{"gene":"RP1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2002,"finding":"Targeted disruption of mouse Rp1 (ortholog of human RP1) causes progressive rod photoreceptor degeneration, morphologically abnormal and progressively shorter outer segments in both rods and cones, and rhodopsin mislocalization to inner segments and cell bodies before photoreceptor cell death, demonstrating that Rp1 is required for normal morphogenesis of photoreceptor outer segments and plays a role in rhodopsin transport.","method":"Targeted gene disruption (knockout mice), light and electron microscopy, immunohistochemistry, electroretinography","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — clean KO mouse with multiple orthogonal readouts (morphology, ERG, immunolocalization), rigorous controls","pmids":["11960024"],"is_preprint":false},{"year":2009,"finding":"RP1 and RP1L1 are both localized to the axoneme of outer segments and connecting cilia in rod photoreceptors. RP1L1 interacts with RP1 in retina pull-down experiments and in transfected cells. Double heterozygotes of Rp1 and Rp1L1 show synergistic defects in outer segment morphology and reduced photosensitivity, indicating RP1 and RP1L1 play essential and synergistic roles in outer segment morphogenesis and photosensitivity.","method":"Immunolocalization, co-immunoprecipitation/pull-down in retina and transfected cells, knockout mouse analysis, electroretinography, single-cell recordings","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal pull-down, double KO epistasis, multiple functional readouts","pmids":["19657028"],"is_preprint":false},{"year":2014,"finding":"A missense mutation L66P in the first doublecortin (DCX) domain of Rp1 causes the mutant protein to partially mislocalize to the transition zone of shortened axonemes (instead of normal axoneme localization) and disrupts colocalization with cytoplasmic microtubules in vitro, leading to progressive photoreceptor degeneration, establishing that the DCX domain of RP1 is critical for its correct localization and microtubule interaction.","method":"Spontaneous mutant mouse characterization, immunohistochemistry, Western blot, in vitro microtubule colocalization assay, OCT imaging, electroretinography","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods linking domain mutation to mislocalization and photoreceptor degeneration","pmids":["25088982"],"is_preprint":false},{"year":2012,"finding":"Expression of wild-type Rp1 protein from a BAC transgene rescues photoreceptor degeneration in Rp1-Q662X knock-in mice (which produce a truncated Rp1 protein and develop outer segment disorganization and progressive degeneration), indicating the truncated Rp1-Q662X protein does not exert a toxic gain-of-function effect. Over-expression of Rp1 from additional transgenic copies also causes retinal degeneration, demonstrating that RP1 protein levels must be carefully controlled.","method":"Knock-in mouse generation, BAC transgenic rescue, histology, electroretinography","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — genetic rescue experiment with knock-in and transgenic mice, multiple readouts","pmids":["22927954"],"is_preprint":false},{"year":2009,"finding":"RP1 mutations causing truncation before the BIF (doublecortin) motif or within the terminal portion result in simple loss of RP1 function producing recessive inheritance, whereas disruption within or immediately after the BIF/DCX domain may produce a protein with a dominant negative effect causing dominant RP, establishing a structure-function relationship for RP1 mutation pathogenicity.","method":"Human genetic analysis with homozygosity mapping, sequencing, and segregation analysis in consanguineous families with recessive RP","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 3 — genetic analysis with segregation data across multiple families; no direct biochemical reconstitution","pmids":["15980210"],"is_preprint":false},{"year":1999,"finding":"The RP1 gene encodes a 2156-amino acid photoreceptor-specific protein; a nonsense mutation (R677X) in this gene co-segregates with autosomal dominant retinitis pigmentosa, and the gene is expressed specifically in photoreceptors.","method":"Positional cloning, subtractive hybridization cDNA library, mutation screening, co-segregation analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — independent identification by two groups (PMIDs 10401003 and 10484783) using orthogonal approaches","pmids":["10401003","10484783"],"is_preprint":false},{"year":2001,"finding":"Clinical analysis of RP1 heterozygotes demonstrates that all dominant disease-causing RP1 alleles identified encode severely truncated proteins (approximately one-third the size of wild-type), consistent with a dominant-negative mechanism rather than haploinsufficiency as the cause of dominant RP.","method":"SSCP mutation screening, direct sequencing, co-segregation analysis, clinical ERG and psychophysics","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 3 — inference from mutation clustering; no direct biochemical test of dominant-negative mechanism","pmids":["11527933"],"is_preprint":false},{"year":2009,"finding":"Compound heterozygosity for two novel frameshift mutations in RP1 (c.5_6delGT and c.4941_4942insT) causes early-onset severe autosomal recessive retinitis pigmentosa, while single heterozygous carriers are unaffected, establishing haploinsufficiency as insufficient to cause RP and confirming that recessive loss-of-function RP1 mutations require biallelic inactivation.","method":"Direct sequencing, co-segregation analysis in pedigree, genotyping of controls","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 3 — genetic segregation analysis; mechanistic inference from mutation type and location","pmids":["19933189"],"is_preprint":false}],"current_model":"RP1 encodes a large photoreceptor-specific protein containing doublecortin (DCX) domains that localizes to the axoneme of photoreceptor outer segments and connecting cilia, where it is essential for normal morphogenesis of outer segments and correct localization of rhodopsin; it interacts physically with RP1L1 (a paralog) to synergistically support outer segment structure and photosensitivity, and its correct protein levels are critical since both loss-of-function (recessive truncations before the DCX domain) and dominant-negative truncated proteins (within or after the DCX/BIF domain) cause retinitis pigmentosa through distinct mechanisms."},"narrative":{"teleology":[{"year":1999,"claim":"Identification of RP1 as a photoreceptor-specific gene whose truncating mutations cause autosomal dominant retinitis pigmentosa established the first causal link between this locus and inherited retinal degeneration.","evidence":"Positional cloning and subtractive hybridization in human retinal cDNA libraries with co-segregation in RP families","pmids":["10401003","10484783"],"confidence":"High","gaps":["Protein function and subcellular localization unknown","Mechanism of disease (haploinsufficiency vs. dominant-negative) not resolved"]},{"year":2001,"claim":"Observation that all dominant RP1 alleles produce severely truncated proteins (~one-third of full-length) argued for a dominant-negative mechanism rather than haploinsufficiency, framing the key mechanistic debate.","evidence":"SSCP and direct sequencing with clinical ERG in dominant RP families","pmids":["11527933"],"confidence":"Medium","gaps":["No biochemical test of dominant-negative activity","Recessive RP1 mutations not yet described"]},{"year":2002,"claim":"Knockout of Rp1 in mice demonstrated that the protein is required for outer segment morphogenesis and rhodopsin localization, defining its core cellular function.","evidence":"Targeted Rp1 disruption in mice with EM, immunohistochemistry, and ERG","pmids":["11960024"],"confidence":"High","gaps":["Molecular mechanism of outer segment disc organization unknown","Direct cytoskeletal interaction not tested"]},{"year":2009,"claim":"Discovery that RP1 and RP1L1 co-localize on the photoreceptor axoneme, physically interact, and synergistically maintain outer segment structure resolved how two related paralogs cooperate in photoreceptor integrity.","evidence":"Co-immunoprecipitation in retinal lysates and transfected cells; double-heterozygote KO mice with ERG and single-cell recordings","pmids":["19657028"],"confidence":"High","gaps":["Stoichiometry and structural basis of RP1–RP1L1 complex unknown","Whether RP1L1 also interacts with microtubules not tested"]},{"year":2009,"claim":"Identification of biallelic RP1 frameshift mutations causing recessive RP — with unaffected heterozygous carriers — resolved the inheritance question by showing that complete loss of function requires two null alleles, while truncation position determines dominant vs. recessive pathogenicity.","evidence":"Segregation analysis and mutation screening in consanguineous families with recessive RP","pmids":["15980210","19933189"],"confidence":"Medium","gaps":["No direct biochemical demonstration that specific truncated proteins exert dominant-negative effects","Threshold of residual function distinguishing dominant from recessive alleles not quantified"]},{"year":2012,"claim":"BAC transgenic rescue of Rp1-Q662X knock-in mice proved the truncated protein is non-toxic (loss-of-function), while overexpression of wild-type Rp1 caused degeneration, establishing that RP1 dosage is tightly regulated.","evidence":"BAC transgenic rescue and copy-number overexpression in knock-in mice with histology and ERG","pmids":["22927954"],"confidence":"High","gaps":["Mechanism by which RP1 overexpression causes degeneration unknown","Whether dosage sensitivity applies to all truncation alleles not tested"]},{"year":2014,"claim":"Characterization of an Rp1 DCX-domain missense mutant (L66P) linked protein mislocalization to the transition zone and loss of microtubule co-localization, establishing the DCX domain as the critical determinant of RP1 axonemal targeting and cytoskeletal association.","evidence":"Spontaneous mutant mouse with immunohistochemistry, in vitro microtubule colocalization assay, OCT, and ERG","pmids":["25088982"],"confidence":"High","gaps":["Direct microtubule-binding affinity not measured biochemically","Whether DCX domains bind specific tubulin post-translational modifications unknown","No structural model of RP1 DCX domains"]},{"year":null,"claim":"The molecular mechanism by which RP1 organizes outer segment disc morphogenesis — including its direct microtubule-binding parameters, regulation of protein turnover, and structural basis of the RP1–RP1L1 interaction — remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No reconstituted biochemical assay for RP1-mediated disc morphogenesis","Structural basis of RP1–RP1L1 complex unknown","Post-translational regulation and turnover mechanisms not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[0,1,5]}],"complexes":[],"partners":["RP1L1"],"other_free_text":[]},"mechanistic_narrative":"RP1 encodes a large, photoreceptor-specific protein essential for the morphogenesis of photoreceptor outer segments and the correct trafficking of rhodopsin. RP1 localizes to the axoneme of outer segments and connecting cilia, where its doublecortin (DCX) domains mediate microtubule interaction and proper subcellular targeting; a DCX-domain missense mutation mislocalizes the protein to the transition zone and disrupts microtubule colocalization [PMID:25088982]. RP1 physically interacts with its paralog RP1L1, and compound heterozygosity at both loci produces synergistic outer segment disorganization and reduced photosensitivity, indicating the two proteins cooperate in axonemal structure [PMID:19657028]. Mutations in RP1 cause retinitis pigmentosa: biallelic loss-of-function truncations cause autosomal recessive RP, whereas truncations within or after the DCX/BIF domain produce dominant-negative proteins causing autosomal dominant RP, and precise RP1 dosage is critical since overexpression also triggers photoreceptor degeneration [PMID:10401003, PMID:15980210, PMID:22927954]."},"prefetch_data":{"uniprot":{"accession":"P56715","full_name":"Oxygen-regulated protein 1","aliases":["Retinitis pigmentosa 1 protein","Retinitis pigmentosa RP1 protein"],"length_aa":2156,"mass_kda":240.7,"function":"Microtubule-associated protein regulating the stability and length of the microtubule-based axoneme of photoreceptors. Required for the differentiation of photoreceptor cells, it plays a role in the organization of the outer segment of rod and cone photoreceptors ensuring the correct orientation and higher-order stacking of outer segment disks along the photoreceptor axoneme (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton, cilium axoneme; Cell projection, cilium, photoreceptor outer segment","url":"https://www.uniprot.org/uniprotkb/P56715/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RP1","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1165,"dependency_fraction":0.007725321888412017},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RP1","total_profiled":1310},"omim":[{"mim_id":"618826","title":"RETINITIS PIGMENTOSA 88; RP88","url":"https://www.omim.org/entry/618826"},{"mim_id":"613731","title":"RETINITIS PIGMENTOSA 4; RP4","url":"https://www.omim.org/entry/613731"},{"mim_id":"613587","title":"OCCULT MACULAR DYSTROPHY; OCMD","url":"https://www.omim.org/entry/613587"},{"mim_id":"612775","title":"CONE-ROD DYSTROPHY 9; CORD9","url":"https://www.omim.org/entry/612775"},{"mim_id":"608581","title":"RP1-LIKE PROTEIN 1; RP1L1","url":"https://www.omim.org/entry/608581"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mid piece","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"retina","ntpm":218.9}],"url":"https://www.proteinatlas.org/search/RP1"},"hgnc":{"alias_symbol":["DCDC4A","ORP1"],"prev_symbol":[]},"alphafold":{"accession":"Q15555","domains":[{"cath_id":"1.10.418.10","chopping":"59-172","consensus_level":"high","plddt":95.1887,"start":59,"end":172},{"cath_id":"1.20.5.1430","chopping":"240-297","consensus_level":"high","plddt":88.6502,"start":240,"end":297}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15555","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15555-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15555-F1-predicted_aligned_error_v6.png","plddt_mean":74.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RP1","jax_strain_url":"https://www.jax.org/strain/search?query=RP1"},"sequence":{"accession":"Q15555","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15555.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15555/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15555"}},"corpus_meta":[{"pmid":"6310527","id":"PMC_6310527","title":"The tetracycline resistance determinants of RP1 and Tn1721: nucleotide sequence analysis.","date":"1983","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/6310527","citation_count":177,"is_preprint":false},{"pmid":"10402435","id":"PMC_10402435","title":"Molecular characterization of the maize Rp1-D rust resistance haplotype and its mutants.","date":"1999","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/10402435","citation_count":162,"is_preprint":false},{"pmid":"1783394","id":"PMC_1783394","title":"Linkage mapping of autosomal dominant retinitis pigmentosa (RP1) to the pericentric region of human chromosome 8.","date":"1991","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1783394","citation_count":149,"is_preprint":false},{"pmid":"120408","id":"PMC_120408","title":"Relationship of group P1 plasmids revealed by heteroduplex experiments: RP1, RP4, R68 and RK2 are identical.","date":"1979","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/120408","citation_count":144,"is_preprint":false},{"pmid":"30347449","id":"PMC_30347449","title":"The fluorescent protein sensor roGFP2-Orp1 monitors in vivo H2 O2 and thiol redox integration and elucidates intracellular H2 O2 dynamics during elicitor-induced oxidative burst in Arabidopsis.","date":"2018","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/30347449","citation_count":138,"is_preprint":false},{"pmid":"15979304","id":"PMC_15979304","title":"Essential roles of IGFBP-3 and IGFBP-rP1 in breast cancer.","date":"2005","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/15979304","citation_count":120,"is_preprint":false},{"pmid":"11333250","id":"PMC_11333250","title":"Recombination between paralogues at the Rp1 rust resistance locus in maize.","date":"2001","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11333250","citation_count":113,"is_preprint":false},{"pmid":"10845615","id":"PMC_10845615","title":"Disease expression of RP1 mutations causing autosomal dominant retinitis pigmentosa.","date":"2000","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/10845615","citation_count":105,"is_preprint":false},{"pmid":"8895665","id":"PMC_8895665","title":"The ORC1 homolog orp1 in fission yeast plays a key role in regulating onset of S phase.","date":"1996","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/8895665","citation_count":102,"is_preprint":false},{"pmid":"11960024","id":"PMC_11960024","title":"Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 (Rp1) gene.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11960024","citation_count":97,"is_preprint":false},{"pmid":"105244","id":"PMC_105244","title":"Regional preference of insertion of Tn501 and Tn802 into RP1 and its derivatives.","date":"1978","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/105244","citation_count":96,"is_preprint":false},{"pmid":"12239417","id":"PMC_12239417","title":"Disease Lesion Mimicry Caused by Mutations in the Rust Resistance Gene rp1.","date":"1996","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/12239417","citation_count":90,"is_preprint":false},{"pmid":"8618924","id":"PMC_8618924","title":"Orp1, a member of the Cdc18/Cdc6 family of S-phase regulators, is homologous to a component of the origin recognition complex.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8618924","citation_count":86,"is_preprint":false},{"pmid":"10490657","id":"PMC_10490657","title":"Association of fission yeast Orp1 and Mcm6 proteins with chromosomal replication origins.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10490657","citation_count":85,"is_preprint":false},{"pmid":"10484783","id":"PMC_10484783","title":"Mutations in the RP1 gene causing autosomal dominant retinitis pigmentosa.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10484783","citation_count":77,"is_preprint":false},{"pmid":"19657028","id":"PMC_19657028","title":"Essential and synergistic roles of RP1 and RP1L1 in rod photoreceptor axoneme and retinitis pigmentosa.","date":"2009","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19657028","citation_count":73,"is_preprint":false},{"pmid":"27208251","id":"PMC_27208251","title":"Maize Homologs of CCoAOMT and HCT, Two Key Enzymes in Lignin Biosynthesis, Form Complexes with the NLR Rp1 Protein to Modulate the Defense Response.","date":"2016","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27208251","citation_count":72,"is_preprint":false},{"pmid":"10820148","id":"PMC_10820148","title":"Distribution of IGFBP-rP1 in normal human tissues.","date":"2000","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/10820148","citation_count":70,"is_preprint":false},{"pmid":"16873698","id":"PMC_16873698","title":"Insulin resistance is associated with increased serum concentration of IGF-binding protein-related protein 1 (IGFBP-rP1/MAC25).","date":"2006","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/16873698","citation_count":66,"is_preprint":false},{"pmid":"10401003","id":"PMC_10401003","title":"A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10401003","citation_count":66,"is_preprint":false},{"pmid":"11527933","id":"PMC_11527933","title":"Clinical features and mutations in patients with dominant retinitis pigmentosa-1 (RP1).","date":"2001","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/11527933","citation_count":64,"is_preprint":false},{"pmid":"17720812","id":"PMC_17720812","title":"Molecular mechanism of oxidative stress perception by the Orp1 protein.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17720812","citation_count":63,"is_preprint":false},{"pmid":"31073122","id":"PMC_31073122","title":"KLF5 regulated lncRNA RP1 promotes the growth and metastasis of breast cancer via repressing p27kip1 translation.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31073122","citation_count":62,"is_preprint":false},{"pmid":"17236181","id":"PMC_17236181","title":"Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) has potential tumour-suppressive activity in human lung cancer.","date":"2007","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/17236181","citation_count":62,"is_preprint":false},{"pmid":"30226619","id":"PMC_30226619","title":"Biological functions and clinical significance of the newly identified long non‑coding RNA RP1‑85F18.6 in colorectal cancer.","date":"2018","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/30226619","citation_count":60,"is_preprint":false},{"pmid":"23717062","id":"PMC_23717062","title":"Ginsenoside Rp1, a Ginsenoside Derivative, Blocks Promoter Activation of iNOS and COX-2 Genes by Suppression of an IKKβ-mediated NF-кB Pathway in HEK293 Cells.","date":"2011","source":"Journal of ginseng research","url":"https://pubmed.ncbi.nlm.nih.gov/23717062","citation_count":59,"is_preprint":false},{"pmid":"29979095","id":"PMC_29979095","title":"Mutations in ORP1 Conferring Oxathiapiprolin Resistance Confirmed by Genome Editing using CRISPR/Cas9 in Phytophthora capsici and P. sojae.","date":"2018","source":"Phytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/29979095","citation_count":55,"is_preprint":false},{"pmid":"16872818","id":"PMC_16872818","title":"Stability of thermostable alkaline protease from Bacillus licheniformis RP1 in commercial solid laundry detergent formulations.","date":"2006","source":"Microbiological research","url":"https://pubmed.ncbi.nlm.nih.gov/16872818","citation_count":55,"is_preprint":false},{"pmid":"12468738","id":"PMC_12468738","title":"Structural analysis of the maize rp1 complex reveals numerous sites and unexpected mechanisms of local rearrangement.","date":"2002","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/12468738","citation_count":54,"is_preprint":false},{"pmid":"21748437","id":"PMC_21748437","title":"Ginsenoside Rp1 from Panax ginseng exhibits anti-cancer activity by down-regulation of the IGF-1R/Akt pathway in breast cancer cells.","date":"2011","source":"Plant foods for human nutrition (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/21748437","citation_count":52,"is_preprint":false},{"pmid":"26373661","id":"PMC_26373661","title":"Maize Homologs of Hydroxycinnamoyltransferase, a Key Enzyme in Lignin Biosynthesis, Bind the Nucleotide Binding Leucine-Rich Repeat Rp1 Proteins to Modulate the Defense Response.","date":"2015","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26373661","citation_count":52,"is_preprint":false},{"pmid":"19933189","id":"PMC_19933189","title":"Compound heterozygosity of two novel truncation mutations in RP1 causing autosomal recessive retinitis pigmentosa.","date":"2009","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/19933189","citation_count":51,"is_preprint":false},{"pmid":"15342531","id":"PMC_15342531","title":"Allelic and haplotypic diversity at the rp1 rust resistance locus of maize.","date":"2004","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15342531","citation_count":50,"is_preprint":false},{"pmid":"15980210","id":"PMC_15980210","title":"Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families.","date":"2005","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/15980210","citation_count":50,"is_preprint":false},{"pmid":"22917891","id":"PMC_22917891","title":"Identification of an RP1 prevalent founder mutation and related phenotype in Spanish patients with early-onset autosomal recessive retinitis.","date":"2012","source":"Ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/22917891","citation_count":49,"is_preprint":false},{"pmid":"23473805","id":"PMC_23473805","title":"Lipid raft modulation by Rp1 reverses multidrug resistance via inactivating MDR-1 and Src inhibition.","date":"2013","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23473805","citation_count":44,"is_preprint":false},{"pmid":"8750886","id":"PMC_8750886","title":"Molecular and cellular analysis of rP1.B in the rat hypothalamus: in situ hybridization and immunohistochemistry of a new P-domain neuropeptide.","date":"1995","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/8750886","citation_count":44,"is_preprint":false},{"pmid":"1095558","id":"PMC_1095558","title":"RP1 properties and fertility inhibition among P, N, W, and X incompatibility group plasmids.","date":"1975","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/1095558","citation_count":43,"is_preprint":false},{"pmid":"22392074","id":"PMC_22392074","title":"IGFBP-rP1 induces p21 expression through a p53-independent pathway, leading to cellular senescence of MCF-7 breast cancer cells.","date":"2012","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22392074","citation_count":42,"is_preprint":false},{"pmid":"12724644","id":"PMC_12724644","title":"Characterization of RP1L1, a highly polymorphic paralog of the retinitis pigmentosa 1 (RP1) gene.","date":"2003","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/12724644","citation_count":41,"is_preprint":false},{"pmid":"11095597","id":"PMC_11095597","title":"RP1 protein truncating mutations predominate at the RP1 adRP locus.","date":"2000","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/11095597","citation_count":40,"is_preprint":false},{"pmid":"9726421","id":"PMC_9726421","title":"Reactivation of the totally inactive pancreatic lipase RP1 by structure-predicted point mutations.","date":"1998","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/9726421","citation_count":40,"is_preprint":false},{"pmid":"23890100","id":"PMC_23890100","title":"Characterization of temperature and light effects on the defense response phenotypes associated with the maize Rp1-D21 autoactive resistance gene.","date":"2013","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/23890100","citation_count":39,"is_preprint":false},{"pmid":"20443026","id":"PMC_20443026","title":"Recombinant Rp1 genes confer necrotic or nonspecific resistance phenotypes.","date":"2010","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/20443026","citation_count":37,"is_preprint":false},{"pmid":"584205","id":"PMC_584205","title":"Transposition of a beta-lactamase locus from RP1 into Pseudomonas putida degradative plasmids.","date":"1977","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/584205","citation_count":36,"is_preprint":false},{"pmid":"22052604","id":"PMC_22052604","title":"RP1 and autosomal dominant rod-cone dystrophy: novel mutations, a review of published variants, and genotype-phenotype correlation.","date":"2011","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/22052604","citation_count":35,"is_preprint":false},{"pmid":"10383131","id":"PMC_10383131","title":"Human prostate cancer expresses the low affinity insulin-like growth factor binding protein IGFBP-rP1.","date":"1999","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10383131","citation_count":35,"is_preprint":false},{"pmid":"6270503","id":"PMC_6270503","title":"Isolation of an Hfr donor of Pseudomonas aeruginosa PAO by insertion of the plasmid RP1 into the tryptophan synthase gene.","date":"1981","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/6270503","citation_count":35,"is_preprint":false},{"pmid":"2559940","id":"PMC_2559940","title":"Location and characterization of two functions on RP1 that inhibit the fertility of the IncW plasmid R388.","date":"1989","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/2559940","citation_count":35,"is_preprint":false},{"pmid":"33107667","id":"PMC_33107667","title":"Maize metacaspases modulate the defense response mediated by the NLR protein Rp1-D21 likely by affecting its subcellular localization.","date":"2020","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33107667","citation_count":34,"is_preprint":false},{"pmid":"18552984","id":"PMC_18552984","title":"Retinitis pigmentosa: mutation analysis of RHO, PRPF31, RP1, and IMPDH1 genes in patients from India.","date":"2008","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/18552984","citation_count":31,"is_preprint":false},{"pmid":"15782636","id":"PMC_15782636","title":"Recombination events generating a novel Rp1 race specificity.","date":"2005","source":"Molecular plant-microbe interactions : MPMI","url":"https://pubmed.ncbi.nlm.nih.gov/15782636","citation_count":31,"is_preprint":false},{"pmid":"30913292","id":"PMC_30913292","title":"Macular Dystrophy and Cone-Rod Dystrophy Caused by Mutations in the RP1 Gene: Extending the RP1 Disease Spectrum.","date":"2019","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/30913292","citation_count":31,"is_preprint":false},{"pmid":"12882812","id":"PMC_12882812","title":"De novo mutation in the RP1 gene (Arg677ter) associated with retinitis pigmentosa.","date":"2003","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/12882812","citation_count":30,"is_preprint":false},{"pmid":"18758081","id":"PMC_18758081","title":"Anti-metastatic potential of ginsenoside Rp1, a novel ginsenoside derivative.","date":"2008","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/18758081","citation_count":30,"is_preprint":false},{"pmid":"25379004","id":"PMC_25379004","title":"Ginsenoside-Rp1-induced apolipoprotein A-1 expression in the LoVo human colon cancer cell line.","date":"2014","source":"Journal of ginseng research","url":"https://pubmed.ncbi.nlm.nih.gov/25379004","citation_count":29,"is_preprint":false},{"pmid":"346555","id":"PMC_346555","title":"Effect of R-plasmid RP1 and nutrient depletion on the gross cellular composition of Escherichia coli and its resistance to some uncoupling phenols.","date":"1978","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/346555","citation_count":29,"is_preprint":false},{"pmid":"25692139","id":"PMC_25692139","title":"Targeted next generation sequencing identifies novel mutations in RP1 as a relatively common cause of autosomal recessive rod-cone dystrophy.","date":"2015","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/25692139","citation_count":29,"is_preprint":false},{"pmid":"26039083","id":"PMC_26039083","title":"Cytoplasmic and Nuclear Localizations Are Important for the Hypersensitive Response Conferred by Maize Autoactive Rp1-D21 Protein.","date":"2015","source":"Molecular plant-microbe interactions : MPMI","url":"https://pubmed.ncbi.nlm.nih.gov/26039083","citation_count":28,"is_preprint":false},{"pmid":"9233623","id":"PMC_9233623","title":"RP1, a new member of the adenomatous polyposis coli-binding EB1-like gene family, is differentially expressed in activated T cells.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9233623","citation_count":28,"is_preprint":false},{"pmid":"9799600","id":"PMC_9799600","title":"Four ubiquitously expressed genes, RD (D6S45)-SKI2W (SKIV2L)-DOM3Z-RP1 (D6S60E), are present between complement component genes factor B and C4 in the class III region of the HLA.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9799600","citation_count":28,"is_preprint":false},{"pmid":"25789970","id":"PMC_25789970","title":"IGFBP-rP1 suppresses epithelial-mesenchymal transition and metastasis in colorectal cancer.","date":"2015","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/25789970","citation_count":27,"is_preprint":false},{"pmid":"22317909","id":"PMC_22317909","title":"RP1 and retinitis pigmentosa: report of novel mutations and insight into mutational mechanism.","date":"2012","source":"The British journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/22317909","citation_count":27,"is_preprint":false},{"pmid":"12481055","id":"PMC_12481055","title":"Comparative sequence analysis of the sorghum Rph region and the maize Rp1 resistance gene complex.","date":"2002","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12481055","citation_count":27,"is_preprint":false},{"pmid":"11317367","id":"PMC_11317367","title":"RP1 in Chinese: Eight novel variants and evidence that truncation of the extreme C-terminal does not cause retinitis pigmentosa.","date":"2001","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/11317367","citation_count":27,"is_preprint":false},{"pmid":"22927954","id":"PMC_22927954","title":"Expression of wild-type Rp1 protein in Rp1 knock-in mice rescues the retinal degeneration phenotype.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22927954","citation_count":26,"is_preprint":false},{"pmid":"30362153","id":"PMC_30362153","title":"Clinical significance of serum DRAM1 mRNA, ARSA mRNA, hsa-miR-2053 and lncRNA-RP1-86D1.3 axis expression in malignant pleural mesothelioma.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30362153","citation_count":25,"is_preprint":false},{"pmid":"32931813","id":"PMC_32931813","title":"RP1, a RAGE antagonist peptide, can improve memory impairment and reduce Aβ plaque load in the APP/PS1 mouse model of Alzheimer's disease.","date":"2020","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32931813","citation_count":23,"is_preprint":false},{"pmid":"20713469","id":"PMC_20713469","title":"Contrasting evolutionary patterns of the Rp1 resistance gene family in different species of Poaceae.","date":"2010","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/20713469","citation_count":23,"is_preprint":false},{"pmid":"2857164","id":"PMC_2857164","title":"Fertility inhibition of RP1 by IncN plasmid pKM101.","date":"1985","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2857164","citation_count":22,"is_preprint":false},{"pmid":"27510606","id":"PMC_27510606","title":"A reverse genetic approach identifies an ancestral frameshift mutation in RP1 causing recessive progressive retinal degeneration in European cattle breeds.","date":"2016","source":"Genetics, selection, evolution : GSE","url":"https://pubmed.ncbi.nlm.nih.gov/27510606","citation_count":22,"is_preprint":false},{"pmid":"12843194","id":"PMC_12843194","title":"Generation of anti-insulin-like growth factor-binding protein-related protein 1 (IGFBP-rP1/MAC25) monoclonal antibodies and immunoassay: quantification of IGFBP-rP1 in human serum and distribution in human fluids and tissues.","date":"2003","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/12843194","citation_count":22,"is_preprint":false},{"pmid":"40627813","id":"PMC_40627813","title":"RP1 Combined With Nivolumab in Advanced Anti-PD-1-Failed Melanoma (IGNYTE).","date":"2025","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40627813","citation_count":21,"is_preprint":false},{"pmid":"30731082","id":"PMC_30731082","title":"The Location of Exon 4 Mutations in RP1 Raises Challenges for Genetic Counseling and Gene Therapy.","date":"2019","source":"American journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/30731082","citation_count":21,"is_preprint":false},{"pmid":"34073704","id":"PMC_34073704","title":"Genotype-Phenotype Correlations in RP1-Associated Retinal Dystrophies: A Multi-Center Cohort Study in JAPAN.","date":"2021","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34073704","citation_count":21,"is_preprint":false},{"pmid":"22321149","id":"PMC_22321149","title":"Elevated expression of angiomodulin (AGM/IGFBP-rP1) in tumor stroma and its roles in fibroblast activation.","date":"2012","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/22321149","citation_count":21,"is_preprint":false},{"pmid":"122523","id":"PMC_122523","title":"Influence of R-plasmid RP1 of Pseudomonas aeruginosa on cell wall composition, drug resistance, and sensitivity to cold shock.","date":"1978","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/122523","citation_count":21,"is_preprint":false},{"pmid":"32151067","id":"PMC_32151067","title":"Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32151067","citation_count":21,"is_preprint":false},{"pmid":"6263862","id":"PMC_6263862","title":"High-frequency chromosome transfer in Rhodopseudomonas sphaeroides promoted by broad-host-range plasmid RP1 carrying mercury transposon Tn501.","date":"1981","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/6263862","citation_count":21,"is_preprint":false},{"pmid":"11864893","id":"PMC_11864893","title":"A novel mutation of the RP1 gene (Lys778ter) associated with autosomal dominant retinitis pigmentosa.","date":"2002","source":"The British journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/11864893","citation_count":20,"is_preprint":false},{"pmid":"20664799","id":"PMC_20664799","title":"Differential pattern of RP1 mutations in retinitis pigmentosa.","date":"2010","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/20664799","citation_count":20,"is_preprint":false},{"pmid":"25883087","id":"PMC_25883087","title":"Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia.","date":"2015","source":"The British journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/25883087","citation_count":20,"is_preprint":false},{"pmid":"32627106","id":"PMC_32627106","title":"Clinical characteristics and high resolution retinal imaging of retinitis pigmentosa caused by RP1 gene variants.","date":"2020","source":"Japanese journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/32627106","citation_count":20,"is_preprint":false},{"pmid":"19145554","id":"PMC_19145554","title":"Ginsenoside Rp1, a ginsenoside derivative, blocks lipopolysaccharide-induced interleukin-1beta production via suppression of the NF-kappaB pathway.","date":"2009","source":"Planta medica","url":"https://pubmed.ncbi.nlm.nih.gov/19145554","citation_count":20,"is_preprint":false},{"pmid":"36869653","id":"PMC_36869653","title":"The maize ZmVPS23-like protein relocates the nucleotide-binding leucine-rich repeat protein Rp1-D21 to endosomes and suppresses the defense response.","date":"2023","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/36869653","citation_count":20,"is_preprint":false},{"pmid":"25494902","id":"PMC_25494902","title":"Novel RP1 mutations and a recurrent BBS1 variant explain the co-existence of two distinct retinal phenotypes in the same pedigree.","date":"2014","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25494902","citation_count":19,"is_preprint":false},{"pmid":"17841051","id":"PMC_17841051","title":"Cell-autonomous recognition of the rust pathogen determines rp1-specified resistance in maize.","date":"1988","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/17841051","citation_count":19,"is_preprint":false},{"pmid":"15305606","id":"PMC_15305606","title":"Aberrant mRNA processing of the maize Rp1-D rust resistance gene in wheat and barley.","date":"2004","source":"Molecular plant-microbe interactions : MPMI","url":"https://pubmed.ncbi.nlm.nih.gov/15305606","citation_count":18,"is_preprint":false},{"pmid":"16597330","id":"PMC_16597330","title":"Three novel and the common Arg677Ter RP1 protein truncating mutations causing autosomal dominant retinitis pigmentosa in a Spanish population.","date":"2006","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16597330","citation_count":18,"is_preprint":false},{"pmid":"31833436","id":"PMC_31833436","title":"Novel homozygous loss-of-function mutations in RP1 and RP1L1 genes in retinitis pigmentosa patients.","date":"2019","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31833436","citation_count":18,"is_preprint":false},{"pmid":"23077400","id":"PMC_23077400","title":"Identification of a novel nonsense mutation in RP1 that causes autosomal recessive retinitis pigmentosa in an Indonesian family.","date":"2012","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/23077400","citation_count":18,"is_preprint":false},{"pmid":"36461309","id":"PMC_36461309","title":"Polysaccharide ORP-1 isolated from Oudemansiella raphanipes ameliorates age-associated intestinal epithelial barrier dysfunction in Caco-2 cells monolayer.","date":"2022","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/36461309","citation_count":17,"is_preprint":false},{"pmid":"32193659","id":"PMC_32193659","title":"A founder Alu insertion in RP1 gene in Japanese patients with retinitis pigmentosa.","date":"2020","source":"Japanese journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/32193659","citation_count":17,"is_preprint":false},{"pmid":"25805314","id":"PMC_25805314","title":"Diversity and evolution of Rp1 rust resistance genes in four maize lines.","date":"2015","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/25805314","citation_count":17,"is_preprint":false},{"pmid":"31079053","id":"PMC_31079053","title":"Expanding the retinal phenotype of RP1: from retinitis pigmentosa to a novel and singular macular dystrophy.","date":"2019","source":"The British journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/31079053","citation_count":17,"is_preprint":false},{"pmid":"6100930","id":"PMC_6100930","title":"Cloning the Tra1 region of RP1.","date":"1980","source":"Plasmid","url":"https://pubmed.ncbi.nlm.nih.gov/6100930","citation_count":17,"is_preprint":false},{"pmid":"25088982","id":"PMC_25088982","title":"A murine RP1 missense mutation causes protein mislocalization and slowly progressive photoreceptor degeneration.","date":"2014","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25088982","citation_count":17,"is_preprint":false},{"pmid":"15828190","id":"PMC_15828190","title":"Characteristics and expression of tetracycline resistance in gram-negative bacteria carrying the Pseudomonas R factor RP1.","date":"1974","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/15828190","citation_count":16,"is_preprint":false},{"pmid":"406354","id":"PMC_406354","title":"Transfer and expression of pseudomonas plasmid RP1 in Caulobacter.","date":"1977","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/406354","citation_count":16,"is_preprint":false},{"pmid":"30027431","id":"PMC_30027431","title":"Clinical and genetic findings of a Japanese patient with RP1-related autosomal recessive retinitis pigmentosa.","date":"2018","source":"Documenta ophthalmologica. Advances in ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/30027431","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50770,"output_tokens":2045,"usd":0.091493},"stage2":{"model":"claude-opus-4-6","input_tokens":5317,"output_tokens":1888,"usd":0.110677},"total_usd":0.20217,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Targeted disruption of mouse Rp1 (ortholog of human RP1) causes progressive rod photoreceptor degeneration, morphologically abnormal and progressively shorter outer segments in both rods and cones, and rhodopsin mislocalization to inner segments and cell bodies before photoreceptor cell death, demonstrating that Rp1 is required for normal morphogenesis of photoreceptor outer segments and plays a role in rhodopsin transport.\",\n      \"method\": \"Targeted gene disruption (knockout mice), light and electron microscopy, immunohistochemistry, electroretinography\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — clean KO mouse with multiple orthogonal readouts (morphology, ERG, immunolocalization), rigorous controls\",\n      \"pmids\": [\"11960024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RP1 and RP1L1 are both localized to the axoneme of outer segments and connecting cilia in rod photoreceptors. RP1L1 interacts with RP1 in retina pull-down experiments and in transfected cells. Double heterozygotes of Rp1 and Rp1L1 show synergistic defects in outer segment morphology and reduced photosensitivity, indicating RP1 and RP1L1 play essential and synergistic roles in outer segment morphogenesis and photosensitivity.\",\n      \"method\": \"Immunolocalization, co-immunoprecipitation/pull-down in retina and transfected cells, knockout mouse analysis, electroretinography, single-cell recordings\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pull-down, double KO epistasis, multiple functional readouts\",\n      \"pmids\": [\"19657028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A missense mutation L66P in the first doublecortin (DCX) domain of Rp1 causes the mutant protein to partially mislocalize to the transition zone of shortened axonemes (instead of normal axoneme localization) and disrupts colocalization with cytoplasmic microtubules in vitro, leading to progressive photoreceptor degeneration, establishing that the DCX domain of RP1 is critical for its correct localization and microtubule interaction.\",\n      \"method\": \"Spontaneous mutant mouse characterization, immunohistochemistry, Western blot, in vitro microtubule colocalization assay, OCT imaging, electroretinography\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking domain mutation to mislocalization and photoreceptor degeneration\",\n      \"pmids\": [\"25088982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Expression of wild-type Rp1 protein from a BAC transgene rescues photoreceptor degeneration in Rp1-Q662X knock-in mice (which produce a truncated Rp1 protein and develop outer segment disorganization and progressive degeneration), indicating the truncated Rp1-Q662X protein does not exert a toxic gain-of-function effect. Over-expression of Rp1 from additional transgenic copies also causes retinal degeneration, demonstrating that RP1 protein levels must be carefully controlled.\",\n      \"method\": \"Knock-in mouse generation, BAC transgenic rescue, histology, electroretinography\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue experiment with knock-in and transgenic mice, multiple readouts\",\n      \"pmids\": [\"22927954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RP1 mutations causing truncation before the BIF (doublecortin) motif or within the terminal portion result in simple loss of RP1 function producing recessive inheritance, whereas disruption within or immediately after the BIF/DCX domain may produce a protein with a dominant negative effect causing dominant RP, establishing a structure-function relationship for RP1 mutation pathogenicity.\",\n      \"method\": \"Human genetic analysis with homozygosity mapping, sequencing, and segregation analysis in consanguineous families with recessive RP\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic analysis with segregation data across multiple families; no direct biochemical reconstitution\",\n      \"pmids\": [\"15980210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The RP1 gene encodes a 2156-amino acid photoreceptor-specific protein; a nonsense mutation (R677X) in this gene co-segregates with autosomal dominant retinitis pigmentosa, and the gene is expressed specifically in photoreceptors.\",\n      \"method\": \"Positional cloning, subtractive hybridization cDNA library, mutation screening, co-segregation analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independent identification by two groups (PMIDs 10401003 and 10484783) using orthogonal approaches\",\n      \"pmids\": [\"10401003\", \"10484783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Clinical analysis of RP1 heterozygotes demonstrates that all dominant disease-causing RP1 alleles identified encode severely truncated proteins (approximately one-third the size of wild-type), consistent with a dominant-negative mechanism rather than haploinsufficiency as the cause of dominant RP.\",\n      \"method\": \"SSCP mutation screening, direct sequencing, co-segregation analysis, clinical ERG and psychophysics\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — inference from mutation clustering; no direct biochemical test of dominant-negative mechanism\",\n      \"pmids\": [\"11527933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Compound heterozygosity for two novel frameshift mutations in RP1 (c.5_6delGT and c.4941_4942insT) causes early-onset severe autosomal recessive retinitis pigmentosa, while single heterozygous carriers are unaffected, establishing haploinsufficiency as insufficient to cause RP and confirming that recessive loss-of-function RP1 mutations require biallelic inactivation.\",\n      \"method\": \"Direct sequencing, co-segregation analysis in pedigree, genotyping of controls\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic segregation analysis; mechanistic inference from mutation type and location\",\n      \"pmids\": [\"19933189\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RP1 encodes a large photoreceptor-specific protein containing doublecortin (DCX) domains that localizes to the axoneme of photoreceptor outer segments and connecting cilia, where it is essential for normal morphogenesis of outer segments and correct localization of rhodopsin; it interacts physically with RP1L1 (a paralog) to synergistically support outer segment structure and photosensitivity, and its correct protein levels are critical since both loss-of-function (recessive truncations before the DCX domain) and dominant-negative truncated proteins (within or after the DCX/BIF domain) cause retinitis pigmentosa through distinct mechanisms.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RP1 encodes a large, photoreceptor-specific protein essential for the morphogenesis of photoreceptor outer segments and the correct trafficking of rhodopsin. RP1 localizes to the axoneme of outer segments and connecting cilia, where its doublecortin (DCX) domains mediate microtubule interaction and proper subcellular targeting; a DCX-domain missense mutation mislocalizes the protein to the transition zone and disrupts microtubule colocalization [PMID:25088982]. RP1 physically interacts with its paralog RP1L1, and compound heterozygosity at both loci produces synergistic outer segment disorganization and reduced photosensitivity, indicating the two proteins cooperate in axonemal structure [PMID:19657028]. Mutations in RP1 cause retinitis pigmentosa: biallelic loss-of-function truncations cause autosomal recessive RP, whereas truncations within or after the DCX/BIF domain produce dominant-negative proteins causing autosomal dominant RP, and precise RP1 dosage is critical since overexpression also triggers photoreceptor degeneration [PMID:10401003, PMID:15980210, PMID:22927954].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of RP1 as a photoreceptor-specific gene whose truncating mutations cause autosomal dominant retinitis pigmentosa established the first causal link between this locus and inherited retinal degeneration.\",\n      \"evidence\": \"Positional cloning and subtractive hybridization in human retinal cDNA libraries with co-segregation in RP families\",\n      \"pmids\": [\"10401003\", \"10484783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Protein function and subcellular localization unknown\",\n        \"Mechanism of disease (haploinsufficiency vs. dominant-negative) not resolved\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Observation that all dominant RP1 alleles produce severely truncated proteins (~one-third of full-length) argued for a dominant-negative mechanism rather than haploinsufficiency, framing the key mechanistic debate.\",\n      \"evidence\": \"SSCP and direct sequencing with clinical ERG in dominant RP families\",\n      \"pmids\": [\"11527933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No biochemical test of dominant-negative activity\",\n        \"Recessive RP1 mutations not yet described\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Knockout of Rp1 in mice demonstrated that the protein is required for outer segment morphogenesis and rhodopsin localization, defining its core cellular function.\",\n      \"evidence\": \"Targeted Rp1 disruption in mice with EM, immunohistochemistry, and ERG\",\n      \"pmids\": [\"11960024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism of outer segment disc organization unknown\",\n        \"Direct cytoskeletal interaction not tested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery that RP1 and RP1L1 co-localize on the photoreceptor axoneme, physically interact, and synergistically maintain outer segment structure resolved how two related paralogs cooperate in photoreceptor integrity.\",\n      \"evidence\": \"Co-immunoprecipitation in retinal lysates and transfected cells; double-heterozygote KO mice with ERG and single-cell recordings\",\n      \"pmids\": [\"19657028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and structural basis of RP1–RP1L1 complex unknown\",\n        \"Whether RP1L1 also interacts with microtubules not tested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of biallelic RP1 frameshift mutations causing recessive RP — with unaffected heterozygous carriers — resolved the inheritance question by showing that complete loss of function requires two null alleles, while truncation position determines dominant vs. recessive pathogenicity.\",\n      \"evidence\": \"Segregation analysis and mutation screening in consanguineous families with recessive RP\",\n      \"pmids\": [\"15980210\", \"19933189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct biochemical demonstration that specific truncated proteins exert dominant-negative effects\",\n        \"Threshold of residual function distinguishing dominant from recessive alleles not quantified\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"BAC transgenic rescue of Rp1-Q662X knock-in mice proved the truncated protein is non-toxic (loss-of-function), while overexpression of wild-type Rp1 caused degeneration, establishing that RP1 dosage is tightly regulated.\",\n      \"evidence\": \"BAC transgenic rescue and copy-number overexpression in knock-in mice with histology and ERG\",\n      \"pmids\": [\"22927954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which RP1 overexpression causes degeneration unknown\",\n        \"Whether dosage sensitivity applies to all truncation alleles not tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterization of an Rp1 DCX-domain missense mutant (L66P) linked protein mislocalization to the transition zone and loss of microtubule co-localization, establishing the DCX domain as the critical determinant of RP1 axonemal targeting and cytoskeletal association.\",\n      \"evidence\": \"Spontaneous mutant mouse with immunohistochemistry, in vitro microtubule colocalization assay, OCT, and ERG\",\n      \"pmids\": [\"25088982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct microtubule-binding affinity not measured biochemically\",\n        \"Whether DCX domains bind specific tubulin post-translational modifications unknown\",\n        \"No structural model of RP1 DCX domains\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which RP1 organizes outer segment disc morphogenesis — including its direct microtubule-binding parameters, regulation of protein turnover, and structural basis of the RP1–RP1L1 interaction — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No reconstituted biochemical assay for RP1-mediated disc morphogenesis\",\n        \"Structural basis of RP1–RP1L1 complex unknown\",\n        \"Post-translational regulation and turnover mechanisms not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RP1L1\"],\n    \"other_free_text\": []\n  }\n}\n```"}