{"gene":"OPN1LW","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2015,"finding":"Unique haplotypes in OPN1LW (specifically the LVAVA haplotype) are responsible for X-linked high myopia mapped to MYP1; a frameshift mutation (c.617_620dup, p.Phe208Argfs*51) in OPN1LW was also identified as causative, and the haplotype cosegregated with high myopia in families.","method":"Whole-exome sequencing, whole-genome sequencing, Sanger sequencing, long-range PCR, LOD score analysis","journal":"Investigative Ophthalmology & Visual Science","confidence":"Medium","confidence_rationale":"Tier 2 — genetic segregation with defined molecular variant, single lab with multiple sequencing methods","pmids":["26114493"],"is_preprint":false},{"year":2016,"finding":"De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline can create pathogenic haplotypes (e.g., LIAVA) causing Blue Cone Monochromacy; specific exon 3 haplotypes of OPN1LW/OPN1MW cause aberrant pre-mRNA splicing (exon 3 skipping) resulting in loss of functional photopigment and cone dysfunction.","method":"Semi-quantitative minigene splicing assay, long-range PCR, Sanger sequencing, pedigree analysis","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct experimental splicing assay (minigene) combined with pedigree-based gene conversion evidence","pmids":["27339364"],"is_preprint":false},{"year":2021,"finding":"Intermixing of OPN1LW and OPN1MW genes through unequal recombination generates exon 3 haplotypes that disrupt the exonic splicing code, causing profound exon 3 skipping during pre-mRNA splicing; cones expressing skipping haplotypes are nearly devoid of photopigment, resulting in an array of vision disorders including Blue Cone Monochromacy and X-linked cone dystrophy.","method":"Minigene splicing assay, molecular genetic analysis of haplotypes, review of functional splicing data","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic splicing model supported by experimental minigene data across multiple haplotypes","pmids":["34440353"],"is_preprint":false},{"year":2022,"finding":"OPN1LW exon 3 haplotypes that cause profound exon 3 skipping are associated with high myopia; cones expressing skipping haplotypes have abnormally low photopigment content while adjacent cones expressing non-skipping haplotypes have relatively full photopigment, and the resulting abnormal contrast signals between adjacent cones are hypothesized to stimulate axial elongation driving myopia.","method":"Long-distance PCR, Sanger sequencing, association analysis of spherical equivalent refraction with OPN1LW haplotype in males of European ancestry, contrast-reducing spectacle lens trial","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 — genetic association of defined molecular haplotypes with refractive error plus functional model, single lab","pmids":["35741704"],"is_preprint":false}],"current_model":"OPN1LW encodes the long-wavelength-sensitive cone opsin; specific exon 3 haplotypes (e.g., LVAVA, LIAVA) arising from unequal recombination/gene conversion between OPN1LW and OPN1MW disrupt the exonic splicing code, causing profound exon 3 skipping during pre-mRNA splicing that leaves cones nearly devoid of photopigment, leading to cone dysfunction disorders (Blue Cone Monochromacy, X-linked cone dystrophy) and high myopia, with the differential photopigment content between adjacent cones proposed to generate abnormal contrast signals that drive axial elongation."},"narrative":{"teleology":[{"year":2015,"claim":"Establishing that pathogenic OPN1LW variants—including the LVAVA exon 3 haplotype and a frameshift mutation—are the molecular basis of X-linked high myopia at the MYP1 locus resolved the long-sought genetic identity of this condition.","evidence":"Whole-exome/whole-genome sequencing with Sanger validation and LOD score analysis in myopia families","pmids":["26114493"],"confidence":"Medium","gaps":["Cosegregation shown in limited families; independent replication in large cohorts not yet reported","Mechanism by which opsin defects drive axial elongation was not determined","No functional assay of the LVAVA haplotype's effect on splicing was performed in this study"]},{"year":2016,"claim":"Demonstrating that de novo intrachromosomal gene conversion from OPN1MW to OPN1LW creates pathogenic haplotypes (e.g., LIAVA) that cause exon 3 skipping established the molecular mechanism linking opsin gene rearrangement to Blue Cone Monochromacy.","evidence":"Semi-quantitative minigene splicing assay, long-range PCR and Sanger sequencing with pedigree analysis","pmids":["27339364"],"confidence":"Medium","gaps":["Minigene assay in heterologous system; splicing behavior not confirmed in cone photoreceptors in vivo","Quantitative relationship between residual correctly spliced transcript and photopigment levels not established","Frequency of de novo gene conversion events in the germline not determined"]},{"year":2021,"claim":"Systematic characterization of multiple exon 3 haplotypes unified diverse cone dysfunction phenotypes (Blue Cone Monochromacy, X-linked cone dystrophy) under a single splicing-disruption mechanism driven by unequal recombination between OPN1LW and OPN1MW.","evidence":"Minigene splicing assays across multiple haplotypes combined with molecular genetic analysis","pmids":["34440353"],"confidence":"Medium","gaps":["No structural or biochemical explanation for why specific amino acid combinations disrupt exonic splicing enhancers","In vivo photoreceptor-level confirmation of exon 3 skipping still lacking","Genotype–phenotype correlation for intermediate-skipping haplotypes not resolved"]},{"year":2022,"claim":"Linking exon 3-skipping haplotypes to common refractive error extended the disease relevance of OPN1LW splicing defects beyond rare cone dystrophies to high myopia, proposing that differential photopigment content between adjacent cones generates aberrant contrast signals that drive axial elongation.","evidence":"Long-distance PCR genotyping, association analysis of spherical equivalent refraction with OPN1LW haplotype in males of European ancestry, contrast-reducing spectacle lens trial","pmids":["35741704"],"confidence":"Medium","gaps":["Association study from a single lab; independent replication in diverse populations not reported","Contrast-signal hypothesis for axial elongation remains a model without direct experimental test of the signaling pathway","Whether female carriers with mosaic cone expression also show myopia-related phenotype is unexplored"]},{"year":null,"claim":"Key unresolved questions include: why specific exon 3 codon combinations disrupt exonic splicing enhancers at the RNA/protein level, whether exon 3 skipping occurs in human cone photoreceptors in vivo, and what retinal signaling pathway converts abnormal inter-cone contrast into axial elongation.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or cis-regulatory element mapping explains haplotype-specific splicing disruption","No in vivo photoreceptor transcript data confirming exon 3 skipping in patient tissue","Downstream signaling cascade linking cone contrast abnormalities to scleral remodeling and axial elongation is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["OPN1MW"],"other_free_text":[]},"mechanistic_narrative":"OPN1LW encodes the long-wavelength-sensitive (red) cone opsin, and specific exon 3 haplotypes (e.g., LVAVA, LIAVA) generated by unequal recombination or intrachromosomal gene conversion between OPN1LW and OPN1MW disrupt an exonic splicing code, causing profound exon 3 skipping during pre-mRNA splicing and leaving cones nearly devoid of functional photopigment [PMID:27339364, PMID:34440353]. These splicing-defective haplotypes cause X-linked cone dysfunction disorders including Blue Cone Monochromacy and cone dystrophy, as well as X-linked high myopia (MYP1), with a frameshift mutation (c.617_620dup) in OPN1LW independently identified as causative for high myopia [PMID:26114493, PMID:34440353]. The differential photopigment content between adjacent cones expressing skipping versus non-skipping haplotypes generates abnormal contrast signals that are associated with axial elongation and myopia development [PMID:35741704]."},"prefetch_data":{"uniprot":{"accession":"P04000","full_name":"Long-wave-sensitive opsin 1","aliases":["Red cone photoreceptor pigment","Red-sensitive opsin","ROP"],"length_aa":364,"mass_kda":40.6,"function":"Visual pigments are the light-absorbing molecules that mediate vision. They consist of an apoprotein, opsin, covalently linked to cis-retinal","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P04000/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OPN1LW","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1165,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OPN1LW","total_profiled":1310},"omim":[{"mim_id":"607795","title":"PRE-mRNA-PROCESSING FACTOR 4; PRPF4","url":"https://www.omim.org/entry/607795"},{"mim_id":"312173","title":"RIBOSOMAL PROTEIN L10; RPL10","url":"https://www.omim.org/entry/312173"},{"mim_id":"303900","title":"COLORBLINDNESS, PARTIAL, PROTAN SERIES; CBP","url":"https://www.omim.org/entry/303900"},{"mim_id":"303700","title":"BLUE CONE MONOCHROMACY; BCM","url":"https://www.omim.org/entry/303700"},{"mim_id":"300824","title":"OPN1LW AND OPN1MW GENES, CONTROLLER OF","url":"https://www.omim.org/entry/300824"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"retina","ntpm":237.8}],"url":"https://www.proteinatlas.org/search/OPN1LW"},"hgnc":{"alias_symbol":["COD5"],"prev_symbol":["CBBM","RCP","CBP"]},"alphafold":{"accession":"P04000","domains":[{"cath_id":"1.20.1070.10","chopping":"51-340","consensus_level":"high","plddt":91.1029,"start":51,"end":340}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P04000","model_url":"https://alphafold.ebi.ac.uk/files/AF-P04000-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P04000-F1-predicted_aligned_error_v6.png","plddt_mean":82.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OPN1LW","jax_strain_url":"https://www.jax.org/strain/search?query=OPN1LW"},"sequence":{"accession":"P04000","fasta_url":"https://rest.uniprot.org/uniprotkb/P04000.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P04000/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P04000"}},"corpus_meta":[{"pmid":"8413673","id":"PMC_8413673","title":"Phosphorylated 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33124191","citation_count":48,"is_preprint":false},{"pmid":"26114493","id":"PMC_26114493","title":"Unique Variants in OPN1LW Cause Both Syndromic and Nonsyndromic X-Linked High Myopia Mapped to MYP1.","date":"2015","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/26114493","citation_count":47,"is_preprint":false},{"pmid":"25797267","id":"PMC_25797267","title":"Ku80 cooperates with CBP to promote COX-2 expression and tumor growth.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25797267","citation_count":47,"is_preprint":false},{"pmid":"32042335","id":"PMC_32042335","title":"CBP mediated DOT1L acetylation confers DOT1L stability and promotes cancer metastasis.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32042335","citation_count":44,"is_preprint":false},{"pmid":"16768624","id":"PMC_16768624","title":"Differential role for CBP and p300 CREB-binding domain in motor skill learning.","date":"2006","source":"Behavioral neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16768624","citation_count":44,"is_preprint":false},{"pmid":"30924641","id":"PMC_30924641","title":"Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP.","date":"2019","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30924641","citation_count":43,"is_preprint":false},{"pmid":"23579242","id":"PMC_23579242","title":"CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)-mediated apoptosis.","date":"2013","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/23579242","citation_count":41,"is_preprint":false},{"pmid":"12748286","id":"PMC_12748286","title":"Inhibition of p300/CBP by early B-cell factor.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12748286","citation_count":41,"is_preprint":false},{"pmid":"23745704","id":"PMC_23745704","title":"Role of CGRP-receptor component protein (RCP) in CLR/RAMP function.","date":"2013","source":"Current protein & peptide science","url":"https://pubmed.ncbi.nlm.nih.gov/23745704","citation_count":40,"is_preprint":false},{"pmid":"27332697","id":"PMC_27332697","title":"Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112.","date":"2016","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27332697","citation_count":40,"is_preprint":false},{"pmid":"37276143","id":"PMC_37276143","title":"Discovery of Exceptionally Potent, Selective, and Efficacious PROTAC Degraders of CBP and p300 Proteins.","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37276143","citation_count":39,"is_preprint":false},{"pmid":"11115752","id":"PMC_11115752","title":"Viral replication and the coactivators p300 and CBP.","date":"2000","source":"Trends in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11115752","citation_count":38,"is_preprint":false},{"pmid":"33910019","id":"PMC_33910019","title":"SIRT6-CBP-dependent nuclear Tau accumulation and its role in protein synthesis.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33910019","citation_count":38,"is_preprint":false},{"pmid":"11948408","id":"PMC_11948408","title":"Acetyltransferase machinery conserved in p300/CBP-family proteins.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11948408","citation_count":38,"is_preprint":false},{"pmid":"29531224","id":"PMC_29531224","title":"CoA synthase regulates mitotic fidelity via CBP-mediated acetylation.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29531224","citation_count":37,"is_preprint":false},{"pmid":"30856481","id":"PMC_30856481","title":"CBP/p300 in brain development and plasticity: disentangling the KAT's cradle.","date":"2019","source":"Current opinion in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/30856481","citation_count":32,"is_preprint":false},{"pmid":"32728068","id":"PMC_32728068","title":"Zeb1 for RCP-induced oral cancer cell invasion and its suppression by resveratrol.","date":"2020","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32728068","citation_count":32,"is_preprint":false},{"pmid":"30137413","id":"PMC_30137413","title":"DYRK1A interacts with histone acetyl transferase p300 and CBP and localizes to enhancers.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/30137413","citation_count":32,"is_preprint":false},{"pmid":"35741704","id":"PMC_35741704","title":"Insight from OPN1LW Gene Haplotypes into the Cause and Prevention of Myopia.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35741704","citation_count":30,"is_preprint":false},{"pmid":"26113042","id":"PMC_26113042","title":"The LIM protein Ajuba promotes adipogenesis by enhancing PPARγ and p300/CBP interaction.","date":"2015","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/26113042","citation_count":30,"is_preprint":false},{"pmid":"29173896","id":"PMC_29173896","title":"The aPKC-CBP Pathway Regulates Post-stroke Neurovascular Remodeling and Functional Recovery.","date":"2017","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29173896","citation_count":29,"is_preprint":false},{"pmid":"27339364","id":"PMC_27339364","title":"De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in Blue Cone Monochromacy.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27339364","citation_count":29,"is_preprint":false},{"pmid":"18187554","id":"PMC_18187554","title":"CBP/p300-interacting protein CITED1 modulates parathyroid hormone regulation of osteoblastic differentiation.","date":"2008","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18187554","citation_count":29,"is_preprint":false},{"pmid":"30850733","id":"PMC_30850733","title":"CBP and SRF co-regulate dendritic growth and synaptic maturation.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/30850733","citation_count":28,"is_preprint":false},{"pmid":"10475063","id":"PMC_10475063","title":"The coactivators p300 and CBP have different functions during the differentiation of F9 cells.","date":"1999","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/10475063","citation_count":28,"is_preprint":false},{"pmid":"9459278","id":"PMC_9459278","title":"Prospects of riboflavin carrier protein (RCP) as an antifertility vaccine in male and female mammals.","date":"1997","source":"Human reproduction update","url":"https://pubmed.ncbi.nlm.nih.gov/9459278","citation_count":27,"is_preprint":false},{"pmid":"34440353","id":"PMC_34440353","title":"Intermixing the OPN1LW and OPN1MW Genes Disrupts the Exonic Splicing Code Causing an Array of Vision Disorders.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34440353","citation_count":26,"is_preprint":false},{"pmid":"29700289","id":"PMC_29700289","title":"RCP induces FAK phosphorylation and ovarian cancer cell invasion with inhibition by curcumin.","date":"2018","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29700289","citation_count":26,"is_preprint":false},{"pmid":"27477692","id":"PMC_27477692","title":"CBP/p300 acetyltransferases regulate the expression of NKG2D ligands on tumor cells.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27477692","citation_count":25,"is_preprint":false},{"pmid":"19272189","id":"PMC_19272189","title":"Spatiotemporal expression of histone acetyltransferases, p300 and CBP, in developing embryonic hearts.","date":"2009","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/19272189","citation_count":25,"is_preprint":false},{"pmid":"11097423","id":"PMC_11097423","title":"Insight into the tumor suppressor function of CBP through the viral oncoprotein tax.","date":"2000","source":"Gene expression","url":"https://pubmed.ncbi.nlm.nih.gov/11097423","citation_count":25,"is_preprint":false},{"pmid":"19273299","id":"PMC_19273299","title":"Biochemical characterization of riboflavin carrier protein (RCP) in prostate cancer.","date":"2009","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/19273299","citation_count":25,"is_preprint":false},{"pmid":"31792240","id":"PMC_31792240","title":"Gene activation by dCas9-CBP and the SAM system differ in target preference.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31792240","citation_count":24,"is_preprint":false},{"pmid":"18819102","id":"PMC_18819102","title":"Interleukin-4 activates androgen receptor through CBP/p300.","date":"2009","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/18819102","citation_count":24,"is_preprint":false},{"pmid":"30761451","id":"PMC_30761451","title":"Rab25 and RCP in cancer progression.","date":"2019","source":"Archives of pharmacal research","url":"https://pubmed.ncbi.nlm.nih.gov/30761451","citation_count":23,"is_preprint":false},{"pmid":"33827682","id":"PMC_33827682","title":"The impact of CBP expression in estrogen receptor-positive breast cancer.","date":"2021","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/33827682","citation_count":23,"is_preprint":false},{"pmid":"34663789","id":"PMC_34663789","title":"Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34663789","citation_count":22,"is_preprint":false},{"pmid":"37874694","id":"PMC_37874694","title":"P300/CBP Regulates HIF-1-Dependent Sympathetic Activation and Hypertension by Intermittent Hypoxia.","date":"2024","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37874694","citation_count":22,"is_preprint":false},{"pmid":"31899788","id":"PMC_31899788","title":"USP12 translocation maintains interferon antiviral efficacy by inhibiting CBP acetyltransferase activity.","date":"2020","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/31899788","citation_count":22,"is_preprint":false},{"pmid":"26604986","id":"PMC_26604986","title":"CBP binding outside of promoters and enhancers in Drosophila melanogaster.","date":"2015","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/26604986","citation_count":22,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42210,"output_tokens":1317,"usd":0.073192},"stage2":{"model":"claude-opus-4-6","input_tokens":4300,"output_tokens":1573,"usd":0.091237},"total_usd":0.164429,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about OPN1LW specifically. The vast majority of papers are about CBP (CREBBP/CREB-binding protein), which is a completely different gene. Let me identify the papers that are actually about OPN1LW.\n\nPapers relevant to OPN1LW:\n- PMID 26114493: OPN1LW variants (LVAVA haplotype) cause X-linked high myopia\n- PMID 27339364: OPN1LW/OPN1MW gene conversion mechanisms and splicing defects\n- PMID 35741704: OPN1LW haplotypes and exon-3 skipping associated with myopia\n- PMID 34440353: OPN1LW/OPN1MW exon 3 haplotypes cause exon-skipping and vision disorders\n\nThese papers describe mechanistic findings about OPN1LW splicing and function.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Unique haplotypes in OPN1LW (specifically the LVAVA haplotype) are responsible for X-linked high myopia mapped to MYP1; a frameshift mutation (c.617_620dup, p.Phe208Argfs*51) in OPN1LW was also identified as causative, and the haplotype cosegregated with high myopia in families.\",\n      \"method\": \"Whole-exome sequencing, whole-genome sequencing, Sanger sequencing, long-range PCR, LOD score analysis\",\n      \"journal\": \"Investigative Ophthalmology & Visual Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic segregation with defined molecular variant, single lab with multiple sequencing methods\",\n      \"pmids\": [\"26114493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline can create pathogenic haplotypes (e.g., LIAVA) causing Blue Cone Monochromacy; specific exon 3 haplotypes of OPN1LW/OPN1MW cause aberrant pre-mRNA splicing (exon 3 skipping) resulting in loss of functional photopigment and cone dysfunction.\",\n      \"method\": \"Semi-quantitative minigene splicing assay, long-range PCR, Sanger sequencing, pedigree analysis\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct experimental splicing assay (minigene) combined with pedigree-based gene conversion evidence\",\n      \"pmids\": [\"27339364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Intermixing of OPN1LW and OPN1MW genes through unequal recombination generates exon 3 haplotypes that disrupt the exonic splicing code, causing profound exon 3 skipping during pre-mRNA splicing; cones expressing skipping haplotypes are nearly devoid of photopigment, resulting in an array of vision disorders including Blue Cone Monochromacy and X-linked cone dystrophy.\",\n      \"method\": \"Minigene splicing assay, molecular genetic analysis of haplotypes, review of functional splicing data\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic splicing model supported by experimental minigene data across multiple haplotypes\",\n      \"pmids\": [\"34440353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OPN1LW exon 3 haplotypes that cause profound exon 3 skipping are associated with high myopia; cones expressing skipping haplotypes have abnormally low photopigment content while adjacent cones expressing non-skipping haplotypes have relatively full photopigment, and the resulting abnormal contrast signals between adjacent cones are hypothesized to stimulate axial elongation driving myopia.\",\n      \"method\": \"Long-distance PCR, Sanger sequencing, association analysis of spherical equivalent refraction with OPN1LW haplotype in males of European ancestry, contrast-reducing spectacle lens trial\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic association of defined molecular haplotypes with refractive error plus functional model, single lab\",\n      \"pmids\": [\"35741704\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OPN1LW encodes the long-wavelength-sensitive cone opsin; specific exon 3 haplotypes (e.g., LVAVA, LIAVA) arising from unequal recombination/gene conversion between OPN1LW and OPN1MW disrupt the exonic splicing code, causing profound exon 3 skipping during pre-mRNA splicing that leaves cones nearly devoid of photopigment, leading to cone dysfunction disorders (Blue Cone Monochromacy, X-linked cone dystrophy) and high myopia, with the differential photopigment content between adjacent cones proposed to generate abnormal contrast signals that drive axial elongation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OPN1LW encodes the long-wavelength-sensitive (red) cone opsin, and specific exon 3 haplotypes (e.g., LVAVA, LIAVA) generated by unequal recombination or intrachromosomal gene conversion between OPN1LW and OPN1MW disrupt an exonic splicing code, causing profound exon 3 skipping during pre-mRNA splicing and leaving cones nearly devoid of functional photopigment [PMID:27339364, PMID:34440353]. These splicing-defective haplotypes cause X-linked cone dysfunction disorders including Blue Cone Monochromacy and cone dystrophy, as well as X-linked high myopia (MYP1), with a frameshift mutation (c.617_620dup) in OPN1LW independently identified as causative for high myopia [PMID:26114493, PMID:34440353]. The differential photopigment content between adjacent cones expressing skipping versus non-skipping haplotypes generates abnormal contrast signals that are associated with axial elongation and myopia development [PMID:35741704].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that pathogenic OPN1LW variants—including the LVAVA exon 3 haplotype and a frameshift mutation—are the molecular basis of X-linked high myopia at the MYP1 locus resolved the long-sought genetic identity of this condition.\",\n      \"evidence\": \"Whole-exome/whole-genome sequencing with Sanger validation and LOD score analysis in myopia families\",\n      \"pmids\": [\"26114493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cosegregation shown in limited families; independent replication in large cohorts not yet reported\",\n        \"Mechanism by which opsin defects drive axial elongation was not determined\",\n        \"No functional assay of the LVAVA haplotype's effect on splicing was performed in this study\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that de novo intrachromosomal gene conversion from OPN1MW to OPN1LW creates pathogenic haplotypes (e.g., LIAVA) that cause exon 3 skipping established the molecular mechanism linking opsin gene rearrangement to Blue Cone Monochromacy.\",\n      \"evidence\": \"Semi-quantitative minigene splicing assay, long-range PCR and Sanger sequencing with pedigree analysis\",\n      \"pmids\": [\"27339364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Minigene assay in heterologous system; splicing behavior not confirmed in cone photoreceptors in vivo\",\n        \"Quantitative relationship between residual correctly spliced transcript and photopigment levels not established\",\n        \"Frequency of de novo gene conversion events in the germline not determined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Systematic characterization of multiple exon 3 haplotypes unified diverse cone dysfunction phenotypes (Blue Cone Monochromacy, X-linked cone dystrophy) under a single splicing-disruption mechanism driven by unequal recombination between OPN1LW and OPN1MW.\",\n      \"evidence\": \"Minigene splicing assays across multiple haplotypes combined with molecular genetic analysis\",\n      \"pmids\": [\"34440353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural or biochemical explanation for why specific amino acid combinations disrupt exonic splicing enhancers\",\n        \"In vivo photoreceptor-level confirmation of exon 3 skipping still lacking\",\n        \"Genotype–phenotype correlation for intermediate-skipping haplotypes not resolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking exon 3-skipping haplotypes to common refractive error extended the disease relevance of OPN1LW splicing defects beyond rare cone dystrophies to high myopia, proposing that differential photopigment content between adjacent cones generates aberrant contrast signals that drive axial elongation.\",\n      \"evidence\": \"Long-distance PCR genotyping, association analysis of spherical equivalent refraction with OPN1LW haplotype in males of European ancestry, contrast-reducing spectacle lens trial\",\n      \"pmids\": [\"35741704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Association study from a single lab; independent replication in diverse populations not reported\",\n        \"Contrast-signal hypothesis for axial elongation remains a model without direct experimental test of the signaling pathway\",\n        \"Whether female carriers with mosaic cone expression also show myopia-related phenotype is unexplored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: why specific exon 3 codon combinations disrupt exonic splicing enhancers at the RNA/protein level, whether exon 3 skipping occurs in human cone photoreceptors in vivo, and what retinal signaling pathway converts abnormal inter-cone contrast into axial elongation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural or cis-regulatory element mapping explains haplotype-specific splicing disruption\",\n        \"No in vivo photoreceptor transcript data confirming exon 3 skipping in patient tissue\",\n        \"Downstream signaling cascade linking cone contrast abnormalities to scleral remodeling and axial elongation is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"OPN1MW\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}