photoreceptor and RPE preservation despite profound vision loss -- a structural window relevant to gene-therapy candidacy.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Results: LCA5 patients show retained photoreceptors mainly in the central retina, with retinal laminar disorganization increasing toward the periphery.
Show evidence (1 reference)
PMID:19503738 SUPPORT Human Clinical
"LCA5 patients had evidence of retained photoreceptors mainly in the central retina. Retinal remodeling was present in pericentral regions in both patients."
Establishes the central-preservation-with-peripheral-remodeling imaging pattern used to characterize disease structure and identify the therapeutic window in LCA5.
🔬

Clinical Trials

1
NCT05616793 PHASE_I RECRUITING
Ongoing open-label, nonrandomized, single ascending dose-escalation trial (now expanded to a phase 1b/2a/3 registrational design) of subretinal OPGx-001 / OPGx-LCA5 AAV8 gene augmentation in LCA5-associated Leber congenital amaurosis.
Target Phenotypes: Severe visual impairment HP:0007875 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Severe visual impairment, annotated with Congenital blindness (HP:0007875). HP:0007875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT05616793 SUPPORT Human Clinical
"to evaluate the safety and preliminary efficacy of subretinal gene therapy with OPGx-001 in patients with inherited retinal degeneration due to biallelic mutations in the LCA5 gene"
Registry record for the first-in-human OPGx-001/OPGx-LCA5 gene-therapy trial in LCA5-associated LCA.
🐁

Animal Models

1
Lca5 gene-trap (Lca5gt/gt) mouse
A lebercilin-deficient mouse produced by gene-trap disruption of Lca5. Homozygous (HOM) mice show early-onset, progressive retinal degeneration with axonemal defects at the photoreceptor bulge region, while heterozygous (HET) littermates serve as unaffected comparators.
Species
Mouse
Genotype
Lca5 gene-trap homozygous (Lca5gt/gt); Lca5+/gt heterozygous littermates used as comparator
Genes
LCA5 hgnc:31923 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns LCA5 (hgnc:31923). hgnc:31923 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:37071472
Pathograph links
Photoreceptor Outer Segment Degeneration recapitulates fidelity: high The Lca5gt/gt mouse fully recapitulates the early-onset, progressive photoreceptor degeneration of human LCA5-related retinopathy.
Readouts
Outer nuclear layer thickness
Photoreceptor nuclear-layer content assessed histologically in HOM mice over postnatal development.
Direction: DECREASED
Interpretation: Progressive loss of the outer nuclear layer is the structural correlate of photoreceptor degeneration in this model.
Show evidence (1 reference)
PMID:37071472 SUPPORT Model Organism
"with only a few layers of photoreceptor nuclei left in the outer nuclear layer (ONL) at P28"
Reports the near-complete loss of the outer nuclear layer by P28 in the HOM mouse model.
Show evidence (1 reference)
PMID:37071472 SUPPORT Model Organism
"Phenotypically, this mouse model fully recapitulates LCA in humans, showing an early-onset, progressive retinal degeneration, with only a few layers of photoreceptor nuclei left in the outer nuclear layer (ONL) at P28"
The authors explicitly state that this mouse model fully recapitulates human LCA, supporting its use as informative for the photoreceptor degeneration node.
Lebercilin Loss and Bulge Region Ciliary Axoneme Disruption rescues fidelity: moderate AAV-mediated LCA5 gene augmentation in HOM mice partially rescues the bulge-region axonemal defect caused by lebercilin loss.
Limitations: Rescue was partial and heterogeneous: ectopic lebercilin localization along the entire distal axoneme and at the centrioles (rather than restricted to the bulge region) was observed, and the degree of restoration varied between replicates.
Readouts
Bulge-region axoneme structure and OS membrane disc formation
Bulge-region structure, axoneme integrity, and membrane disc formation assessed by ultrastructure expansion microscopy after AAV-LCA5 gene augmentation in HOM mice.
Direction: RESTORED
Interpretation: Gene augmentation restores the molecular/structural lesion at its source, the mechanistic basis for the human gene-therapy trial.
Show evidence (1 reference)
PMID:37071472 SUPPORT Model Organism
"adeno-associated virus–based LCA5 gene augmentation partially restored the bulge region, preserved OS axoneme structure and membrane disc formation, and resulted in photoreceptor cell survival."
Directly reports partial restoration of the bulge region, OS axoneme structure, and membrane disc formation following gene augmentation.
Show evidence (1 reference)
PMID:37071472 SUPPORT Model Organism
"we show that exogenous lebercilin expression in photoreceptors partially rescues axoneme defects, RP1 and IFT protein localization, and CC length and is associated with improved photoreceptor survival."
Confirms that restoring lebercilin expression rescues the bulge-region axonemal defect and its downstream consequences (RP1 and IFT mislocalization, CC length), supporting this model as informative for the rescue arm of the mechanism.
Show evidence (1 reference)
PMID:37071472 SUPPORT Model Organism
"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."
Establishes the lebercilin-deficient mouse as informative for the LCA5 disease mechanism, directly linking loss of lebercilin to bulge-region axonemal defects, reduced RP1/IFT levels, and photoreceptor death.
{ }

Source YAML

click to show 
name: LCA5-Related Retinopathy
creation_date: "2026-08-13T21:00:00Z"
category: Mendelian
description: >-
  LCA5-related retinopathy (Leber congenital amaurosis 5, LCA5) is a severe,
  early-onset autosomal recessive inherited retinal ciliopathy caused by
  biallelic loss-of-function variants in LCA5, which encodes the ciliary
  protein lebercilin. Lebercilin localizes, together with retinitis pigmentosa
  1 protein (RP1) and the intraflagellar transport (IFT) proteins IFT81 and
  IFT88, to the "bulge region" of the photoreceptor connecting-cilium
  axoneme -- a site distal to the CEP290 transition zone that is required for
  outer-segment membrane disc formation. Loss of lebercilin destabilizes this
  region, reduces RP1 and IFT protein levels, and disrupts intraflagellar
  cargo delivery, impairing outer-segment disc formation and causing
  progressive photoreceptor degeneration. LCA5-related retinopathy presents
  in infancy with severe visual impairment, nystagmus, and hyperopia.
  Natural-history imaging shows a distinctive dissociation of
  retinal structure and function: central photoreceptors and retinal pigment
  epithelium can remain relatively preserved despite profound vision loss,
  while more peripheral retina shows laminar disorganization -- a structural
  window that AAV8-based lebercilin gene-augmentation therapy (OPGx-001 /
  OPGx-LCA5) has targeted, with an ongoing phase 1b/2a/3 trial reporting
  sustained cone-mediated vision gains without serious adverse events.
disease_term:
  preferred_term: LCA5-related retinopathy
  term:
    id: MONDO:0100445
    label: LCA5-related retinopathy
synonyms:
- Leber congenital amaurosis 5
- LCA5
- LCA5 retinopathy
- Leber congenital amaurosis type 5
- LCA5 Leber congenital amaurosis
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
- Ciliopathy

mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011473
      label: Leber congenital amaurosis 5
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO

notes: >-
  OMIM phenotype entry #604537 "LEBER CONGENITAL AMAUROSIS 5; LCA5" (gene
  *611408 LCA5/lebercilin, chromosome 6q14). LCA5 mRNA is also expressed in
  ciliated respiratory epithelium (nasopharynx, trachea, lung) and lebercilin
  was originally identified in the bronchial-epithelium ciliary axoneme
  proteome; one reported LCA5-null infant died at 11 months of age from
  asphyxia during sleep, raising the possibility of a wider ciliopathy
  phenotype spectrum, but to date isolated LCA remains the only phenotype
  unambiguously established for LCA5 pathogenic variants (PMID:18334959).

references:
- reference: PMID:30285347
  title: "Nonsyndromic Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview"
  tags:
  - GeneReviews
  findings:
  - statement: >-
      This GeneReviews entry is a multi-gene nonsyndromic LCA/EOSRD overview
      rather than an LCA5-specific chapter, and the available cached record
      is a generic purpose/scope abstract without quotable, disease-specific
      clinical, prevalence, or management text. Disease-specific claims in
      this entry, including LCA5's distinctive dissociation of retinal
      structure and function, are therefore sourced from primary literature
      (Sohocki 2000, den Hollander 2007, Ramprasad 2008, Jacobson 2009, Faber
      2023, Aleman 2025) rather than from quotable GeneReviews snippets; the
      overview is retained as the tagged clinical baseline reference.
    supporting_text: "characteristics of nonsyndromic Leber congenital amaurosis"

inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    LCA5-related retinopathy is caused by biallelic (homozygous or compound
    heterozygous) pathogenic LCA5 variants.
  evidence:
  - reference: PMID:17546029
    reference_title: "Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected homozygous nonsense and frameshift mutations in LCA5 in five families affected with LCA."
    explanation: >-
      Homozygous LCA5 genotypes identified by homozygosity mapping across
      five independent families establish autosomal recessive inheritance.
  - reference: PMID:18334959
    reference_title: "Identification of a novel splice-site mutation in the Lebercilin (LCA5) gene causing Leber congenital amaurosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present a homozygosity mapping analysis in a consanguineous sibship that led to the identification of a mutation in the recently discovered LCA5 gene."
    explanation: >-
      Independent confirmation via homozygosity mapping in a consanguineous
      sibship with two affected siblings, the classic pedigree pattern of
      autosomal recessive inheritance.

pathophysiology:
- name: Lebercilin Loss and Bulge Region Ciliary Axoneme Disruption
  biological_scale: MOLECULAR
  description: >-
    LCA5 encodes lebercilin, a ciliary protein that localizes, together with
    retinitis pigmentosa 1 protein (RP1) and the intraflagellar transport
    (IFT) proteins IFT81 and IFT88, to the "bulge region" of the
    photoreceptor outer-segment connecting-cilium axoneme -- a site distal to
    the CEP290 transition zone that is required for outer-segment membrane
    disc formation. Biallelic loss-of-function LCA5 variants (nonsense,
    frameshift, or splicing-disrupting) abolish lebercilin function and
    destabilize this bulge region.
  gene:
    preferred_term: LCA5
    modifier: DECREASED
    term:
      id: hgnc:31923
      label: LCA5
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:17546029
    reference_title: "Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lebercilin localizes to the connecting cilia of photoreceptors and to the microtubules, centrioles and primary cilia of cultured mammalian cells."
    explanation: >-
      Establishes lebercilin as a ciliary protein localizing to the
      photoreceptor connecting cilium, the structural basis for its role in
      ciliary axoneme organization.
  - reference: PMID:37071472
    reference_title: "Gene augmentation of LCA5-associated Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that LCA5-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."
    explanation: >-
      Precisely localizes lebercilin, RP1, and IFT81/IFT88 to the bulge
      region of the photoreceptor outer-segment axoneme, the structural node
      required for outer-segment disc formation.
  downstream:
  - target: Impaired IFT Cargo Delivery and Outer Segment Disc Formation Failure
    description: >-
      Loss of lebercilin destabilizes the bulge region, reducing RP1 and IFT
      protein levels and disrupting delivery of outer-segment-building cargo
      along the distal axoneme.
    evidence:
    - reference: PMID:37071472
      reference_title: "Gene augmentation of LCA5-associated Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "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."
      explanation: >-
        Directly demonstrates that lebercilin loss in mice causes bulge-region
        and distal-axoneme defects with reduced RP1/IFT protein levels,
        mechanistically linking the molecular lesion to impaired disc
        formation and photoreceptor death.

- name: Impaired IFT Cargo Delivery and Outer Segment Disc Formation Failure
  biological_scale: CELLULAR
  description: >-
    With the bulge region destabilized, intraflagellar transport of
    outer-segment membrane and phototransduction cargo along the distal
    connecting-cilium axoneme fails, preventing normal outer-segment disc
    morphogenesis and renewal.
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  biological_processes:
  - preferred_term: intraciliary transport
    term:
      id: GO:0042073
      label: intraciliary transport
    modifier: DECREASED
  - preferred_term: protein localization to cilium
    term:
      id: GO:0061512
      label: protein localization to cilium
    modifier: DECREASED
  evidence:
  - reference: PMID:37071472
    reference_title: "Gene augmentation of LCA5-associated Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "adeno-associated virus–based LCA5 gene augmentation partially restored the bulge region, preserved OS axoneme structure and membrane disc formation, and resulted in photoreceptor cell survival."
    explanation: >-
      Restoring lebercilin via gene augmentation rescues bulge-region
      structure, axoneme integrity, and disc formation, confirming that
      disc-formation failure is the mechanistic consequence of impaired IFT
      cargo delivery when lebercilin is absent.
  downstream:
  - target: Photoreceptor Outer Segment Degeneration
    description: >-
      Failure of outer-segment disc formation and maintenance leads to
      progressive photoreceptor degeneration.
    evidence:
    - reference: PMID:37071472
      reference_title: "Gene augmentation of LCA5-associated Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "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."
      explanation: >-
        Links disc-formation failure directly to downstream photoreceptor
        cell death in the lebercilin-deficient mouse model.

- name: Photoreceptor Outer Segment Degeneration
  conforms_to: "ciliopathy_dysfunction#Photoreceptor Connecting Cilium Degeneration"
  biological_scale: TISSUE
  description: >-
    Progressive rod and cone photoreceptor degeneration produces severe
    congenital visual impairment with a paradoxical dissociation of retinal
    structure and function: central (foveal) photoreceptors and retinal
    pigment epithelium can remain relatively retained on imaging despite
    profound visual loss, while more peripheral retina shows laminar
    disorganization -- a structural window that gene-augmentation therapy
    has targeted.
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  biological_processes:
  - preferred_term: photoreceptor cell maintenance
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:19503738
    reference_title: "Leber congenital amaurosis caused by Lebercilin (LCA5) mutation: retained photoreceptors adjacent to retinal disorganization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With increasing eccentricity, there was retinal laminar disorganization."
    explanation: >-
      Directly documents progressive structural disorganization with
      increasing retinal eccentricity outside the fovea in LCA5 patients.
  - reference: PMID:19503738
    reference_title: "Leber congenital amaurosis caused by Lebercilin (LCA5) mutation: retained photoreceptors adjacent to retinal disorganization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LCA5 patients had evidence of retained photoreceptors mainly in the central retina. Retinal remodeling was present in pericentral regions in both patients."
    explanation: >-
      Establishes the central-preservation-with-peripheral-remodeling pattern
      that defines the structure-function dissociation and therapeutic
      window in LCA5.

phenotypes:
- category: Ophthalmological
  name: Severe congenital visual impairment
  frequency: VERY_FREQUENT
  description: >-
    Profound visual impairment or blindness at or within a few months of
    birth is the defining presenting feature of LCA5-related retinopathy.
  phenotype_term:
    preferred_term: Severe visual impairment
    term:
      id: HP:0007875
      label: Congenital blindness
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:17546029
    reference_title: "Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leber congenital amaurosis (LCA) causes blindness or severe visual impairment at or within a few months of birth."
    explanation: >-
      Establishes severe early-onset vision loss as the defining clinical
      feature, from the original LCA5 gene-discovery paper.
- category: Ophthalmological
  name: Undetectable electroretinogram
  frequency: VERY_FREQUENT
  description: >-
    A non-recordable (flat/abnormal) electroretinogram is the diagnostic
    electrophysiological hallmark of LCA5-related retinopathy, present in
    essentially all affected patients from early infancy.
  phenotype_term:
    preferred_term: Undetectable electroretinogram
    term:
      id: HP:0000550
      label: Undetectable electroretinogram
  reports_on:
  - target: Photoreceptor Outer Segment Degeneration
    relationship: READOUT_OF
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The flat/abnormal ERG directly measures the near-complete loss of
      functional rod and cone photoreceptor signaling in LCA5-related
      retinopathy.
  evidence:
  - reference: PMID:10615133
    reference_title: "Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with LCA are diagnosed at birth or in the first few months of life with severely impaired vision or blindness, nystagmus and an abnormal or flat electroretinogram (ERG)."
    explanation: >-
      This original LCA gene-discovery paper establishes the abnormal or
      flat ERG as a defining diagnostic feature of LCA, of which LCA5 is a
      genetic subtype.
- category: Ophthalmological
  name: Nystagmus
  frequency: VERY_FREQUENT
  description: >-
    Nystagmus is a consistent early feature of LCA5-related retinopathy.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:19503738
    reference_title: "Leber congenital amaurosis caused by Lebercilin (LCA5) mutation: retained photoreceptors adjacent to retinal disorganization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both LCA5 patients had light perception vision only, hyperopia, and nystagmus."
    explanation: >-
      Documents nystagmus alongside severe visual impairment and hyperopia in
      two independent LCA5 patients.
- category: Ophthalmological
  name: Hyperopia
  frequency: FREQUENT
  description: >-
    High hyperopia is commonly associated with LCA5-related retinopathy, as
    with Leber congenital amaurosis generally.
  phenotype_term:
    preferred_term: Hyperopia
    term:
      id: HP:0000540
      label: Hypermetropia
  evidence:
  - reference: PMID:19503738
    reference_title: "Leber congenital amaurosis caused by Lebercilin (LCA5) mutation: retained photoreceptors adjacent to retinal disorganization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both LCA5 patients had light perception vision only, hyperopia, and nystagmus."
    explanation: >-
      Documents hyperopia alongside severe visual impairment and nystagmus in
      two independent LCA5 patients.
- category: Ophthalmological
  name: Pigmentary retinopathy
  frequency: FREQUENT
  description: >-
    A prominent central island of retinal pigment epithelium surrounded by
    alternating areas of pigmentation change is a characteristic fundus
    finding in LCA5-related retinopathy.
  phenotype_term:
    preferred_term: Pigmentary retinopathy
    term:
      id: HP:0000580
      label: Pigmentary retinopathy
  evidence:
  - reference: PMID:19503738
    reference_title: "Leber congenital amaurosis caused by Lebercilin (LCA5) mutation: retained photoreceptors adjacent to retinal disorganization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1 showed a prominent central island of retinal pigment epithelium (RPE) surrounded by alternating elliptical-appearing areas of decreased and increased pigmentation."
    explanation: >-
      Directly documents the characteristic pigmentary fundus pattern in
      LCA5-related retinopathy.

genetic:
- name: LCA5
  gene_term:
    preferred_term: LCA5
    term:
      id: hgnc:31923
      label: LCA5
  association: Causative
  features: >-
    Homozygous or compound-heterozygous loss-of-function LCA5 variants
    (nonsense, frameshift, and splicing-disrupting) have been identified
    across multiple independent families. To date, isolated LCA is the only
    phenotype unambiguously established for LCA5 pathogenic variants.
  evidence:
  - reference: PMID:17546029
    reference_title: "Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a sixth family, the LCA5 transcript was completely absent."
    explanation: >-
      Documents a complete loss-of-transcript LCA5 genotype as an additional
      independent disease-causing mechanism beyond point mutations.
  - reference: PMID:18334959
    reference_title: "Identification of a novel splice-site mutation in the Lebercilin (LCA5) gene causing Leber congenital amaurosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A c.955G>A missense mutation in the last base of exon 6 causing disruption of the splice donor site was identified in both the affected sibs."
    explanation: >-
      Documents a splice-disrupting LCA5 variant as an independent
      disease-causing mechanism, illustrating the allelic spectrum beyond
      nonsense/frameshift variants.

treatments:
- name: OPGx-001 / OPGx-LCA5 AAV8 Gene Augmentation Therapy
  therapeutic_modality: GENE_THERAPY
  description: >-
    A recombinant adeno-associated virus serotype 8 (AAV8) vector carrying
    native human LCA5 cDNA (OPGx-001, now advancing as OPGx-LCA5),
    administered by subretinal injection. In an ongoing phase 1b/2a/3
    dose-escalation trial (NCT05616793), the first three treated adults with
    LCA5-associated LCA had no serious treatment-related adverse events and
    showed improvements in cone-mediated vision detectable at 1 month and
    sustained for at least 12 months, with visual acuity returning to
    baseline or improving in all treated eyes. Mouse preclinical data show
    that gene augmentation restores bulge-region axoneme structure and
    outer-segment disc formation.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Lebercilin Loss and Bulge Region Ciliary Axoneme Disruption
    treatment_effect: RESTORES
    description: >-
      AAV8-delivered LCA5 cDNA restores lebercilin expression, repairing the
      bulge-region axoneme defect at its molecular source.
    evidence:
    - reference: PMID:37071472
      reference_title: "Gene augmentation of LCA5-associated Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "adeno-associated virus–based LCA5 gene augmentation partially restored the bulge region, preserved OS axoneme structure and membrane disc formation, and resulted in photoreceptor cell survival."
      explanation: >-
        Mouse preclinical data directly demonstrate that LCA5 gene
        augmentation restores the bulge-region axoneme defect, the molecular
        mechanism target of this treatment.
  evidence:
  - reference: PMID:40598770
    reference_title: "Recovery of cone-mediated vision in Lebercilin associated retinal ciliopathy after gene therapy: one-year results of a phase I/II trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We assessed the preliminary safety of a recombinant adeno-associated virus serotype 8 vector carrying the native human LCA5 cDNA (OPGx-001) in LCA5-associated Leber congenital amaurosis (LCA5-LCA), a congenital blindness."
    explanation: >-
      Defines the therapy (AAV8-delivered LCA5 cDNA) and its target
      population.
  - reference: PMID:40598770
    reference_title: "Recovery of cone-mediated vision in Lebercilin associated retinal ciliopathy after gene therapy: one-year results of a phase I/II trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were no serious adverse events related to OPGx-001 or the procedure."
    explanation: >-
      Establishes the favorable safety profile in the first-in-human trial.
  - reference: PMID:40598770
    reference_title: "Recovery of cone-mediated vision in Lebercilin associated retinal ciliopathy after gene therapy: one-year results of a phase I/II trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chromatic full-field stimulus testing showed improvements in cone-mediated vision averaging ∼1 log10 unit."
    explanation: >-
      Quantifies the cone-mediated visual function improvement, the trial's
      key efficacy signal.
  - reference: PMID:40598770
    reference_title: "Recovery of cone-mediated vision in Lebercilin associated retinal ciliopathy after gene therapy: one-year results of a phase I/II trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Visual acuity returned to baseline or improved in the treated eyes of all participants."
    explanation: >-
      Documents visual acuity outcomes across all three treated participants.
  - reference: PMID:37071472
    reference_title: "Gene augmentation of LCA5-associated Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "adeno-associated virus–based LCA5 gene augmentation partially restored the bulge region, preserved OS axoneme structure and membrane disc formation, and resulted in photoreceptor cell survival."
    explanation: >-
      Mouse preclinical data establish the mechanistic proof-of-concept
      underlying the human gene-therapy trial.
- name: Low-vision supportive care
  therapeutic_modality: OTHER
  description: >-
    Outside of clinical trials, management consists of low-vision support and
    routine ophthalmological monitoring, with early referral for LCA5
    gene-therapy trial eligibility once biallelic LCA5 variants are
    molecularly confirmed.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic counseling
  therapeutic_modality: OTHER
  description: >-
    Genetic counseling is indicated given the autosomal recessive inheritance
    pattern of LCA5-related retinopathy.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:18334959
    reference_title: "Identification of a novel splice-site mutation in the Lebercilin (LCA5) gene causing Leber congenital amaurosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present a homozygosity mapping analysis in a consanguineous sibship that led to the identification of a mutation in the recently discovered LCA5 gene."
    explanation: >-
      Consanguineous-family transmission underlies the recessive-inheritance
      basis for genetic counseling.

classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: NEUROLOGIC

diagnosis:
- name: Electroretinography
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Full-field ERG is the defining electrophysiological test for LCA5-related
    retinopathy: it is abnormal or non-recordable (flat) in essentially all
    affected individuals from birth or the first few months of life, directly
    measuring the near-total loss of functional rod and cone photoreceptor
    signaling.
  results: >-
    An abnormal or flat ERG is present alongside severely impaired vision or
    blindness and nystagmus from early infancy.
  evidence:
  - reference: PMID:10615133
    reference_title: "Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with LCA are diagnosed at birth or in the first few months of life with severely impaired vision or blindness, nystagmus and an abnormal or flat electroretinogram (ERG)."
    explanation: >-
      This original LCA gene-discovery paper establishes the abnormal or
      flat ERG as a defining diagnostic feature of LCA, of which LCA5 is a
      genetic subtype.
- name: Molecular genetic testing
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Sequencing of LCA5 confirms the molecular diagnosis by identifying
    biallelic (homozygous or compound heterozygous) loss-of-function
    variants, which is required to establish eligibility for AAV8 lebercilin
    gene-augmentation clinical trials.
  results: >-
    Homozygous or compound-heterozygous nonsense, frameshift, or
    splice-disrupting LCA5 variants confirm the diagnosis.
  evidence:
  - reference: PMID:17546029
    reference_title: "Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected homozygous nonsense and frameshift mutations in LCA5 in five families affected with LCA."
    explanation: >-
      Homozygosity mapping across five independent families establishes the
      molecular genotype-confirmation approach used to diagnose LCA5-related
      retinopathy.
- name: Multimodal retinal imaging
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Optical coherence tomography and other multimodal retinal imaging assess
    the distinctive dissociation of retinal structure and function in LCA5,
    identifying central photoreceptor and RPE preservation despite profound
    vision loss -- a structural window relevant to gene-therapy candidacy.
  results: >-
    LCA5 patients show retained photoreceptors mainly in the central retina,
    with retinal laminar disorganization increasing toward the periphery.
  evidence:
  - reference: PMID:19503738
    reference_title: "Leber congenital amaurosis caused by Lebercilin (LCA5) mutation: retained photoreceptors adjacent to retinal disorganization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LCA5 patients had evidence of retained photoreceptors mainly in the central retina. Retinal remodeling was present in pericentral regions in both patients."
    explanation: >-
      Establishes the central-preservation-with-peripheral-remodeling
      imaging pattern used to characterize disease structure and identify
      the therapeutic window in LCA5.

clinical_trials:
- name: NCT05616793
  phase: PHASE_I
  status: RECRUITING
  description: >-
    Ongoing open-label, nonrandomized, single ascending dose-escalation trial
    (now expanded to a phase 1b/2a/3 registrational design) of subretinal
    OPGx-001 / OPGx-LCA5 AAV8 gene augmentation in LCA5-associated Leber
    congenital amaurosis.
  target_phenotypes:
  - preferred_term: Severe visual impairment
    term:
      id: HP:0007875
      label: Congenital blindness
  evidence:
  - reference: clinicaltrials:NCT05616793
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to evaluate the safety and preliminary efficacy of subretinal gene therapy with OPGx-001 in patients with inherited retinal degeneration due to biallelic mutations in the LCA5 gene"
    explanation: >-
      Registry record for the first-in-human OPGx-001/OPGx-LCA5 gene-therapy
      trial in LCA5-associated LCA.

animal_models:
- name: Lca5 gene-trap (Lca5gt/gt) mouse
  species: Mouse
  genotype: Lca5 gene-trap homozygous (Lca5gt/gt); Lca5+/gt heterozygous littermates used as comparator
  genes:
  - preferred_term: LCA5
    term:
      id: hgnc:31923
      label: LCA5
  publication: PMID:37071472
  description: >-
    A lebercilin-deficient mouse produced by gene-trap disruption of Lca5.
    Homozygous (HOM) mice show early-onset, progressive retinal degeneration
    with axonemal defects at the photoreceptor bulge region, while
    heterozygous (HET) littermates serve as unaffected comparators.
  evidence:
  - reference: PMID:37071472
    reference_title: "Gene augmentation of LCA5-associated Leber congenital amaurosis ameliorates bulge region defects of the photoreceptor ciliary axoneme."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "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."
    explanation: >-
      Establishes the lebercilin-deficient mouse as informative for the
      LCA5 disease mechanism, directly linking loss of lebercilin to
      bulge-region axonemal defects, reduced RP1/IFT levels, and
      photoreceptor death.
  modeled_mechanisms:
  - target: Photoreceptor Outer Segment Degeneration
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The Lca5gt/gt mouse fully recapitulates the early-onset, progressive
      photoreceptor degeneration of human LCA5-related retinopathy.
    readouts:
    - name: Outer nuclear layer thickness
      target: Photoreceptor Outer Segment Degeneration
      description: >-
        Photoreceptor nuclear-layer content assessed histologically in HOM
        mice over postnatal development.
      direction: DECREASED
      interpretation: >-
        Progressive loss of the outer nuclear layer is the structural
        correlate of photoreceptor degeneration in this model.
      evidence:
      - reference: PMID:37071472
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "with only a few layers of photoreceptor nuclei left in the outer nuclear layer (ONL) at P28"
        explanation: >-
          Reports the near-complete loss of the outer nuclear layer by P28
          in the HOM mouse model.
    evidence:
    - reference: PMID:37071472
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Phenotypically, this mouse model fully recapitulates LCA in humans, showing an early-onset, progressive retinal degeneration, with only a few layers of photoreceptor nuclei left in the outer nuclear layer (ONL) at P28"
      explanation: >-
        The authors explicitly state that this mouse model fully
        recapitulates human LCA, supporting its use as informative for the
        photoreceptor degeneration node.
  - target: Lebercilin Loss and Bulge Region Ciliary Axoneme Disruption
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      AAV-mediated LCA5 gene augmentation in HOM mice partially rescues the
      bulge-region axonemal defect caused by lebercilin loss.
    limitations: >-
      Rescue was partial and heterogeneous: ectopic lebercilin localization
      along the entire distal axoneme and at the centrioles (rather than
      restricted to the bulge region) was observed, and the degree of
      restoration varied between replicates.
    readouts:
    - name: Bulge-region axoneme structure and OS membrane disc formation
      target: Lebercilin Loss and Bulge Region Ciliary Axoneme Disruption
      description: >-
        Bulge-region structure, axoneme integrity, and membrane disc
        formation assessed by ultrastructure expansion microscopy after
        AAV-LCA5 gene augmentation in HOM mice.
      direction: RESTORED
      interpretation: >-
        Gene augmentation restores the molecular/structural lesion at its
        source, the mechanistic basis for the human gene-therapy trial.
      evidence:
      - reference: PMID:37071472
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "adeno-associated virus–based LCA5 gene augmentation partially restored the bulge region, preserved OS axoneme structure and membrane disc formation, and resulted in photoreceptor cell survival."
        explanation: >-
          Directly reports partial restoration of the bulge region, OS
          axoneme structure, and membrane disc formation following gene
          augmentation.
    evidence:
    - reference: PMID:37071472
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we show that exogenous lebercilin expression in photoreceptors partially rescues axoneme defects, RP1 and IFT protein localization, and CC length and is associated with improved photoreceptor survival."
      explanation: >-
        Confirms that restoring lebercilin expression rescues the
        bulge-region axonemal defect and its downstream consequences (RP1
        and IFT mislocalization, CC length), supporting this model as
        informative for the rescue arm of the mechanism.
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References & Deep Research

References

1
PMID:30285347
Nonsyndromic Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview
1 finding
This GeneReviews entry is a multi-gene nonsyndromic LCA/EOSRD overview rather than an LCA5-specific chapter, and the available cached record is a generic purpose/scope abstract without quotable, disease-specific clinical, prevalence, or management text. Disease-specific claims in this entry, including LCA5's distinctive dissociation of retinal structure and function, are therefore sourced from primary literature (Sohocki 2000, den Hollander 2007, Ramprasad 2008, Jacobson 2009, Faber 2023, Aleman 2025) rather than from quotable GeneReviews snippets; the overview is retained as the tagged clinical baseline reference.
"characteristics of nonsyndromic Leber congenital amaurosis"