Affinage

LRMDA

Leucine-rich melanocyte differentiation-associated protein · UniProt Q9H2I8

Length
198 aa
Mass
22.6 kDa
Annotated
2026-06-10
33 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2008 Medium

    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

    PMID:18336583

    Open questions at the time
    • Relevance of Wnt/beta-catenin link to the mammalian protein not independently validated
    • No biochemical mechanism connecting the protein to beta-catenin
    • Invertebrate system
  2. 2013 High

    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

    PMID:23395477

    Open questions at the time
    • No molecular mechanism or binding partner identified
    • Subcellular site of action within melanocytes unresolved
  3. 2022 High

    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

    PMID:36334630

    Open questions at the time
    • Downstream effector machinery recruited by LRMDA not yet identified
    • Mechanism linking RAB32 binding to PMEL processing and pH control unresolved
  4. 2022 High

    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

    PMID:36261399

    Open questions at the time
    • Molecular mechanism by which LRMDA alters membrane tension not defined
    • How Ca2+ influx regulates LRMDA function unresolved
  5. 2025 High

    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

    PMID:41038817

    Open questions at the time
    • Structural basis of the RAB32-LRMDA-Commander assembly not solved
    • Cargo recycled by this pathway not enumerated
  6. 2025 High

    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)

    PMID:40791432

    Open questions at the time
    • Preprint, not peer-reviewed
    • Endolysosomal cargo controlled in immune cells not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No structure of the assembly
  • Cargo recycled by the complex not defined
  • Connection between cognitive 10q22 deletion phenotype and protein function uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 1 GO:0005886 plasma membrane 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9609507 Protein localization 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
COMMANDERRAB32RAB38RETRIEVERSNX17TRPV2
Complex memberships
Commander/Retriever complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 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. Immunohistochemistry (localization in human fetal tissue), morpholino knockdown in zebrafish with wild-type vs. mutant rescue American journal of human genetics High 23395477
2008 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. Morpholino loss-of-function screening, downstream gene expression assay, epistasis rescue with constitutively active beta-catenin, dosage-sensitive interaction analysis in Ciona embryos Development, growth & differentiation Medium 18336583
2022 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. 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 The Journal of biological chemistry High 36334630
2022 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. 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 Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 36261399
2025 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. Unbiased proteomics, recombinant protein reconstitution, computational modelling, functional analysis in human melanocytes with KO/KD, co-IP binding assays with mutant LRMDA variants Nature communications High 41038817
2025 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. 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 bioRxivpreprint High 40791432
2009 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. Array comparative genomic hybridization, array painting breakpoint analysis, expression data from public databases European journal of human genetics Low 19844253

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Increasing the complexity: new genes and new types of albinism. Pigment cell & melanoma research 150 24066960
2014 Mutational analysis of oculocutaneous albinism: a compact review. BioMed research international 94 25093188
2013 Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism. American journal of human genetics 84 23395477
2016 DNA methylation profiling in human lung tissue identifies genes associated with COPD. Epigenetics 73 27564456
2011 A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese. Human molecular genetics 52 22180457
2019 A pathogenic haplotype, common in Europeans, causes autosomal recessive albinism and uncovers missing heritability in OCA1. Scientific reports 37 30679655
2022 The Transient Receptor Potential Vanilloid 2 (TRPV2) Channel Facilitates Virus Infection Through the Ca2+ -LRMDA Axis in Myeloid Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 25 36261399
2015 Pharmacogenomics toward personalized tamoxifen therapy for breast cancer. Pharmacogenomics 21 25712191
2020 Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: Increased carriage of TYR and OCA2 variants. PloS one 20 32966289
2009 Chromosome aberrations involving 10q22: report of three overlapping interstitial deletions and a balanced translocation disrupting C10orf11. European journal of human genetics : EJHG 19 19844253
2022 Clinical and Mutation Spectrum of Autosomal Recessive Non-Syndromic Oculocutaneous Albinism (nsOCA) in Pakistan: A Review. Genes 15 35741834
2022 OCA7 is a melanosome membrane protein that defines pigmentation by regulating early stages of melanosome biogenesis. The Journal of biological chemistry 15 36334630
2008 Novel genes involved in canonical Wnt/beta-catenin signaling pathway in early Ciona intestinalis embryos. Development, growth & differentiation 15 18336583
2017 Genetic diseases associated with an increased risk of skin cancer development in childhood. Current opinion in pediatrics 11 28525403
2016 Homozygosity mapping in albinism patients using a novel panel of 13 STR markers inside the nonsyndromic OCA genes: introducing 5 novel mutations. Journal of human genetics 9 26818737
2017 Ophthalmo-genetic analysis of Pakistani patients with nonsyndromic oculocutaneous albinism through whole exome sequencing. JPMA. The Journal of the Pakistan Medical Association 8 28507374
2013 SLC45A2 mutation frequency in Oculocutaneous Albinism Italian patients doesn't differ from other European studies. Gene 8 24096233
2022 Variants influencing age at diagnosis of HNF1A-MODY. Molecular medicine (Cambridge, Mass.) 6 36104811
2020 Mapping the TYR gene reveals novel and previously reported variants in Eastern Indian patients highlighting preponderance of the same changes in multiple unrelated ethnicities. Annals of human genetics 6 32115698
2025 Proteomic biomarkers of emphysema-predominant and non-emphysema-predominant chronic obstructive pulmonary disease. EBioMedicine 5 40505416
2024 Clinical and mutational characteristics of oculocutaneous albinism type 7. Scientific reports 5 38555393
2020 Identification and Computational Analysis of Novel TYR and SLC45A2 Gene Mutations in Pakistani Families With Identical Non-syndromic Oculocutaneous Albinism. Frontiers in genetics 5 32849781
2022 NGS-based targeted sequencing identified two novel variants in Southwestern Chinese families with oculocutaneous albinism. BMC genomics 3 35488210
2019 Clinical and molecular findings of FRMD7 related congenital nystagmus as adifferential diagnosis of ocular albinism. Ophthalmic genetics 3 30942644
2016 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. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 3 27031267
2025 Genome-wide association study identifies novel genetic variants associated with widespread pain in the UK Biobank (N = 172,230). Molecular pain 2 40509746
2025 Genomic landscape of endometrial polyps. Genome medicine 2 41137179
2024 DNA Methylation Patterns Associated with Tinnitus in Young Adults-A Pilot Study. Journal of the Association for Research in Otolaryngology : JARO 2 39147981
2019 Clinical and molecular cytogenetic characterization of a novel 10q interstitial deletion: a case report and review of the literature. Molecular cytogenetics 2 31131026
2025 The Rab32-LRMDA-Retriever Complex is a Key Regulator of Intestinal Immune Homeostasis. bioRxiv : the preprint server for biology 1 40791432
2025 Identification of a RAB32-LRMDA-Commander membrane trafficking complex reveals the molecular mechanism of human oculocutaneous albinism type 7. Nature communications 1 41038817
2025 Identification of a RAB32-LRMDA-Commander membrane trafficking complex reveals the molecular mechanism of human oculocutaneous albinism type 7. bioRxiv : the preprint server for biology 0 39975051
2023 Whole genome sequencing analysis of four patients: Are de novo copy number variations in non-coding region responsible for microtia with lung hypoplasia? International journal of pediatric otorhinolaryngology 0 37329699

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