{"gene":"LRMDA","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2013,"finding":"C10orf11 (LRMDA) encodes a leucine-rich repeat protein expressed in melanoblasts and melanocytes (but not retinal pigment epithelium) in human fetal tissue; knockdown of the zebrafish homolog with morpholinos caused substantially decreased pigmentation and reduced number of pigmented melanocytes, a phenotype rescued by wild-type but not mutant C10orf11, establishing it as a melanocyte-differentiation gene required for pigmentation.","method":"Immunohistochemistry (human fetal tissue), morpholino knockdown in zebrafish with wild-type and mutant rescue","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (IHC localization, morpholino KD, mutant rescue) in a single study; foundational gene-function paper","pmids":["23395477"],"is_preprint":false},{"year":2008,"finding":"The Ciona intestinalis ortholog of C10orf11 (Ci-C10orf11), encoding a leucine-rich repeat protein, acts upstream of or parallel to beta-catenin in the canonical Wnt/beta-catenin signaling pathway during early embryogenesis; morpholino knockdown suppressed beta-catenin target gene expression and endoderm formation, rescued only by constitutively active (not wild-type) beta-catenin.","method":"Morpholino loss-of-function screen in Ciona; epistasis analysis with constitutively active beta-catenin rescue; dosage-sensitive interaction assays","journal":"Development, growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with multiple readouts in a single lab; ortholog context consistent with mammalian LRMDA","pmids":["18336583"],"is_preprint":false},{"year":2022,"finding":"OCA7 (C10orf11/LRMDA) localizes to the limiting membrane of melanosomes via interaction with Rab32 and Rab38 through a canonical effector-binding surface; loss of OCA7 in MNT1 cells impairs melanosome maturation, disrupts PMEL processing and fibrillation (stage I-to-II transition), and reduces melanosome lumen pH, collectively decreasing melanin levels.","method":"Fluorescence localization (live imaging and immunofluorescence), OCA7-KO cell line generation, pulldown with Rab32/Rab38, PMEL processing assays, pH measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — KO cells with multiple orthogonal mechanistic readouts (localization, Rab interaction, PMEL processing, organelle pH) in one study","pmids":["36334630"],"is_preprint":false},{"year":2022,"finding":"TRPV2-mediated Ca2+ influx in myeloid cells upregulates Lrmda expression; Lrmda knockdown reduces cell membrane tension and mobility and inhibits viral (HSV-1, VSV) penetration and infection, while LRMDA complementation in TRPV2-KO dendritic cells partially restores membrane tension/mobility and viral penetration, placing LRMDA downstream of Ca2+ in the TRPV2-Ca2+-LRMDA axis controlling viral entry.","method":"TRPV2 conditional knockout mice, shRNA knockdown of Lrmda, LRMDA reconstitution, membrane tension/mobility assays, viral infection assays in BMDCs/BMDMs","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO, KD, reconstitution, functional assays) establishing pathway position and cellular function","pmids":["36261399"],"is_preprint":false},{"year":2025,"finding":"LRMDA is a component of a RAB32-LRMDA-Commander membrane trafficking complex; LRMDA simultaneously binds active RAB32 and the endosomal Commander assembly through a mechanism shared with SNX17 (but mutually exclusive with SNX17-Commander), and this complex is essential for melanosome biogenesis and pigmentation. OCA7-causing LRMDA mutations uncouple RAB32 binding from Commander binding, establishing the molecular mechanism of disease.","method":"Unbiased proteomics, recombinant protein reconstitution, co-immunoprecipitation, computational modelling, functional analysis in human melanocytes, OCA7 patient mutation analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — reconstitution + proteomics + mutagenesis + functional validation in melanocytes; mechanistic basis of OCA7 established","pmids":["41038817"],"is_preprint":false},{"year":2025,"finding":"LRMDA functions primarily in CD11c+ innate immune cells (mucosal dendritic cells and macrophages) to regulate endolysosomal trafficking; LRMDA directly and cooperatively interacts with Rab32 and the endosomal recycling complex Retriever. Loss of LRMDA increases susceptibility to DSS-induced colitis and impairs clearance of Listeria monocytogenes, establishing the Rab32-LRMDA-Retriever complex as a critical regulator of intestinal immune homeostasis.","method":"ENU forward genetic screen, CRISPR/Cas9 validation, hematopoietic chimeras, conditional knockouts, proteomic/biochemical interaction analyses, DSS colitis model, Listeria infection assay","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1-2 — forward genetic screen validated by CRISPR KO, biochemical interaction studies, and multiple in vivo functional readouts","pmids":["40791432"],"is_preprint":true}],"current_model":"LRMDA (C10orf11/OCA7) is a leucine-rich repeat melanosome membrane protein that simultaneously binds active RAB32 and the endosomal Commander recycling complex, forming a RAB32-LRMDA-Commander assembly that is essential for melanosome biogenesis and pigmentation by regulating PMEL processing, organelle pH, and stage I-to-II melanosome transition; in myeloid innate immune cells LRMDA additionally functions downstream of TRPV2-mediated Ca2+ influx to regulate membrane tension and viral entry, and interacts with Rab32 and the Retriever complex to control endolysosomal trafficking required for intestinal immune homeostasis."},"narrative":{"teleology":[{"year":2008,"claim":"Before any mammalian function was known, epistasis analysis in Ciona intestinalis established that the LRMDA ortholog acts upstream of or parallel to β-catenin in canonical Wnt signaling during early embryogenesis, providing the first evidence that this leucine-rich repeat protein participates in developmental signaling.","evidence":"Morpholino knockdown in Ciona with constitutively active β-catenin rescue and dosage-sensitive interaction assays","pmids":["18336583"],"confidence":"Medium","gaps":["Relevance of Wnt-pathway function to mammalian LRMDA has not been tested","Direct molecular target within the Wnt pathway remains unidentified","Whether this developmental role extends to melanocyte or immune lineages is unknown"]},{"year":2013,"claim":"LRMDA was identified as a melanocyte-differentiation gene: it is expressed in melanoblasts and melanocytes in human fetal tissue, and loss of function in zebrafish caused reduced pigmentation and melanocyte number, rescued by wild-type but not mutant protein — establishing its requirement for pigmentation and linking it to OCA7.","evidence":"Immunohistochemistry on human fetal tissue; morpholino knockdown in zebrafish with wild-type and mutant rescue","pmids":["23395477"],"confidence":"High","gaps":["Molecular mechanism by which LRMDA promotes melanocyte differentiation or pigmentation was unknown","Subcellular localization and binding partners had not been identified","Whether the pigmentation defect reflects melanosome biogenesis failure or melanocyte specification defect was unclear"]},{"year":2022,"claim":"The mechanism of LRMDA in melanosome biogenesis was elucidated: LRMDA localizes to the melanosome limiting membrane via RAB32/RAB38 effector binding, and its loss impairs PMEL processing, organelle acidification, and the stage I-to-II melanosome transition — resolving how LRMDA controls pigmentation at the organelle level.","evidence":"OCA7-KO MNT1 melanocyte cell lines; live imaging and immunofluorescence; pulldown with Rab32/Rab38; PMEL processing and luminal pH assays","pmids":["36334630"],"confidence":"High","gaps":["How LRMDA regulates organelle pH mechanistically was not resolved","Downstream trafficking machinery recruited by LRMDA was not identified","Structural basis of the RAB32/38-LRMDA interaction was unknown"]},{"year":2022,"claim":"A non-melanocyte function was discovered: in myeloid innate immune cells, LRMDA acts downstream of TRPV2-mediated Ca²⁺ influx to regulate membrane tension and mobility, controlling viral penetration — revealing that LRMDA has cell-type-specific roles beyond pigmentation.","evidence":"TRPV2 conditional KO mice; shRNA knockdown and LRMDA reconstitution in BMDCs/BMDMs; membrane tension, mobility, and viral infection assays","pmids":["36261399"],"confidence":"High","gaps":["Mechanism linking LRMDA to membrane tension changes is unknown","Whether the membrane tension function involves RAB32 or vesicular trafficking was not tested","Relevance to in vivo antiviral immunity was not demonstrated"]},{"year":2025,"claim":"The molecular architecture of the RAB32-LRMDA-Commander complex was resolved: LRMDA simultaneously and independently binds active RAB32 and the Commander endosomal recycling assembly (via a surface shared with SNX17), and OCA7-causing patient mutations specifically uncouple these two interactions — establishing the disease mechanism.","evidence":"Unbiased proteomics, recombinant protein reconstitution, co-immunoprecipitation, computational modelling, OCA7 patient mutation analysis, functional assays in human melanocytes","pmids":["41038817"],"confidence":"High","gaps":["High-resolution structure of the ternary complex has not been determined","Cargo specificity of LRMDA-Commander versus SNX17-Commander is unclear","Whether Commander engagement explains the organelle pH defect remains untested"]},{"year":2025,"claim":"An analogous Rab32-LRMDA-Retriever complex was shown to operate in mucosal innate immune cells (DCs and macrophages) to regulate endolysosomal trafficking, intestinal immune homeostasis, and bacterial clearance — extending the scaffold model to a second cell type and recycling complex.","evidence":"ENU forward genetic screen with CRISPR/Cas9 validation; hematopoietic chimeras and conditional knockouts; proteomic and biochemical interaction studies; DSS colitis and Listeria infection models (preprint)","pmids":["40791432"],"confidence":"High","gaps":["Awaits peer review","Whether Commander and Retriever interactions are truly mutually exclusive or can coexist in immune cells is unresolved","Specific endolysosomal cargoes regulated by LRMDA-Retriever are not identified"]},{"year":null,"claim":"Key open questions include the structural basis of how LRMDA simultaneously engages RAB32 and distinct endosomal recycling complexes (Commander vs. Retriever), the identity of cargoes sorted by LRMDA-containing complexes in immune cells, and whether the membrane tension function in myeloid cells involves the same RAB32-dependent trafficking mechanism.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of any LRMDA complex exists","Cargo specificity in immune cells has not been defined","Relationship between Ca²⁺-dependent membrane tension function and RAB32-recycling complex function is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0043226","term_label":"organelle","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4,5]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,4,5]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,5]}],"complexes":["RAB32-LRMDA-Commander","Rab32-LRMDA-Retriever"],"partners":["RAB32","RAB38","COMMD1","CCDC22","VPS35L","TRPV2"],"other_free_text":[]},"mechanistic_narrative":"LRMDA is a leucine-rich repeat protein that functions as a RAB32/RAB38 effector and scaffold for endosomal recycling complexes, with essential roles in melanosome biogenesis and innate immune cell trafficking. LRMDA localizes to the melanosome limiting membrane via interaction with active RAB32 and RAB38, and simultaneously binds the Commander recycling complex; this RAB32-LRMDA-Commander assembly is required for PMEL processing and fibrillation (stage I-to-II melanosome transition), organelle acidification, and melanin production, and its disruption by patient mutations causes oculocutaneous albinism type 7 (OCA7) [PMID:36334630, PMID:41038817, PMID:23395477]. In myeloid innate immune cells, LRMDA acts downstream of TRPV2-mediated Ca²⁺ influx to regulate plasma membrane tension and mobility, thereby controlling viral penetration and infection [PMID:36261399]. LRMDA also cooperatively interacts with Rab32 and the Retriever complex in mucosal dendritic cells and macrophages to regulate endolysosomal trafficking required for intestinal immune homeostasis and bacterial clearance [PMID:40791432]."},"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: new genes and new types of albinism.","date":"2013","source":"Pigment cell & melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/24066960","citation_count":149,"is_preprint":false},{"pmid":"25093188","id":"PMC_25093188","title":"Mutational analysis of oculocutaneous albinism: a compact review.","date":"2014","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/25093188","citation_count":92,"is_preprint":false},{"pmid":"23395477","id":"PMC_23395477","title":"Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.","date":"2013","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23395477","citation_count":83,"is_preprint":false},{"pmid":"27564456","id":"PMC_27564456","title":"DNA methylation profiling in human lung tissue identifies genes associated with COPD.","date":"2016","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/27564456","citation_count":73,"is_preprint":false},{"pmid":"22180457","id":"PMC_22180457","title":"A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22180457","citation_count":52,"is_preprint":false},{"pmid":"30679655","id":"PMC_30679655","title":"A pathogenic haplotype, common in Europeans, causes autosomal recessive albinism and uncovers missing heritability in OCA1.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30679655","citation_count":37,"is_preprint":false},{"pmid":"36261399","id":"PMC_36261399","title":"The Transient Receptor Potential Vanilloid 2 (TRPV2) Channel Facilitates Virus Infection Through the Ca2+ -LRMDA Axis in Myeloid Cells.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36261399","citation_count":24,"is_preprint":false},{"pmid":"25712191","id":"PMC_25712191","title":"Pharmacogenomics toward personalized tamoxifen therapy for breast cancer.","date":"2015","source":"Pharmacogenomics","url":"https://pubmed.ncbi.nlm.nih.gov/25712191","citation_count":21,"is_preprint":false},{"pmid":"32966289","id":"PMC_32966289","title":"Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: Increased carriage of TYR and OCA2 variants.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32966289","citation_count":20,"is_preprint":false},{"pmid":"19844253","id":"PMC_19844253","title":"Chromosome aberrations involving 10q22: report of three overlapping interstitial deletions and a balanced translocation disrupting C10orf11.","date":"2009","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/19844253","citation_count":19,"is_preprint":false},{"pmid":"18336583","id":"PMC_18336583","title":"Novel genes involved in canonical Wnt/beta-catenin signaling pathway in early Ciona intestinalis embryos.","date":"2008","source":"Development, growth & differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/18336583","citation_count":15,"is_preprint":false},{"pmid":"36334630","id":"PMC_36334630","title":"OCA7 is a melanosome membrane protein that defines pigmentation by regulating early stages of melanosome biogenesis.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36334630","citation_count":14,"is_preprint":false},{"pmid":"35741834","id":"PMC_35741834","title":"Clinical and Mutation Spectrum of Autosomal Recessive Non-Syndromic Oculocutaneous Albinism (nsOCA) in Pakistan: A Review.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35741834","citation_count":14,"is_preprint":false},{"pmid":"28525403","id":"PMC_28525403","title":"Genetic diseases associated with an increased risk of skin cancer development in childhood.","date":"2017","source":"Current opinion in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/28525403","citation_count":11,"is_preprint":false},{"pmid":"26818737","id":"PMC_26818737","title":"Homozygosity mapping in albinism patients using a novel panel of 13 STR markers inside the nonsyndromic OCA genes: introducing 5 novel mutations.","date":"2016","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26818737","citation_count":9,"is_preprint":false},{"pmid":"28507374","id":"PMC_28507374","title":"Ophthalmo-genetic analysis of Pakistani patients with nonsyndromic oculocutaneous albinism through whole exome sequencing.","date":"2017","source":"JPMA. The Journal of the Pakistan Medical Association","url":"https://pubmed.ncbi.nlm.nih.gov/28507374","citation_count":8,"is_preprint":false},{"pmid":"24096233","id":"PMC_24096233","title":"SLC45A2 mutation frequency in Oculocutaneous Albinism Italian patients doesn't differ from other European studies.","date":"2013","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24096233","citation_count":8,"is_preprint":false},{"pmid":"32115698","id":"PMC_32115698","title":"Mapping the TYR gene reveals novel and previously reported variants in Eastern Indian patients highlighting preponderance of the same changes in multiple unrelated ethnicities.","date":"2020","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32115698","citation_count":6,"is_preprint":false},{"pmid":"40505416","id":"PMC_40505416","title":"Proteomic biomarkers of emphysema-predominant and non-emphysema-predominant chronic obstructive pulmonary disease.","date":"2025","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/40505416","citation_count":5,"is_preprint":false},{"pmid":"36104811","id":"PMC_36104811","title":"Variants influencing age at diagnosis of HNF1A-MODY.","date":"2022","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/36104811","citation_count":5,"is_preprint":false},{"pmid":"38555393","id":"PMC_38555393","title":"Clinical and mutational characteristics of oculocutaneous albinism type 7.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38555393","citation_count":5,"is_preprint":false},{"pmid":"32849781","id":"PMC_32849781","title":"Identification and Computational Analysis of Novel TYR and SLC45A2 Gene Mutations in Pakistani Families With Identical Non-syndromic Oculocutaneous Albinism.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32849781","citation_count":5,"is_preprint":false},{"pmid":"27031267","id":"PMC_27031267","title":"De Novo 1.77-Mb Microdeletion of 10q22.2q22.3 in a Girl With Developmental Delay, Speech Delay, Congenital Cleft Palate, and Bilateral Hearing Impairment.","date":"2016","source":"The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association","url":"https://pubmed.ncbi.nlm.nih.gov/27031267","citation_count":3,"is_preprint":false},{"pmid":"35488210","id":"PMC_35488210","title":"NGS-based targeted sequencing identified two novel variants in Southwestern Chinese families with oculocutaneous albinism.","date":"2022","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/35488210","citation_count":3,"is_preprint":false},{"pmid":"39147981","id":"PMC_39147981","title":"DNA Methylation Patterns Associated with Tinnitus in Young Adults-A Pilot Study.","date":"2024","source":"Journal of the Association for Research in Otolaryngology : JARO","url":"https://pubmed.ncbi.nlm.nih.gov/39147981","citation_count":2,"is_preprint":false},{"pmid":"40509746","id":"PMC_40509746","title":"Genome-wide association study identifies novel genetic variants associated with widespread pain in the UK Biobank (N = 172,230).","date":"2025","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/40509746","citation_count":2,"is_preprint":false},{"pmid":"31131026","id":"PMC_31131026","title":"Clinical and molecular cytogenetic characterization of a novel 10q interstitial deletion: a case report and review of the literature.","date":"2019","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/31131026","citation_count":2,"is_preprint":false},{"pmid":"30942644","id":"PMC_30942644","title":"Clinical and molecular findings of FRMD7 related congenital nystagmus as adifferential diagnosis of ocular albinism.","date":"2019","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30942644","citation_count":2,"is_preprint":false},{"pmid":"40791432","id":"PMC_40791432","title":"The Rab32-LRMDA-Retriever Complex is a Key Regulator of Intestinal Immune Homeostasis.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40791432","citation_count":1,"is_preprint":false},{"pmid":"41137179","id":"PMC_41137179","title":"Genomic landscape of endometrial polyps.","date":"2025","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41137179","citation_count":1,"is_preprint":false},{"pmid":"41038817","id":"PMC_41038817","title":"Identification of a RAB32-LRMDA-Commander membrane trafficking complex reveals the molecular mechanism of human oculocutaneous albinism type 7.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41038817","citation_count":0,"is_preprint":false},{"pmid":"39975051","id":"PMC_39975051","title":"Identification of a RAB32-LRMDA-Commander membrane trafficking complex reveals the molecular mechanism of human oculocutaneous albinism type 7.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39975051","citation_count":0,"is_preprint":false},{"pmid":"37329699","id":"PMC_37329699","title":"Whole genome sequencing analysis of four patients: Are de novo copy number variations in non-coding region responsible for microtia with lung hypoplasia?","date":"2023","source":"International journal of pediatric otorhinolaryngology","url":"https://pubmed.ncbi.nlm.nih.gov/37329699","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.19.629410","title":"Genome-wide association analyses in dairy heifers highlight genes overlapping with mouse and human fertility and human health traits","date":"2024-12-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.19.629410","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.05.16.24307395","title":"Genome-Wide Association Study Identifies Novel Genetic Variants Associated with Widespread Pain in the UK Biobank (N=172,230)","date":"2024-05-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.16.24307395","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19292,"output_tokens":1812,"usd":0.042528},"stage2":{"model":"claude-opus-4-6","input_tokens":5047,"output_tokens":2255,"usd":0.122415},"total_usd":0.164943,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"C10orf11 (LRMDA) encodes a leucine-rich repeat protein expressed in melanoblasts and melanocytes (but not retinal pigment epithelium) in human fetal tissue; knockdown of the zebrafish homolog with morpholinos caused substantially decreased pigmentation and reduced number of pigmented melanocytes, a phenotype rescued by wild-type but not mutant C10orf11, establishing it as a melanocyte-differentiation gene required for pigmentation.\",\n      \"method\": \"Immunohistochemistry (human fetal tissue), morpholino knockdown in zebrafish with wild-type and mutant rescue\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (IHC localization, morpholino KD, mutant rescue) in a single study; foundational gene-function paper\",\n      \"pmids\": [\"23395477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The Ciona intestinalis ortholog of C10orf11 (Ci-C10orf11), encoding a leucine-rich repeat protein, acts upstream of or parallel to beta-catenin in the canonical Wnt/beta-catenin signaling pathway during early embryogenesis; morpholino knockdown suppressed beta-catenin target gene expression and endoderm formation, rescued only by constitutively active (not wild-type) beta-catenin.\",\n      \"method\": \"Morpholino loss-of-function screen in Ciona; epistasis analysis with constitutively active beta-catenin rescue; dosage-sensitive interaction assays\",\n      \"journal\": \"Development, growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple readouts in a single lab; ortholog context consistent with mammalian LRMDA\",\n      \"pmids\": [\"18336583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OCA7 (C10orf11/LRMDA) localizes to the limiting membrane of melanosomes via interaction with Rab32 and Rab38 through a canonical effector-binding surface; loss of OCA7 in MNT1 cells impairs melanosome maturation, disrupts PMEL processing and fibrillation (stage I-to-II transition), and reduces melanosome lumen pH, collectively decreasing melanin levels.\",\n      \"method\": \"Fluorescence localization (live imaging and immunofluorescence), OCA7-KO cell line generation, pulldown with Rab32/Rab38, PMEL processing assays, pH measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO cells with multiple orthogonal mechanistic readouts (localization, Rab interaction, PMEL processing, organelle pH) in one study\",\n      \"pmids\": [\"36334630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRPV2-mediated Ca2+ influx in myeloid cells upregulates Lrmda expression; Lrmda knockdown reduces cell membrane tension and mobility and inhibits viral (HSV-1, VSV) penetration and infection, while LRMDA complementation in TRPV2-KO dendritic cells partially restores membrane tension/mobility and viral penetration, placing LRMDA downstream of Ca2+ in the TRPV2-Ca2+-LRMDA axis controlling viral entry.\",\n      \"method\": \"TRPV2 conditional knockout mice, shRNA knockdown of Lrmda, LRMDA reconstitution, 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 — multiple orthogonal methods (KO, KD, reconstitution, functional assays) establishing pathway position and cellular function\",\n      \"pmids\": [\"36261399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRMDA is a component of a RAB32-LRMDA-Commander membrane trafficking complex; LRMDA simultaneously binds active RAB32 and the endosomal Commander assembly through a mechanism shared with SNX17 (but mutually exclusive with SNX17-Commander), and this complex is essential for melanosome biogenesis and pigmentation. OCA7-causing LRMDA mutations uncouple RAB32 binding from Commander binding, establishing the molecular mechanism of disease.\",\n      \"method\": \"Unbiased proteomics, recombinant protein reconstitution, co-immunoprecipitation, computational modelling, functional analysis in human melanocytes, OCA7 patient mutation analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution + proteomics + mutagenesis + functional validation in melanocytes; mechanistic basis of OCA7 established\",\n      \"pmids\": [\"41038817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRMDA functions primarily in CD11c+ innate immune cells (mucosal dendritic cells and macrophages) to regulate endolysosomal trafficking; LRMDA directly and cooperatively interacts with Rab32 and the endosomal recycling complex Retriever. Loss of LRMDA increases susceptibility to DSS-induced colitis and impairs clearance of Listeria monocytogenes, establishing the Rab32-LRMDA-Retriever complex as a critical regulator of intestinal immune homeostasis.\",\n      \"method\": \"ENU forward genetic screen, CRISPR/Cas9 validation, hematopoietic chimeras, conditional knockouts, proteomic/biochemical interaction analyses, DSS colitis model, Listeria infection assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — forward genetic screen validated by CRISPR KO, biochemical interaction studies, and multiple in vivo functional readouts\",\n      \"pmids\": [\"40791432\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LRMDA (C10orf11/OCA7) is a leucine-rich repeat melanosome membrane protein that simultaneously binds active RAB32 and the endosomal Commander recycling complex, forming a RAB32-LRMDA-Commander assembly that is essential for melanosome biogenesis and pigmentation by regulating PMEL processing, organelle pH, and stage I-to-II melanosome transition; in myeloid innate immune cells LRMDA additionally functions downstream of TRPV2-mediated Ca2+ influx to regulate membrane tension and viral entry, and interacts with Rab32 and the Retriever complex to control endolysosomal trafficking required for intestinal immune homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LRMDA is a leucine-rich repeat protein that functions as a RAB32/RAB38 effector and scaffold for endosomal recycling complexes, with essential roles in melanosome biogenesis and innate immune cell trafficking. LRMDA localizes to the melanosome limiting membrane via interaction with active RAB32 and RAB38, and simultaneously binds the Commander recycling complex; this RAB32-LRMDA-Commander assembly is required for PMEL processing and fibrillation (stage I-to-II melanosome transition), organelle acidification, and melanin production, and its disruption by patient mutations causes oculocutaneous albinism type 7 (OCA7) [PMID:36334630, PMID:41038817, PMID:23395477]. In myeloid innate immune cells, LRMDA acts downstream of TRPV2-mediated Ca²⁺ influx to regulate plasma membrane tension and mobility, thereby controlling viral penetration and infection [PMID:36261399]. LRMDA also cooperatively interacts with Rab32 and the Retriever complex in mucosal dendritic cells and macrophages to regulate endolysosomal trafficking required for intestinal immune homeostasis and bacterial clearance [PMID:40791432].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Before any mammalian function was known, epistasis analysis in Ciona intestinalis established that the LRMDA ortholog acts upstream of or parallel to β-catenin in canonical Wnt signaling during early embryogenesis, providing the first evidence that this leucine-rich repeat protein participates in developmental signaling.\",\n      \"evidence\": \"Morpholino knockdown in Ciona with constitutively active β-catenin rescue and dosage-sensitive interaction assays\",\n      \"pmids\": [\"18336583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relevance of Wnt-pathway function to mammalian LRMDA has not been tested\",\n        \"Direct molecular target within the Wnt pathway remains unidentified\",\n        \"Whether this developmental role extends to melanocyte or immune lineages is unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"LRMDA was identified as a melanocyte-differentiation gene: it is expressed in melanoblasts and melanocytes in human fetal tissue, and loss of function in zebrafish caused reduced pigmentation and melanocyte number, rescued by wild-type but not mutant protein — establishing its requirement for pigmentation and linking it to OCA7.\",\n      \"evidence\": \"Immunohistochemistry on human fetal tissue; morpholino knockdown in zebrafish with wild-type and mutant rescue\",\n      \"pmids\": [\"23395477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which LRMDA promotes melanocyte differentiation or pigmentation was unknown\",\n        \"Subcellular localization and binding partners had not been identified\",\n        \"Whether the pigmentation defect reflects melanosome biogenesis failure or melanocyte specification defect was unclear\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The mechanism of LRMDA in melanosome biogenesis was elucidated: LRMDA localizes to the melanosome limiting membrane via RAB32/RAB38 effector binding, and its loss impairs PMEL processing, organelle acidification, and the stage I-to-II melanosome transition — resolving how LRMDA controls pigmentation at the organelle level.\",\n      \"evidence\": \"OCA7-KO MNT1 melanocyte cell lines; live imaging and immunofluorescence; pulldown with Rab32/Rab38; PMEL processing and luminal pH assays\",\n      \"pmids\": [\"36334630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How LRMDA regulates organelle pH mechanistically was not resolved\",\n        \"Downstream trafficking machinery recruited by LRMDA was not identified\",\n        \"Structural basis of the RAB32/38-LRMDA interaction was unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A non-melanocyte function was discovered: in myeloid innate immune cells, LRMDA acts downstream of TRPV2-mediated Ca²⁺ influx to regulate membrane tension and mobility, controlling viral penetration — revealing that LRMDA has cell-type-specific roles beyond pigmentation.\",\n      \"evidence\": \"TRPV2 conditional KO mice; shRNA knockdown and LRMDA reconstitution in BMDCs/BMDMs; membrane tension, mobility, and viral infection assays\",\n      \"pmids\": [\"36261399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism linking LRMDA to membrane tension changes is unknown\",\n        \"Whether the membrane tension function involves RAB32 or vesicular trafficking was not tested\",\n        \"Relevance to in vivo antiviral immunity was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The molecular architecture of the RAB32-LRMDA-Commander complex was resolved: LRMDA simultaneously and independently binds active RAB32 and the Commander endosomal recycling assembly (via a surface shared with SNX17), and OCA7-causing patient mutations specifically uncouple these two interactions — establishing the disease mechanism.\",\n      \"evidence\": \"Unbiased proteomics, recombinant protein reconstitution, co-immunoprecipitation, computational modelling, OCA7 patient mutation analysis, functional assays in human melanocytes\",\n      \"pmids\": [\"41038817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"High-resolution structure of the ternary complex has not been determined\",\n        \"Cargo specificity of LRMDA-Commander versus SNX17-Commander is unclear\",\n        \"Whether Commander engagement explains the organelle pH defect remains untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An analogous Rab32-LRMDA-Retriever complex was shown to operate in mucosal innate immune cells (DCs and macrophages) to regulate endolysosomal trafficking, intestinal immune homeostasis, and bacterial clearance — extending the scaffold model to a second cell type and recycling complex.\",\n      \"evidence\": \"ENU forward genetic screen with CRISPR/Cas9 validation; hematopoietic chimeras and conditional knockouts; proteomic and biochemical interaction studies; DSS colitis and Listeria infection models (preprint)\",\n      \"pmids\": [\"40791432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Awaits peer review\",\n        \"Whether Commander and Retriever interactions are truly mutually exclusive or can coexist in immune cells is unresolved\",\n        \"Specific endolysosomal cargoes regulated by LRMDA-Retriever are not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of how LRMDA simultaneously engages RAB32 and distinct endosomal recycling complexes (Commander vs. Retriever), the identity of cargoes sorted by LRMDA-containing complexes in immune cells, and whether the membrane tension function in myeloid cells involves the same RAB32-dependent trafficking mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of any LRMDA complex exists\",\n        \"Cargo specificity in immune cells has not been defined\",\n        \"Relationship between Ca²⁺-dependent membrane tension function and RAB32-recycling complex function is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0043226\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [\n      \"RAB32-LRMDA-Commander\",\n      \"Rab32-LRMDA-Retriever\"\n    ],\n    \"partners\": [\n      \"RAB32\",\n      \"RAB38\",\n      \"COMMD1\",\n      \"CCDC22\",\n      \"VPS35L\",\n      \"TRPV2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}