{"gene":"CHM","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2004,"finding":"Crystal structure of REP-1 in complex with monoprenylated or C-terminally truncated Rab7 revealed that Rab7 interacts with the Rab binding platform of REP-1 via Switch 1 and 2 regions; the C terminus of REP-1 functions as a mobile lid covering a conserved hydrophobic patch that coordinates the Rab C terminus in the complex. Using semisynthetic fluorescent Rab27A, Rab27A can be prenylated by REP-2 but this reaction is effectively inhibited by other Rab proteins competing for REP, providing a mechanistic explanation for accumulation of unprenylated Rab27A in choroideremia.","method":"X-ray crystallography (crystal structure of REP-1:Rab7 complex), semisynthetic fluorescent Rab27A prenylation assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by in vitro prenylation assay, published in high-impact peer-reviewed journal","pmids":["15186776"],"is_preprint":false},{"year":1999,"finding":"RabGGTase forms a stable ternary complex with Rab7-REP-1 independent of the lipid substrate geranylgeranyl pyrophosphate, with a Kd of ~120 nM; association rate constant ~10^8 M^-1 s^-1. The nucleotide state of Rab7 (GDP vs GTP) does not influence RabGGTase affinity for the Rab7-REP-1 complex. Rab7 C-terminal truncation or mutation of the last 16 amino acids only modestly reduces RabGGTase binding, demonstrating that RabGGTase recognizes the overall Rab-REP complex structure rather than a C-terminal sequence motif.","method":"Fluorescence binding assays (three independent assays), gel filtration, Rab7 C-terminal mutagenesis","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with quantitative kinetics, multiple orthogonal fluorescence assays, and mutagenesis in a single study","pmids":["10491170"],"is_preprint":false},{"year":1998,"finding":"REP-1 binds the GDP-bound form of Rab7 with higher affinity (Kd=1 nM) than the GTP-bound form (Kd=20 nM); the difference arises from differential dissociation rates (0.012 s^-1 for GDP form vs 0.2 s^-1 for GTP form). The association reaction with Rab7·GDP proceeds in two steps: a fast bimolecular step (k+1 ~10^7 M^-1 s^-1) followed by a slow conformational equilibration.","method":"Fluorescence kinetics using GDP and GTP analogs at the Rab7 active site","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro kinetic assays with fluorescent nucleotide analogs, rigorous mechanistic dissection of on/off rates","pmids":["9563513"],"is_preprint":false},{"year":2001,"finding":"REP-1 can associate with RabGGTase in the absence of Rab protein, and this interaction is dramatically strengthened by the presence of phosphoisoprenoids such as geranylgeranyl pyrophosphate (GGpp); in the presence of GGpp the Kd is ~10 nM, while in its absence affinity is in the micromolar range. Binding of Rab7 to the RabGGTase·GGpp·REP-1 complex occurs without prior dissociation of REP-1, identifying the RabGGTase·GGpp·REP-1 complex as a kinetically competent prenylation intermediate.","method":"Affinity precipitation, gel filtration, fluorescence-based binding assays, kinetic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biochemical methods (affinity precipitation, gel filtration, fluorescence) with quantitative Kd measurements in a single study","pmids":["11675392"],"is_preprint":false},{"year":2001,"finding":"CHM/REP-1 is an essential component of the catalytic geranylgeranyltransferase II (GGTase-II) complex that presents newly synthesized Rab GTPases for post-translational geranylgeranylation; CHM/REP family members are structurally and functionally related to GDI family proteins, forming the GDI/CHM superfamily involved in Rab recycling and membrane targeting.","method":"Biochemical and structural analyses synthesizing existing data; comparative structural analysis","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comprehensive mechanistic synthesis of biochemical and structural data, multiple prior studies integrated, but primarily a review/analysis paper","pmids":["11489211"],"is_preprint":false},{"year":2009,"finding":"siRNA knockdown of REP-1 in human fetal RPE cells did not affect photoreceptor outer segment (POS) internalization but reduced phagosomal acidification and delayed POS protein clearance. REP-1 depletion decreased association of POS-containing phagosomes with late endosomal markers (Rab7, LAMP-1) and increased secretion of MCP-1 and IL-8, indicating REP-1 is required for phagosome-lysosome fusion in RPE cells.","method":"siRNA knockdown in human fetal RPE cells; measurement of phagosomal pH, POS rhodopsin proteolysis, phagosome-endosome co-localization by immunofluorescence, ELISA for cytokine secretion","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean siRNA knockdown with multiple orthogonal functional readouts (pH, proteolysis, co-localization, secretion) in a relevant cell type","pmids":["19741243"],"is_preprint":false},{"year":2009,"finding":"Primary monocytes and fibroblasts from CHM patients with loss-of-function REP-1 mutations showed increased lysosomal pH, reduced rates of proteolytic degradation, and altered secretion of cytokines/growth factors (reduced MCP-1, PEDF, TNF-alpha, FGF-beta, IL-8). Gene expression microarray revealed dysregulation of genes involved in immune response, small GTPase regulation, and exocytosis in CHM patient cells.","method":"Functional assays in patient-derived primary cells: pHrodo bioparticle phagocytosis, fluorescent bead tracking, DQ-ovalbumin proteolysis assay; ELISA for secreted proteins; microarray gene expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in patient-derived cells with 13 CHM patients vs 9 controls, but single lab study","pmids":["20027300"],"is_preprint":false},{"year":2012,"finding":"Lentiviral delivery of CHM/REP-1 cDNA to CHM mouse RPE cells in vivo restored prenylation activity (measured by in vitro prenylation assay) and decreased the amount of unprenylated Rab proteins in CHM mouse RPE, demonstrating functional rescue of the REP-1 prenylation defect.","method":"Lentiviral transduction of mouse RPE (subretinal injection); in vitro prenylation assay; immunoblotting for unprenylated Rabs; immunofluorescence and confocal microscopy","journal":"The journal of gene medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene delivery with functional prenylation assay validation; single lab, multiple methods","pmids":["22228595"],"is_preprint":false},{"year":2008,"finding":"In C. elegans, REP-1 disruption causes a mild defect in synaptic transmission and defecation; genetic epistasis using exocytic Rab mutants showed REP-1 functions specifically in the RAB-27 pathway, not the RAB-3 pathway, for synaptic transmission at neuromuscular junctions. Disruption of REP-1 did not impair RAB-27 in the defecation pathway, and some Rab proteins that did not physically interact with REP-1 had unaffected localization upon REP-1 disruption, demonstrating tissue-specific and Rab-specific requirements for REP-1.","method":"C. elegans genetics: rep-1 mutant analysis, double-mutant epistasis with rab-3 and rab-27 mutants, behavioral assays (synaptic transmission, defecation), co-immunoprecipitation/binding studies","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in C. elegans ortholog with multiple behavioral readouts and binding studies; ortholog study (C. elegans), single lab","pmids":["19090809"],"is_preprint":false},{"year":2017,"finding":"Two independent families with choroideremia carry mutations at position c.-98 (C>A and C>T) in the CHM promoter region. These mutations abolish CHM mRNA and REP-1 protein expression, and abrogated luciferase reporter activity. The CHM promoter was functionally defined as the region encompassing nucleotides c.-119 to c.-76 by luciferase reporter assays.","method":"Whole-genome sequencing, RT-PCR and immunoblot for mRNA/protein absence, luciferase reporter assay with promoter deletion constructs","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assays with multiple constructs plus patient mRNA/protein validation; single lab, two families","pmids":["28271586"],"is_preprint":false},{"year":2022,"finding":"A novel CHM splicing variant causing in-frame skipping of exon 10 produces a shorter REP-1 isoform; molecular modeling of the ternary REP-1/Rab/RGGT complex predicted that this in-frame deletion significantly impairs REP-1/Rab binding without altering REP-1/RGGT interaction, suggesting a potential dominant-negative mechanism by sequestering RGGT away from Rab prenylation.","method":"Exome sequencing, mRNA analysis (RT-PCR), molecular modeling of REP1/Rab/RGGT ternary complex","journal":"Genes","confidence":"Low","confidence_rationale":"Tier 4 / Weak — dominant-negative mechanism is proposed based on computational modeling only; no biochemical validation of REP1 mutant binding or dominant-negative activity was performed","pmids":["35886051"],"is_preprint":false},{"year":2020,"finding":"An SVA retrotransposon insertion in exon 2 of CHM (c.97_98insSVA) causes exon 2 skipping in CHM mRNA (r.50_116del) and results in complete absence of REP-1 protein, establishing SVA insertion as a novel class of loss-of-function mutation mechanism for CHM.","method":"Patient-derived lymphoblastoid cell line; RT-PCR and sequencing of CHM transcript; immunoblot for REP-1 protein","journal":"Ophthalmic genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean molecular characterization at mRNA and protein level from patient-derived cells; single case, single lab","pmids":["32441177"],"is_preprint":false},{"year":1998,"finding":"A nucleotide substitution at the +3 position of the IVS13 splice-donor site (IVS13+3 A>C) in CHM results in complete skipping of exon 13 from REP-1 mRNA, with no normal transcript detectable, creating a premature stop codon.","method":"SSCP from genomic DNA; RT-PCR amplification of lymphocyte-derived mRNA; direct sequencing of aberrant transcript","journal":"Current eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct mRNA analysis demonstrating splice consequence; single patient, single lab, mechanistic outcome clearly established","pmids":["9678418"],"is_preprint":false}],"current_model":"CHM encodes REP-1 (Rab Escort Protein 1), which binds newly synthesized Rab GTPases (preferentially in the GDP-bound state) via their Switch 1/2 regions and presents them to the RabGGTase (GGTase-II) complex for geranylgeranylation; the RabGGTase·GGpp·REP-1 ternary complex is a kinetically competent prenylation intermediate, and after prenylation REP-1 delivers the modified Rab to its target membrane. Loss of REP-1 causes under-prenylation of specific Rab GTPases, impairing vesicular trafficking in RPE cells—particularly phagosome-lysosome fusion and polarized cytokine secretion—leading to progressive degeneration of the RPE, photoreceptors, and choroid in choroideremia."},"narrative":{"mechanistic_narrative":"CHM encodes REP-1 (Rab Escort Protein 1), an essential component of the Rab geranylgeranyltransferase (RabGGTase/GGTase-II) machinery that presents newly synthesized Rab GTPases for post-translational geranylgeranylation [PMID:11489211]. REP-1 captures Rab GTPases through their Switch 1 and Switch 2 regions on a dedicated Rab binding platform, while its mobile C-terminal lid coordinates the Rab C terminus over a conserved hydrophobic patch [PMID:15186776]. REP-1 binds the GDP-bound conformation with substantially higher affinity than the GTP-bound form, driven by differential dissociation rates [PMID:9563513], and then recruits RabGGTase: the enzyme forms a stable ternary complex with the Rab-REP-1 assembly, recognizing the overall complex shape rather than a Rab C-terminal sequence motif [PMID:10491170]. Phosphoisoprenoids such as geranylgeranyl pyrophosphate dramatically strengthen the REP-1·RabGGTase interaction, and Rab can join this RabGGTase·GGpp·REP-1 assembly without REP-1 dissociation, defining a kinetically competent prenylation intermediate [PMID:11675392]. Because Rab proteins compete for limiting REP, loss of REP-1 produces selective under-prenylation of specific Rabs such as Rab27A [PMID:15186776], with Rab- and tissue-specific consequences demonstrated genetically through the RAB-27 pathway [PMID:19090809]. In retinal pigment epithelium, REP-1 depletion impairs phagosome-lysosome fusion—reducing phagosomal acidification, delaying photoreceptor outer-segment clearance, lowering association with late-endosomal markers Rab7 and LAMP-1, and altering cytokine secretion [PMID:19741243, PMID:20027300]. Loss-of-function CHM mutations spanning splice-site defects, promoter mutations, and retrotransposon insertions abolish REP-1 expression and cause choroideremia [PMID:28271586, PMID:32441177, PMID:9678418], and lentiviral re-expression of REP-1 in CHM RPE restores prenylation activity in vivo [PMID:22228595].","teleology":[{"year":1998,"claim":"Established that REP-1 discriminates Rab nucleotide state, answering how it selects substrate Rabs for prenylation by preferentially engaging the GDP-bound form.","evidence":"Fluorescence kinetics with GDP/GTP analogs at the Rab7 active site, resolving on/off rates","pmids":["9563513"],"confidence":"High","gaps":["Tested only with Rab7; nucleotide preference across the broader Rab family not mapped","Does not address how preference impacts in vivo prenylation efficiency"]},{"year":1999,"claim":"Defined how RabGGTase recognizes its substrate, showing the enzyme reads the overall Rab-REP-1 complex rather than a C-terminal motif and binds independent of nucleotide state.","evidence":"Quantitative fluorescence binding assays, gel filtration, and Rab7 C-terminal mutagenesis in vitro","pmids":["10491170"],"confidence":"High","gaps":["Reconstituted with Rab7 only","Does not capture the catalytic transfer step itself"]},{"year":2001,"claim":"Identified the catalytically productive prenylation intermediate, resolving the order of assembly by showing GGpp strengthens REP-1·RabGGTase binding and Rab joins without REP-1 dissociation.","evidence":"Affinity precipitation, gel filtration, and fluorescence kinetics with quantitative Kd measurements","pmids":["11675392"],"confidence":"High","gaps":["Post-prenylation membrane delivery step not biochemically dissected","Single Rab substrate examined"]},{"year":2001,"claim":"Placed REP-1 within the GDI/CHM superfamily and the GGTase-II complex, framing its functional role in Rab recycling and membrane targeting.","evidence":"Comparative structural and biochemical synthesis of existing data (review/analysis)","pmids":["11489211"],"confidence":"Medium","gaps":["Synthesis rather than primary experiment","Functional overlap/distinction with GDI not experimentally resolved here"]},{"year":2004,"claim":"Revealed the structural basis of Rab capture and explained selective Rab27A accumulation in choroideremia through inter-Rab competition for limiting REP.","evidence":"X-ray crystallography of REP-1:Rab7 plus semisynthetic fluorescent Rab27A prenylation assays","pmids":["15186776"],"confidence":"High","gaps":["Structure used Rab7/Rab27A; not all Rab substrates characterized","Cellular consequences of differential competition not directly tested in RPE"]},{"year":2008,"claim":"Demonstrated Rab- and tissue-specific requirements for REP-1 in vivo, showing it acts through the RAB-27 (not RAB-3) pathway for synaptic transmission.","evidence":"C. elegans rep-1 mutant genetics, epistasis with rab-3/rab-27 mutants, behavioral assays, binding studies","pmids":["19090809"],"confidence":"Medium","gaps":["Ortholog system may not fully reflect human Rab specificity","Mechanism of pathway selectivity at molecular level unresolved"]},{"year":2009,"claim":"Connected REP-1 loss to a defined cellular trafficking defect, showing it is required for phagosome-lysosome fusion and proper cytokine secretion in disease-relevant cells.","evidence":"siRNA knockdown in human fetal RPE and functional assays in CHM patient primary cells (pH, proteolysis, co-localization, ELISA, microarray)","pmids":["19741243","20027300"],"confidence":"Medium","gaps":["Which specific under-prenylated Rabs drive each defect not pinpointed","Link from RPE trafficking defect to photoreceptor/choroid degeneration not directly established"]},{"year":2012,"claim":"Provided causal proof that restoring REP-1 corrects the biochemical defect, showing gene delivery rescues prenylation in vivo.","evidence":"Lentiviral CHM/REP-1 delivery to CHM mouse RPE with in vitro prenylation assay and unprenylated-Rab immunoblot","pmids":["22228595"],"confidence":"Medium","gaps":["Biochemical rescue shown; functional/structural retinal rescue not established here","Durability and efficiency of correction not quantified long-term"]},{"year":2017,"claim":"Extended the loss-of-function mutational spectrum to non-coding regulatory defects, defining a functional CHM promoter whose mutation abolishes expression.","evidence":"Whole-genome sequencing, patient mRNA/protein analysis, luciferase reporter assays with promoter constructs","pmids":["28271586"],"confidence":"Medium","gaps":["Single lab, two families","Transcription factors binding the c.-119 to c.-76 region not identified"]},{"year":2020,"claim":"Identified retrotransposon insertion as a novel loss-of-function mechanism, broadening the molecular causes of REP-1 deficiency.","evidence":"Patient lymphoblastoid cells, RT-PCR/sequencing of CHM transcript, REP-1 immunoblot","pmids":["32441177"],"confidence":"Medium","gaps":["Single case","Frequency of such insertions in CHM populations unknown"]},{"year":2022,"claim":"Raised the possibility that some in-frame CHM variants act by a dominant-negative mechanism rather than simple loss of expression.","evidence":"Exome sequencing, mRNA analysis, and molecular modeling of the REP-1/Rab/RGGT ternary complex","pmids":["35886051"],"confidence":"Low","gaps":["Dominant-negative mechanism inferred from modeling only; no biochemical validation of mutant binding or sequestration","Cellular dominant-negative activity not tested"]},{"year":null,"claim":"How loss of REP-1-dependent prenylation in RPE mechanistically propagates to progressive photoreceptor and choroidal degeneration remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["The full set of Rab substrates whose under-prenylation drives disease is not defined","Causal chain from RPE trafficking failure to photoreceptor/choroid loss not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,6]}],"complexes":["RabGGTase (GGTase-II) complex"],"partners":["RABGGTA","RABGGTB","RAB7A","RAB27A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P24386","full_name":"Rab proteins geranylgeranyltransferase component A 1","aliases":["Choroideremia protein","Rab escort protein 1","REP-1","TCD protein"],"length_aa":653,"mass_kda":73.5,"function":"Substrate-binding subunit of the Rab geranylgeranyltransferase (GGTase) complex. Binds unprenylated Rab proteins and presents the substrate peptide to the catalytic component B composed of RABGGTA and RABGGTB, and remains bound to it after the geranylgeranyl transfer reaction. The component A is thought to be regenerated by transferring its prenylated Rab back to the donor membrane. Besides, a pre-formed complex consisting of CHM and the Rab GGTase dimer (RGGT or component B) can bind to and prenylate Rab proteins; this alternative pathway is proposed to be the predominant pathway for Rab protein geranylgeranylation","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/P24386/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHM","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000188419","cell_line_id":"CID000076","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":2},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"RABGGTA","stoichiometry":4.0},{"gene":"RAB5C","stoichiometry":0.2},{"gene":"RAB12","stoichiometry":0.2},{"gene":"RAB35","stoichiometry":0.2},{"gene":"DYNC1H1","stoichiometry":0.2},{"gene":"RAB14","stoichiometry":0.2},{"gene":"RAB10","stoichiometry":0.2},{"gene":"RAB5B","stoichiometry":0.2},{"gene":"RAB7A","stoichiometry":0.2},{"gene":"VDAC3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000076","total_profiled":1310},"omim":[{"mim_id":"620367","title":"PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 8; PFBMFT8","url":"https://www.omim.org/entry/620367"},{"mim_id":"618697","title":"RETINITIS PIGMENTOSA 87 WITH CHOROIDAL INVOLVEMENT; RP87","url":"https://www.omim.org/entry/618697"},{"mim_id":"614293","title":"HYDATIDIFORM MOLE, RECURRENT, 2; HYDM2","url":"https://www.omim.org/entry/614293"},{"mim_id":"611687","title":"KHDC3-LIKE PROTEIN, SUBCORTICAL MATERNAL COMPLEX MEMBER; KHDC3L","url":"https://www.omim.org/entry/611687"},{"mim_id":"607444","title":"SBDS RIBOSOME MATURATION FACTOR; SBDS","url":"https://www.omim.org/entry/607444"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CHM"},"hgnc":{"alias_symbol":["REP-1"],"prev_symbol":["TCD","DXS540"]},"alphafold":{"accession":"P24386","domains":[{"cath_id":"3.50.50.60","chopping":"9-94_379-449_559-599","consensus_level":"medium","plddt":93.4932,"start":9,"end":599}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P24386","model_url":"https://alphafold.ebi.ac.uk/files/AF-P24386-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P24386-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHM","jax_strain_url":"https://www.jax.org/strain/search?query=CHM"},"sequence":{"accession":"P24386","fasta_url":"https://rest.uniprot.org/uniprotkb/P24386.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P24386/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P24386"}},"corpus_meta":[{"pmid":"26670617","id":"PMC_26670617","title":"Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.","date":"2015","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26670617","citation_count":376,"is_preprint":false},{"pmid":"20977531","id":"PMC_20977531","title":"Practice standards for transcranial Doppler (TCD) ultrasound. 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A Case Report.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35886051","citation_count":5,"is_preprint":false},{"pmid":"33584532","id":"PMC_33584532","title":"Enhanced Hemodynamic and Clinical Response to αCGRP in Migraine Patients-A TCD Study.","date":"2021","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33584532","citation_count":5,"is_preprint":false},{"pmid":"14597336","id":"PMC_14597336","title":"Noradrenergic constriction of cerebral arteries as detected by transcranial Doppler (TCD) in the rabbit.","date":"2003","source":"Ultrasound in medicine & biology","url":"https://pubmed.ncbi.nlm.nih.gov/14597336","citation_count":5,"is_preprint":false},{"pmid":"36947020","id":"PMC_36947020","title":"TCD screening and spending among children with sickle cell anemia.","date":"2023","source":"The American journal of managed care","url":"https://pubmed.ncbi.nlm.nih.gov/36947020","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50205,"output_tokens":3748,"usd":0.103417,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11361,"output_tokens":3607,"usd":0.07349,"stage2_stop_reason":"end_turn"},"total_usd":0.176907,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of REP-1 in complex with monoprenylated or C-terminally truncated Rab7 revealed that Rab7 interacts with the Rab binding platform of REP-1 via Switch 1 and 2 regions; the C terminus of REP-1 functions as a mobile lid covering a conserved hydrophobic patch that coordinates the Rab C terminus in the complex. Using semisynthetic fluorescent Rab27A, Rab27A can be prenylated by REP-2 but this reaction is effectively inhibited by other Rab proteins competing for REP, providing a mechanistic explanation for accumulation of unprenylated Rab27A in choroideremia.\",\n      \"method\": \"X-ray crystallography (crystal structure of REP-1:Rab7 complex), semisynthetic fluorescent Rab27A prenylation assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by in vitro prenylation assay, published in high-impact peer-reviewed journal\",\n      \"pmids\": [\"15186776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RabGGTase forms a stable ternary complex with Rab7-REP-1 independent of the lipid substrate geranylgeranyl pyrophosphate, with a Kd of ~120 nM; association rate constant ~10^8 M^-1 s^-1. The nucleotide state of Rab7 (GDP vs GTP) does not influence RabGGTase affinity for the Rab7-REP-1 complex. Rab7 C-terminal truncation or mutation of the last 16 amino acids only modestly reduces RabGGTase binding, demonstrating that RabGGTase recognizes the overall Rab-REP complex structure rather than a C-terminal sequence motif.\",\n      \"method\": \"Fluorescence binding assays (three independent assays), gel filtration, Rab7 C-terminal mutagenesis\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with quantitative kinetics, multiple orthogonal fluorescence assays, and mutagenesis in a single study\",\n      \"pmids\": [\"10491170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"REP-1 binds the GDP-bound form of Rab7 with higher affinity (Kd=1 nM) than the GTP-bound form (Kd=20 nM); the difference arises from differential dissociation rates (0.012 s^-1 for GDP form vs 0.2 s^-1 for GTP form). The association reaction with Rab7·GDP proceeds in two steps: a fast bimolecular step (k+1 ~10^7 M^-1 s^-1) followed by a slow conformational equilibration.\",\n      \"method\": \"Fluorescence kinetics using GDP and GTP analogs at the Rab7 active site\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro kinetic assays with fluorescent nucleotide analogs, rigorous mechanistic dissection of on/off rates\",\n      \"pmids\": [\"9563513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"REP-1 can associate with RabGGTase in the absence of Rab protein, and this interaction is dramatically strengthened by the presence of phosphoisoprenoids such as geranylgeranyl pyrophosphate (GGpp); in the presence of GGpp the Kd is ~10 nM, while in its absence affinity is in the micromolar range. Binding of Rab7 to the RabGGTase·GGpp·REP-1 complex occurs without prior dissociation of REP-1, identifying the RabGGTase·GGpp·REP-1 complex as a kinetically competent prenylation intermediate.\",\n      \"method\": \"Affinity precipitation, gel filtration, fluorescence-based binding assays, kinetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biochemical methods (affinity precipitation, gel filtration, fluorescence) with quantitative Kd measurements in a single study\",\n      \"pmids\": [\"11675392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CHM/REP-1 is an essential component of the catalytic geranylgeranyltransferase II (GGTase-II) complex that presents newly synthesized Rab GTPases for post-translational geranylgeranylation; CHM/REP family members are structurally and functionally related to GDI family proteins, forming the GDI/CHM superfamily involved in Rab recycling and membrane targeting.\",\n      \"method\": \"Biochemical and structural analyses synthesizing existing data; comparative structural analysis\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comprehensive mechanistic synthesis of biochemical and structural data, multiple prior studies integrated, but primarily a review/analysis paper\",\n      \"pmids\": [\"11489211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"siRNA knockdown of REP-1 in human fetal RPE cells did not affect photoreceptor outer segment (POS) internalization but reduced phagosomal acidification and delayed POS protein clearance. REP-1 depletion decreased association of POS-containing phagosomes with late endosomal markers (Rab7, LAMP-1) and increased secretion of MCP-1 and IL-8, indicating REP-1 is required for phagosome-lysosome fusion in RPE cells.\",\n      \"method\": \"siRNA knockdown in human fetal RPE cells; measurement of phagosomal pH, POS rhodopsin proteolysis, phagosome-endosome co-localization by immunofluorescence, ELISA for cytokine secretion\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean siRNA knockdown with multiple orthogonal functional readouts (pH, proteolysis, co-localization, secretion) in a relevant cell type\",\n      \"pmids\": [\"19741243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Primary monocytes and fibroblasts from CHM patients with loss-of-function REP-1 mutations showed increased lysosomal pH, reduced rates of proteolytic degradation, and altered secretion of cytokines/growth factors (reduced MCP-1, PEDF, TNF-alpha, FGF-beta, IL-8). Gene expression microarray revealed dysregulation of genes involved in immune response, small GTPase regulation, and exocytosis in CHM patient cells.\",\n      \"method\": \"Functional assays in patient-derived primary cells: pHrodo bioparticle phagocytosis, fluorescent bead tracking, DQ-ovalbumin proteolysis assay; ELISA for secreted proteins; microarray gene expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in patient-derived cells with 13 CHM patients vs 9 controls, but single lab study\",\n      \"pmids\": [\"20027300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Lentiviral delivery of CHM/REP-1 cDNA to CHM mouse RPE cells in vivo restored prenylation activity (measured by in vitro prenylation assay) and decreased the amount of unprenylated Rab proteins in CHM mouse RPE, demonstrating functional rescue of the REP-1 prenylation defect.\",\n      \"method\": \"Lentiviral transduction of mouse RPE (subretinal injection); in vitro prenylation assay; immunoblotting for unprenylated Rabs; immunofluorescence and confocal microscopy\",\n      \"journal\": \"The journal of gene medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene delivery with functional prenylation assay validation; single lab, multiple methods\",\n      \"pmids\": [\"22228595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In C. elegans, REP-1 disruption causes a mild defect in synaptic transmission and defecation; genetic epistasis using exocytic Rab mutants showed REP-1 functions specifically in the RAB-27 pathway, not the RAB-3 pathway, for synaptic transmission at neuromuscular junctions. Disruption of REP-1 did not impair RAB-27 in the defecation pathway, and some Rab proteins that did not physically interact with REP-1 had unaffected localization upon REP-1 disruption, demonstrating tissue-specific and Rab-specific requirements for REP-1.\",\n      \"method\": \"C. elegans genetics: rep-1 mutant analysis, double-mutant epistasis with rab-3 and rab-27 mutants, behavioral assays (synaptic transmission, defecation), co-immunoprecipitation/binding studies\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in C. elegans ortholog with multiple behavioral readouts and binding studies; ortholog study (C. elegans), single lab\",\n      \"pmids\": [\"19090809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Two independent families with choroideremia carry mutations at position c.-98 (C>A and C>T) in the CHM promoter region. These mutations abolish CHM mRNA and REP-1 protein expression, and abrogated luciferase reporter activity. The CHM promoter was functionally defined as the region encompassing nucleotides c.-119 to c.-76 by luciferase reporter assays.\",\n      \"method\": \"Whole-genome sequencing, RT-PCR and immunoblot for mRNA/protein absence, luciferase reporter assay with promoter deletion constructs\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter assays with multiple constructs plus patient mRNA/protein validation; single lab, two families\",\n      \"pmids\": [\"28271586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A novel CHM splicing variant causing in-frame skipping of exon 10 produces a shorter REP-1 isoform; molecular modeling of the ternary REP-1/Rab/RGGT complex predicted that this in-frame deletion significantly impairs REP-1/Rab binding without altering REP-1/RGGT interaction, suggesting a potential dominant-negative mechanism by sequestering RGGT away from Rab prenylation.\",\n      \"method\": \"Exome sequencing, mRNA analysis (RT-PCR), molecular modeling of REP1/Rab/RGGT ternary complex\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — dominant-negative mechanism is proposed based on computational modeling only; no biochemical validation of REP1 mutant binding or dominant-negative activity was performed\",\n      \"pmids\": [\"35886051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"An SVA retrotransposon insertion in exon 2 of CHM (c.97_98insSVA) causes exon 2 skipping in CHM mRNA (r.50_116del) and results in complete absence of REP-1 protein, establishing SVA insertion as a novel class of loss-of-function mutation mechanism for CHM.\",\n      \"method\": \"Patient-derived lymphoblastoid cell line; RT-PCR and sequencing of CHM transcript; immunoblot for REP-1 protein\",\n      \"journal\": \"Ophthalmic genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean molecular characterization at mRNA and protein level from patient-derived cells; single case, single lab\",\n      \"pmids\": [\"32441177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A nucleotide substitution at the +3 position of the IVS13 splice-donor site (IVS13+3 A>C) in CHM results in complete skipping of exon 13 from REP-1 mRNA, with no normal transcript detectable, creating a premature stop codon.\",\n      \"method\": \"SSCP from genomic DNA; RT-PCR amplification of lymphocyte-derived mRNA; direct sequencing of aberrant transcript\",\n      \"journal\": \"Current eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct mRNA analysis demonstrating splice consequence; single patient, single lab, mechanistic outcome clearly established\",\n      \"pmids\": [\"9678418\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHM encodes REP-1 (Rab Escort Protein 1), which binds newly synthesized Rab GTPases (preferentially in the GDP-bound state) via their Switch 1/2 regions and presents them to the RabGGTase (GGTase-II) complex for geranylgeranylation; the RabGGTase·GGpp·REP-1 ternary complex is a kinetically competent prenylation intermediate, and after prenylation REP-1 delivers the modified Rab to its target membrane. Loss of REP-1 causes under-prenylation of specific Rab GTPases, impairing vesicular trafficking in RPE cells—particularly phagosome-lysosome fusion and polarized cytokine secretion—leading to progressive degeneration of the RPE, photoreceptors, and choroid in choroideremia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHM encodes REP-1 (Rab Escort Protein 1), an essential component of the Rab geranylgeranyltransferase (RabGGTase/GGTase-II) machinery that presents newly synthesized Rab GTPases for post-translational geranylgeranylation [#4]. REP-1 captures Rab GTPases through their Switch 1 and Switch 2 regions on a dedicated Rab binding platform, while its mobile C-terminal lid coordinates the Rab C terminus over a conserved hydrophobic patch [#0]. REP-1 binds the GDP-bound conformation with substantially higher affinity than the GTP-bound form, driven by differential dissociation rates [#2], and then recruits RabGGTase: the enzyme forms a stable ternary complex with the Rab-REP-1 assembly, recognizing the overall complex shape rather than a Rab C-terminal sequence motif [#1]. Phosphoisoprenoids such as geranylgeranyl pyrophosphate dramatically strengthen the REP-1\\u00b7RabGGTase interaction, and Rab can join this RabGGTase\\u00b7GGpp\\u00b7REP-1 assembly without REP-1 dissociation, defining a kinetically competent prenylation intermediate [#3]. Because Rab proteins compete for limiting REP, loss of REP-1 produces selective under-prenylation of specific Rabs such as Rab27A [#0], with Rab- and tissue-specific consequences demonstrated genetically through the RAB-27 pathway [#8]. In retinal pigment epithelium, REP-1 depletion impairs phagosome-lysosome fusion\\u2014reducing phagosomal acidification, delaying photoreceptor outer-segment clearance, lowering association with late-endosomal markers Rab7 and LAMP-1, and altering cytokine secretion [#5, #6]. Loss-of-function CHM mutations spanning splice-site defects, promoter mutations, and retrotransposon insertions abolish REP-1 expression and cause choroideremia [#9, #11, #12], and lentiviral re-expression of REP-1 in CHM RPE restores prenylation activity in vivo [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that REP-1 discriminates Rab nucleotide state, answering how it selects substrate Rabs for prenylation by preferentially engaging the GDP-bound form.\",\n      \"evidence\": \"Fluorescence kinetics with GDP/GTP analogs at the Rab7 active site, resolving on/off rates\",\n      \"pmids\": [\"9563513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tested only with Rab7; nucleotide preference across the broader Rab family not mapped\", \"Does not address how preference impacts in vivo prenylation efficiency\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined how RabGGTase recognizes its substrate, showing the enzyme reads the overall Rab-REP-1 complex rather than a C-terminal motif and binds independent of nucleotide state.\",\n      \"evidence\": \"Quantitative fluorescence binding assays, gel filtration, and Rab7 C-terminal mutagenesis in vitro\",\n      \"pmids\": [\"10491170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconstituted with Rab7 only\", \"Does not capture the catalytic transfer step itself\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the catalytically productive prenylation intermediate, resolving the order of assembly by showing GGpp strengthens REP-1\\u00b7RabGGTase binding and Rab joins without REP-1 dissociation.\",\n      \"evidence\": \"Affinity precipitation, gel filtration, and fluorescence kinetics with quantitative Kd measurements\",\n      \"pmids\": [\"11675392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-prenylation membrane delivery step not biochemically dissected\", \"Single Rab substrate examined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Placed REP-1 within the GDI/CHM superfamily and the GGTase-II complex, framing its functional role in Rab recycling and membrane targeting.\",\n      \"evidence\": \"Comparative structural and biochemical synthesis of existing data (review/analysis)\",\n      \"pmids\": [\"11489211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Synthesis rather than primary experiment\", \"Functional overlap/distinction with GDI not experimentally resolved here\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed the structural basis of Rab capture and explained selective Rab27A accumulation in choroideremia through inter-Rab competition for limiting REP.\",\n      \"evidence\": \"X-ray crystallography of REP-1:Rab7 plus semisynthetic fluorescent Rab27A prenylation assays\",\n      \"pmids\": [\"15186776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure used Rab7/Rab27A; not all Rab substrates characterized\", \"Cellular consequences of differential competition not directly tested in RPE\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated Rab- and tissue-specific requirements for REP-1 in vivo, showing it acts through the RAB-27 (not RAB-3) pathway for synaptic transmission.\",\n      \"evidence\": \"C. elegans rep-1 mutant genetics, epistasis with rab-3/rab-27 mutants, behavioral assays, binding studies\",\n      \"pmids\": [\"19090809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog system may not fully reflect human Rab specificity\", \"Mechanism of pathway selectivity at molecular level unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected REP-1 loss to a defined cellular trafficking defect, showing it is required for phagosome-lysosome fusion and proper cytokine secretion in disease-relevant cells.\",\n      \"evidence\": \"siRNA knockdown in human fetal RPE and functional assays in CHM patient primary cells (pH, proteolysis, co-localization, ELISA, microarray)\",\n      \"pmids\": [\"19741243\", \"20027300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which specific under-prenylated Rabs drive each defect not pinpointed\", \"Link from RPE trafficking defect to photoreceptor/choroid degeneration not directly established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided causal proof that restoring REP-1 corrects the biochemical defect, showing gene delivery rescues prenylation in vivo.\",\n      \"evidence\": \"Lentiviral CHM/REP-1 delivery to CHM mouse RPE with in vitro prenylation assay and unprenylated-Rab immunoblot\",\n      \"pmids\": [\"22228595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical rescue shown; functional/structural retinal rescue not established here\", \"Durability and efficiency of correction not quantified long-term\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the loss-of-function mutational spectrum to non-coding regulatory defects, defining a functional CHM promoter whose mutation abolishes expression.\",\n      \"evidence\": \"Whole-genome sequencing, patient mRNA/protein analysis, luciferase reporter assays with promoter constructs\",\n      \"pmids\": [\"28271586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, two families\", \"Transcription factors binding the c.-119 to c.-76 region not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified retrotransposon insertion as a novel loss-of-function mechanism, broadening the molecular causes of REP-1 deficiency.\",\n      \"evidence\": \"Patient lymphoblastoid cells, RT-PCR/sequencing of CHM transcript, REP-1 immunoblot\",\n      \"pmids\": [\"32441177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case\", \"Frequency of such insertions in CHM populations unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Raised the possibility that some in-frame CHM variants act by a dominant-negative mechanism rather than simple loss of expression.\",\n      \"evidence\": \"Exome sequencing, mRNA analysis, and molecular modeling of the REP-1/Rab/RGGT ternary complex\",\n      \"pmids\": [\"35886051\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Dominant-negative mechanism inferred from modeling only; no biochemical validation of mutant binding or sequestration\", \"Cellular dominant-negative activity not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How loss of REP-1-dependent prenylation in RPE mechanistically propagates to progressive photoreceptor and choroidal degeneration remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"The full set of Rab substrates whose under-prenylation drives disease is not defined\", \"Causal chain from RPE trafficking failure to photoreceptor/choroid loss not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\"RabGGTase (GGTase-II) complex\"],\n    \"partners\": [\"RABGGTA\", \"RABGGTB\", \"RAB7A\", \"RAB27A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}