{"gene":"LRMDA","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2013,"finding":"C10orf11 (LRMDA/OCA7) is expressed in melanoblasts and melanocytes in human fetal tissue but not in retinal pigment epithelial cells, as shown by immunohistochemistry. Knockdown of the zebrafish homolog with morpholinos caused substantially decreased pigmentation and reduction in pigmented melanocytes; this phenotype was rescued by wild-type C10orf11 but not by mutant C10orf11, establishing C10orf11 as a melanocyte-differentiation gene required for pigmentation.","method":"Immunohistochemistry (localization in human fetal tissue), morpholino knockdown in zebrafish with wild-type vs. mutant rescue","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence plus morpholino knockdown with mutant-rescue validation; multiple orthogonal methods in a single focused study","pmids":["23395477"],"is_preprint":false},{"year":2008,"finding":"The Ciona intestinalis ortholog of C10orf11 (Ci-C10orf11), which encodes a leucine-rich repeat protein, acts upstream of or parallel to beta-catenin in the canonical Wnt/beta-catenin signaling pathway; morpholino knockdown suppressed beta-catenin downstream gene expression and endoderm formation, and defects were rescued by constitutively active but not wild-type Ci-beta-catenin, with dosage-sensitive genetic interactions between Ci-C10orf11 and Ci-beta-catenin demonstrated.","method":"Morpholino loss-of-function screening, downstream gene expression assay, epistasis rescue with constitutively active beta-catenin, dosage-sensitive interaction analysis in Ciona embryos","journal":"Development, growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple orthogonal readouts in a single lab, but in an invertebrate (Ciona) whose functional relevance to the mammalian protein is not independently validated","pmids":["18336583"],"is_preprint":false},{"year":2022,"finding":"OCA7 (LRMDA) localizes to the limiting membrane of melanosomes via interaction with a canonical effector-binding surface of Rab32 and Rab38. In OCA7-KO MNT1 melanocytes, overall melanin levels are reduced, PMEL processing and fibrillation are impaired (blocking stage I to stage II melanosome transition), and melanosome lumen pH is lower than in controls, establishing OCA7 as a regulator of early melanosome biogenesis.","method":"Immunofluorescence/subcellular fractionation for localization; Co-IP/pulldown with Rab32/Rab38; CRISPR KO (OCA7-KO MNT1 cells) with melanin quantification, PMEL processing assay, and pH measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells with multiple orthogonal mechanistic readouts (localization, binding partner identification, PMEL processing, organelle pH), single rigorous study with comprehensive methodology","pmids":["36334630"],"is_preprint":false},{"year":2022,"finding":"LRMDA is downstream of the TRPV2 Ca2+ channel in myeloid cells: TRPV2 knockout downregulates Lrmda expression in bone marrow-derived dendritic cells (BMDCs) and macrophages. Knockdown of Lrmda reduces cell membrane tension and mobility and inhibits viral (HSV-1, VSV) infection in wild-type but not TRPV2-KO BMDCs. Reconstitution of LRMDA into TRPV2-KO BMDCs partially restores membrane tension/mobility and viral penetration, placing LRMDA downstream of TRPV2-mediated Ca2+ influx in controlling membrane dynamics.","method":"Conditional TRPV2 KO mice (LyZ2-Cre;Trpv2fl/fl), siRNA knockdown of Lrmda, LRMDA reconstitution into KO cells, cell membrane tension/mobility assays, viral infection assays in BMDCs/BMDMs","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO, KD, reconstitution) with defined cellular readouts (membrane tension, viral infection) establishing pathway position","pmids":["36261399"],"is_preprint":false},{"year":2025,"finding":"LRMDA is a Commander complex binding protein that simultaneously associates with Commander and active RAB32, forming a RAB32-LRMDA-Commander assembly that is mutually exclusive with the SNX17-Commander assembly. LRMDA and SNX17 share a common mechanism of Commander association. In human melanocytes, RAB32-LRMDA-Commander is essential for melanosome biogenesis and pigmentation via a distinct pathway from SNX17-Commander. OCA7-causative LRMDA mutations uncouple RAB32 and Commander binding, explaining the molecular basis of the disease.","method":"Unbiased proteomics, recombinant protein reconstitution, computational modelling, functional analysis in human melanocytes with KO/KD, co-IP binding assays with mutant LRMDA variants","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — recombinant reconstitution plus proteomics plus mutagenesis plus functional melanocyte analysis; multiple orthogonal methods in single rigorous study with mechanistic disease link","pmids":["41038817"],"is_preprint":false},{"year":2025,"finding":"LRMDA directly and cooperatively interacts with the endolysosome-specific small GTPase Rab32 and the endosomal recycling complex Retriever (equivalent to the Commander complex) in innate immune cells. Loss of LRMDA in CD11c+ mucosal dendritic cells and macrophages (but not non-hematopoietic cells) increases susceptibility to DSS-induced colitis and impairs clearance of Listeria monocytogenes, establishing the Rab32-LRMDA-Retriever complex as a critical regulator of endolysosomal trafficking for intestinal immune homeostasis.","method":"ENU forward genetic screen, CRISPR/Cas9 validation, hematopoietic chimera, conditional knockouts (CD11c-specific), proteomics, co-IP/biochemical interaction assays, DSS colitis model, Listeria infection assay","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (forward genetics, CRISPR validation, conditional KO, proteomics, biochemical interaction, two in vivo functional assays) in a single comprehensive study","pmids":["40791432"],"is_preprint":true},{"year":2009,"finding":"C10orf11 is disrupted by a balanced translocation breakpoint at 10q22 in a mentally retarded patient, and the gene lies within the commonly deleted interval of overlapping 10q22 deletions in three patients with cognitive defects, suggesting that haploinsufficiency of C10orf11 contributes to cognitive defects in 10q22 deletion patients. The gene is described as brain-expressed.","method":"Array comparative genomic hybridization, array painting breakpoint analysis, expression data from public databases","journal":"European journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — chromosomal mapping/deletion analysis without direct functional experiment on LRMDA protein; single study, inferential","pmids":["19844253"],"is_preprint":false}],"current_model":"LRMDA (OCA7/C10orf11) is a leucine-rich repeat melanosome membrane protein that simultaneously binds active RAB32 and the Commander/Retriever endosomal recycling complex, forming a RAB32-LRMDA-Commander assembly distinct from the SNX17-Commander assembly; this complex is essential for melanosome biogenesis by controlling PMEL processing, stage I-to-II melanosome transition, and organelle pH, and OCA7-causative mutations disrupt RAB32–Commander binding to cause hypopigmentation; in myeloid cells, LRMDA additionally functions downstream of TRPV2-mediated Ca2+ influx to regulate cell membrane tension and endolysosomal trafficking in dendritic cells and macrophages, supporting intestinal immune homeostasis."},"narrative":{"mechanistic_narrative":"LRMDA (OCA7/C10orf11) is a leucine-rich repeat protein required for melanocyte differentiation and pigmentation, identified through its expression in melanoblasts and melanocytes and the loss of pigmentation upon ortholog knockdown that is rescued only by wild-type protein [PMID:23395477]. At the molecular level, LRMDA localizes to the limiting membrane of melanosomes by engaging the canonical effector-binding surface of RAB32/RAB38, and its loss impairs PMEL processing and fibrillation, blocks the stage I-to-II melanosome transition, and lowers melanosome lumen pH, defining LRMDA as a regulator of early melanosome biogenesis [PMID:36334630]. LRMDA acts as an adaptor that simultaneously binds active RAB32 and the Commander/Retriever endosomal recycling complex, forming a RAB32-LRMDA-Commander assembly that is mutually exclusive with the SNX17-Commander assembly and drives pigmentation through a pathway distinct from SNX17; OCA7-causative mutations uncouple RAB32 from Commander binding, providing the molecular basis of the disease [PMID:41038817]. Beyond melanocytes, LRMDA functions in myeloid cells downstream of TRPV2-mediated Ca2+ influx to control cell membrane tension, mobility, and endolysosomal trafficking, where the RAB32-LRMDA-Retriever complex supports intestinal immune homeostasis and pathogen clearance [PMID:36261399, PMID:40791432].","teleology":[{"year":2008,"claim":"Established a developmental signaling context for the gene by placing the C10orf11 ortholog within canonical Wnt/beta-catenin signaling.","evidence":"Morpholino loss-of-function with epistasis rescue by constitutively active beta-catenin and dosage-sensitive genetic interaction in Ciona embryos","pmids":["18336583"],"confidence":"Medium","gaps":["Relevance of Wnt/beta-catenin link to the mammalian protein not independently validated","No biochemical mechanism connecting the protein to beta-catenin","Invertebrate system"]},{"year":2013,"claim":"Defined the gene as a melanocyte-differentiation factor required for pigmentation, answering whether it has a cell-autonomous role in melanocytes.","evidence":"Immunohistochemistry in human fetal tissue plus morpholino knockdown in zebrafish with wild-type vs mutant rescue","pmids":["23395477"],"confidence":"High","gaps":["No molecular mechanism or binding partner identified","Subcellular site of action within melanocytes unresolved"]},{"year":2022,"claim":"Localized the protein to the melanosome membrane via RAB32/RAB38 binding and showed it controls early melanosome maturation, identifying its first physical partners and organelle-level functions.","evidence":"Immunofluorescence/fractionation, Co-IP/pulldown with Rab32/Rab38, and CRISPR KO MNT1 melanocytes with melanin, PMEL processing, and pH readouts","pmids":["36334630"],"confidence":"High","gaps":["Downstream effector machinery recruited by LRMDA not yet identified","Mechanism linking RAB32 binding to PMEL processing and pH control unresolved"]},{"year":2022,"claim":"Extended LRMDA function beyond melanocytes by placing it downstream of TRPV2 Ca2+ signaling in myeloid cells controlling membrane dynamics.","evidence":"Conditional TRPV2 KO mice, siRNA knockdown, LRMDA reconstitution, and membrane tension/mobility and viral infection assays in BMDCs/BMDMs","pmids":["36261399"],"confidence":"High","gaps":["Molecular mechanism by which LRMDA alters membrane tension not defined","How Ca2+ influx regulates LRMDA function unresolved"]},{"year":2025,"claim":"Resolved LRMDA as a Commander/Retriever adaptor that bridges active RAB32 to the complex, defining the molecular basis of OCA7 disease mutations.","evidence":"Unbiased proteomics, recombinant reconstitution, computational modelling, and functional/Co-IP analysis with mutant LRMDA in human melanocytes","pmids":["41038817"],"confidence":"High","gaps":["Structural basis of the RAB32-LRMDA-Commander assembly not solved","Cargo recycled by this pathway not enumerated"]},{"year":2025,"claim":"Demonstrated the RAB32-LRMDA-Retriever complex is required in mucosal myeloid cells for intestinal immune homeostasis and pathogen clearance.","evidence":"ENU forward genetic screen, CRISPR validation, CD11c-conditional KO, proteomics, biochemical interaction, DSS colitis and Listeria infection models (preprint)","pmids":["40791432"],"confidence":"High","gaps":["Preprint, not peer-reviewed","Endolysosomal cargo controlled in immune cells not identified"]},{"year":null,"claim":"How the same RAB32-LRMDA-Commander/Retriever module is differentially deployed in melanosome biogenesis versus immune-cell endolysosomal trafficking, and the structural and cargo-level details of the assembly, remain open.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of the assembly","Cargo recycled by the complex not defined","Connection between cognitive 10q22 deletion phenotype and protein function uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,2]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2]}],"complexes":["Commander/Retriever complex"],"partners":["RAB32","RAB38","COMMANDER","RETRIEVER","SNX17","TRPV2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H2I8","full_name":"Leucine-rich melanocyte differentiation-associated protein","aliases":[],"length_aa":198,"mass_kda":22.6,"function":"Required for melanocyte differentiation","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9H2I8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRMDA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRMDA","total_profiled":1310},"omim":[{"mim_id":"615179","title":"ALBINISM, OCULOCUTANEOUS, TYPE VII; OCA7","url":"https://www.omim.org/entry/615179"},{"mim_id":"614537","title":"LEUCINE-RICH MELANOCYTE DIFFERENTIATION-ASSOCIATED PROTEIN; LRMDA","url":"https://www.omim.org/entry/614537"},{"mim_id":"203100","title":"ALBINISM, OCULOCUTANEOUS, TYPE IA; OCA1A","url":"https://www.omim.org/entry/203100"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adrenal gland","ntpm":61.5}],"url":"https://www.proteinatlas.org/search/LRMDA"},"hgnc":{"alias_symbol":["CDA017","OCA7"],"prev_symbol":["C10orf11"]},"alphafold":{"accession":"Q9H2I8","domains":[{"cath_id":"3.80.10.10","chopping":"5-138","consensus_level":"high","plddt":86.9719,"start":5,"end":138}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2I8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2I8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2I8-F1-predicted_aligned_error_v6.png","plddt_mean":78.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRMDA","jax_strain_url":"https://www.jax.org/strain/search?query=LRMDA"},"sequence":{"accession":"Q9H2I8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H2I8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H2I8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2I8"}},"corpus_meta":[{"pmid":"24066960","id":"PMC_24066960","title":"Increasing the complexity: 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health traits","date":"2024-12-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.19.629410","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19657,"output_tokens":2339,"usd":0.047028,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9478,"output_tokens":2479,"usd":0.054683,"stage2_stop_reason":"end_turn"},"total_usd":0.101711,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"C10orf11 (LRMDA/OCA7) is expressed in melanoblasts and melanocytes in human fetal tissue but not in retinal pigment epithelial cells, as shown by immunohistochemistry. Knockdown of the zebrafish homolog with morpholinos caused substantially decreased pigmentation and reduction in pigmented melanocytes; this phenotype was rescued by wild-type C10orf11 but not by mutant C10orf11, establishing C10orf11 as a melanocyte-differentiation gene required for pigmentation.\",\n      \"method\": \"Immunohistochemistry (localization in human fetal tissue), morpholino knockdown in zebrafish with wild-type vs. mutant rescue\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence plus morpholino knockdown with mutant-rescue validation; multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"23395477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The Ciona intestinalis ortholog of C10orf11 (Ci-C10orf11), which encodes a leucine-rich repeat protein, acts upstream of or parallel to beta-catenin in the canonical Wnt/beta-catenin signaling pathway; morpholino knockdown suppressed beta-catenin downstream gene expression and endoderm formation, and defects were rescued by constitutively active but not wild-type Ci-beta-catenin, with dosage-sensitive genetic interactions between Ci-C10orf11 and Ci-beta-catenin demonstrated.\",\n      \"method\": \"Morpholino loss-of-function screening, downstream gene expression assay, epistasis rescue with constitutively active beta-catenin, dosage-sensitive interaction analysis in Ciona embryos\",\n      \"journal\": \"Development, growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple orthogonal readouts in a single lab, but in an invertebrate (Ciona) whose functional relevance to the mammalian protein is not independently validated\",\n      \"pmids\": [\"18336583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OCA7 (LRMDA) localizes to the limiting membrane of melanosomes via interaction with a canonical effector-binding surface of Rab32 and Rab38. In OCA7-KO MNT1 melanocytes, overall melanin levels are reduced, PMEL processing and fibrillation are impaired (blocking stage I to stage II melanosome transition), and melanosome lumen pH is lower than in controls, establishing OCA7 as a regulator of early melanosome biogenesis.\",\n      \"method\": \"Immunofluorescence/subcellular fractionation for localization; Co-IP/pulldown with Rab32/Rab38; CRISPR KO (OCA7-KO MNT1 cells) with melanin quantification, PMEL processing assay, and pH measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells with multiple orthogonal mechanistic readouts (localization, binding partner identification, PMEL processing, organelle pH), single rigorous study with comprehensive methodology\",\n      \"pmids\": [\"36334630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LRMDA is downstream of the TRPV2 Ca2+ channel in myeloid cells: TRPV2 knockout downregulates Lrmda expression in bone marrow-derived dendritic cells (BMDCs) and macrophages. Knockdown of Lrmda reduces cell membrane tension and mobility and inhibits viral (HSV-1, VSV) infection in wild-type but not TRPV2-KO BMDCs. Reconstitution of LRMDA into TRPV2-KO BMDCs partially restores membrane tension/mobility and viral penetration, placing LRMDA downstream of TRPV2-mediated Ca2+ influx in controlling membrane dynamics.\",\n      \"method\": \"Conditional TRPV2 KO mice (LyZ2-Cre;Trpv2fl/fl), siRNA knockdown of Lrmda, LRMDA reconstitution into KO cells, cell membrane tension/mobility assays, viral infection assays in BMDCs/BMDMs\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO, KD, reconstitution) with defined cellular readouts (membrane tension, viral infection) establishing pathway position\",\n      \"pmids\": [\"36261399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRMDA is a Commander complex binding protein that simultaneously associates with Commander and active RAB32, forming a RAB32-LRMDA-Commander assembly that is mutually exclusive with the SNX17-Commander assembly. LRMDA and SNX17 share a common mechanism of Commander association. In human melanocytes, RAB32-LRMDA-Commander is essential for melanosome biogenesis and pigmentation via a distinct pathway from SNX17-Commander. OCA7-causative LRMDA mutations uncouple RAB32 and Commander binding, explaining the molecular basis of the disease.\",\n      \"method\": \"Unbiased proteomics, recombinant protein reconstitution, computational modelling, functional analysis in human melanocytes with KO/KD, co-IP binding assays with mutant LRMDA variants\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — recombinant reconstitution plus proteomics plus mutagenesis plus functional melanocyte analysis; multiple orthogonal methods in single rigorous study with mechanistic disease link\",\n      \"pmids\": [\"41038817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRMDA directly and cooperatively interacts with the endolysosome-specific small GTPase Rab32 and the endosomal recycling complex Retriever (equivalent to the Commander complex) in innate immune cells. Loss of LRMDA in CD11c+ mucosal dendritic cells and macrophages (but not non-hematopoietic cells) increases susceptibility to DSS-induced colitis and impairs clearance of Listeria monocytogenes, establishing the Rab32-LRMDA-Retriever complex as a critical regulator of endolysosomal trafficking for intestinal immune homeostasis.\",\n      \"method\": \"ENU forward genetic screen, CRISPR/Cas9 validation, hematopoietic chimera, conditional knockouts (CD11c-specific), proteomics, co-IP/biochemical interaction assays, DSS colitis model, Listeria infection assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (forward genetics, CRISPR validation, conditional KO, proteomics, biochemical interaction, two in vivo functional assays) in a single comprehensive study\",\n      \"pmids\": [\"40791432\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C10orf11 is disrupted by a balanced translocation breakpoint at 10q22 in a mentally retarded patient, and the gene lies within the commonly deleted interval of overlapping 10q22 deletions in three patients with cognitive defects, suggesting that haploinsufficiency of C10orf11 contributes to cognitive defects in 10q22 deletion patients. The gene is described as brain-expressed.\",\n      \"method\": \"Array comparative genomic hybridization, array painting breakpoint analysis, expression data from public databases\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — chromosomal mapping/deletion analysis without direct functional experiment on LRMDA protein; single study, inferential\",\n      \"pmids\": [\"19844253\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRMDA (OCA7/C10orf11) is a leucine-rich repeat melanosome membrane protein that simultaneously binds active RAB32 and the Commander/Retriever endosomal recycling complex, forming a RAB32-LRMDA-Commander assembly distinct from the SNX17-Commander assembly; this complex is essential for melanosome biogenesis by controlling PMEL processing, stage I-to-II melanosome transition, and organelle pH, and OCA7-causative mutations disrupt RAB32–Commander binding to cause hypopigmentation; in myeloid cells, LRMDA additionally functions downstream of TRPV2-mediated Ca2+ influx to regulate cell membrane tension and endolysosomal trafficking in dendritic cells and macrophages, supporting intestinal immune homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRMDA (OCA7/C10orf11) is a leucine-rich repeat protein required for melanocyte differentiation and pigmentation, identified through its expression in melanoblasts and melanocytes and the loss of pigmentation upon ortholog knockdown that is rescued only by wild-type protein [#0]. At the molecular level, LRMDA localizes to the limiting membrane of melanosomes by engaging the canonical effector-binding surface of RAB32/RAB38, and its loss impairs PMEL processing and fibrillation, blocks the stage I-to-II melanosome transition, and lowers melanosome lumen pH, defining LRMDA as a regulator of early melanosome biogenesis [#2]. LRMDA acts as an adaptor that simultaneously binds active RAB32 and the Commander/Retriever endosomal recycling complex, forming a RAB32-LRMDA-Commander assembly that is mutually exclusive with the SNX17-Commander assembly and drives pigmentation through a pathway distinct from SNX17; OCA7-causative mutations uncouple RAB32 from Commander binding, providing the molecular basis of the disease [#4]. Beyond melanocytes, LRMDA functions in myeloid cells downstream of TRPV2-mediated Ca2+ influx to control cell membrane tension, mobility, and endolysosomal trafficking, where the RAB32-LRMDA-Retriever complex supports intestinal immune homeostasis and pathogen clearance [#3, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established a developmental signaling context for the gene by placing the C10orf11 ortholog within canonical Wnt/beta-catenin signaling.\",\n      \"evidence\": \"Morpholino loss-of-function with epistasis rescue by constitutively active beta-catenin and dosage-sensitive genetic interaction in Ciona embryos\",\n      \"pmids\": [\"18336583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance of Wnt/beta-catenin link to the mammalian protein not independently validated\", \"No biochemical mechanism connecting the protein to beta-catenin\", \"Invertebrate system\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the gene as a melanocyte-differentiation factor required for pigmentation, answering whether it has a cell-autonomous role in melanocytes.\",\n      \"evidence\": \"Immunohistochemistry in human fetal tissue plus morpholino knockdown in zebrafish with wild-type vs mutant rescue\",\n      \"pmids\": [\"23395477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular mechanism or binding partner identified\", \"Subcellular site of action within melanocytes unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Localized the protein to the melanosome membrane via RAB32/RAB38 binding and showed it controls early melanosome maturation, identifying its first physical partners and organelle-level functions.\",\n      \"evidence\": \"Immunofluorescence/fractionation, Co-IP/pulldown with Rab32/Rab38, and CRISPR KO MNT1 melanocytes with melanin, PMEL processing, and pH readouts\",\n      \"pmids\": [\"36334630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector machinery recruited by LRMDA not yet identified\", \"Mechanism linking RAB32 binding to PMEL processing and pH control unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended LRMDA function beyond melanocytes by placing it downstream of TRPV2 Ca2+ signaling in myeloid cells controlling membrane dynamics.\",\n      \"evidence\": \"Conditional TRPV2 KO mice, siRNA knockdown, LRMDA reconstitution, and membrane tension/mobility and viral infection assays in BMDCs/BMDMs\",\n      \"pmids\": [\"36261399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which LRMDA alters membrane tension not defined\", \"How Ca2+ influx regulates LRMDA function unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved LRMDA as a Commander/Retriever adaptor that bridges active RAB32 to the complex, defining the molecular basis of OCA7 disease mutations.\",\n      \"evidence\": \"Unbiased proteomics, recombinant reconstitution, computational modelling, and functional/Co-IP analysis with mutant LRMDA in human melanocytes\",\n      \"pmids\": [\"41038817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the RAB32-LRMDA-Commander assembly not solved\", \"Cargo recycled by this pathway not enumerated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated the RAB32-LRMDA-Retriever complex is required in mucosal myeloid cells for intestinal immune homeostasis and pathogen clearance.\",\n      \"evidence\": \"ENU forward genetic screen, CRISPR validation, CD11c-conditional KO, proteomics, biochemical interaction, DSS colitis and Listeria infection models (preprint)\",\n      \"pmids\": [\"40791432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Endolysosomal cargo controlled in immune cells not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same RAB32-LRMDA-Commander/Retriever module is differentially deployed in melanosome biogenesis versus immune-cell endolysosomal trafficking, and the structural and cargo-level details of the assembly, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the assembly\", \"Cargo recycled by the complex not defined\", \"Connection between cognitive 10q22 deletion phenotype and protein function uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"Commander/Retriever complex\"],\n    \"partners\": [\"RAB32\", \"RAB38\", \"Commander\", \"Retriever\", \"SNX17\", \"TRPV2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}