{"gene":"HLA-DMA","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1994,"finding":"HLA-DMA and HLA-DMB are both required for MHC class II/peptide complex formation in antigen-presenting cells. Somatic cell mutants with mutations in HLA-DMA showed defective class II/peptide assembly, and transfection of DMA cDNA reversed the mutant phenotype, demonstrating that HLA-DMA encodes a subunit of a functional heterodimer critical for peptide loading onto MHC class II molecules.","method":"Somatic cell mutagenesis, complementation by cDNA transfection, functional rescue assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with defined phenotype, genetic complementation, replicated across multiple mutant lines","pmids":["8139690"],"is_preprint":false},{"year":2014,"finding":"HLA-DMA polymorphic residues directly affect the catalytic activity of the HLA-DM heterodimer as a peptide exchange catalyst for MHC class II. The DMA*0103 variant (carrying G155A substitution) attenuates peptide release velocity, resulting in ~2-fold increased half-life of preloaded peptide-MHCII complexes compared to DMA*0101, and leads to greater persistence of autoimmunity-related antigens in competition with high-affinity peptides.","method":"In vitro peptide exchange assay, peptide dissociation kinetics, direct interaction assays with HLA-DR/peptide complexes, site-specific variant comparison","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted enzymatic assay with multiple orthogonal methods (exchange, dissociation, binding) and defined mutagenesis","pmids":["25505276"],"is_preprint":false},{"year":1994,"finding":"HLA-DMA and HLA-DMB genes have a conserved genomic organization (5 exons for alpha, 6 exons for beta) shared with other class II genes, but with a unique deletion/insertion in exon 3 (membrane-proximal domain), suggesting DM genes originate from a time prior to divergence of classical class II genes.","method":"Genomic sequencing and comparative gene organization analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — structural/genomic characterization without direct functional assay","pmids":["8034636"],"is_preprint":false}],"current_model":"HLA-DMA encodes the alpha subunit of the HLA-DM heterodimer (with HLA-DMB), a non-classical MHC class II molecule that functions as a peptide exchange catalyst in antigen-presenting cells, facilitating the removal of CLIP and loading of antigenic peptides onto classical MHC class II molecules; polymorphisms in the DMA chain (e.g., G155A in DMA*0103) directly modulate the catalytic rate of peptide exchange, altering the peptide repertoire presented to CD4+ T cells."},"narrative":{"teleology":[{"year":1994,"claim":"The fundamental question of whether HLA-DMA encodes a functional gene product required for antigen presentation was resolved: DMA is an essential subunit of a heterodimer needed for MHC class II peptide loading.","evidence":"Somatic cell mutagenesis and cDNA complementation/rescue in antigen-presenting cell lines","pmids":["8139690"],"confidence":"High","gaps":["Catalytic mechanism of DM-mediated peptide exchange not yet defined","Functional significance of DMA polymorphisms unknown","Subcellular site of DM action not resolved in this study"]},{"year":1994,"claim":"Genomic characterization established that HLA-DMA shares the exon-intron organization of classical MHC class II genes but carries unique structural features in the membrane-proximal domain, positioning DM as an ancient divergent class II family member.","evidence":"Genomic sequencing and comparative gene organization analysis","pmids":["8034636"],"confidence":"Medium","gaps":["Evolutionary timing of DM divergence from classical class II loci not precisely dated","Functional consequence of the exon 3 deletion/insertion not tested experimentally"]},{"year":2014,"claim":"The open question of whether natural DMA polymorphisms affect DM catalytic function was answered: the DMA*0103 allele (G155A) reduces peptide exchange velocity approximately twofold, demonstrating that DMA variation tunes the peptide repertoire presented to CD4+ T cells.","evidence":"In vitro reconstituted peptide exchange and dissociation kinetics assays with site-specific DMA variants and HLA-DR/peptide complexes","pmids":["25505276"],"confidence":"High","gaps":["Structural basis for how G155A attenuates catalytic activity not determined","In vivo impact of DMA polymorphisms on CD4+ T cell responses and autoimmunity susceptibility not directly demonstrated","Whether DMA polymorphisms affect interactions with HLA-DO (the endogenous DM inhibitor) is untested"]},{"year":null,"claim":"A structural mechanism explaining how DMA polymorphisms modulate the conformational rearrangement of MHC class II molecules during peptide exchange remains undefined, and the in vivo immunological consequences of DMA allelic variation have not been established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of DMA variant heterodimers in complex with MHC class II","No in vivo studies linking DMA allelic variation to altered immune repertoire or disease susceptibility","Interplay between DMA polymorphisms and HLA-DO regulation unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]}],"complexes":["HLA-DM (DMA/DMB heterodimer)"],"partners":["HLA-DMB"],"other_free_text":[]},"mechanistic_narrative":"HLA-DMA encodes the alpha subunit of the HLA-DM heterodimer, a non-classical MHC class II molecule essential for peptide loading onto classical MHC class II molecules in antigen-presenting cells [PMID:8139690]. HLA-DMA and HLA-DMB are both required for MHC class II/peptide complex formation; somatic cell mutants lacking functional DMA show defective class II/peptide assembly that is reversed by DMA cDNA transfection [PMID:8139690]. Polymorphic residues in HLA-DMA directly modulate the catalytic rate of DM-mediated peptide exchange: the DMA*0103 variant (G155A) attenuates peptide release from MHC class II, increasing the half-life of preloaded peptide complexes and altering the antigenic peptide repertoire [PMID:25505276]."},"prefetch_data":{"uniprot":{"accession":"P28067","full_name":"HLA class II histocompatibility antigen, DM alpha chain","aliases":["MHC class II antigen DMA","Really interesting new gene 6 protein"],"length_aa":261,"mass_kda":29.2,"function":"Plays a critical role in catalyzing the release of class II-associated invariant chain peptide (CLIP) from newly synthesized MHC class II molecules and freeing the peptide binding site for acquisition of antigenic peptides. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO","subcellular_location":"Late endosome membrane; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/P28067/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HLA-DMA","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HLA-DMA","total_profiled":1310},"omim":[{"mim_id":"601540","title":"BROMODOMAIN-CONTAINING PROTEIN 2; BRD2","url":"https://www.omim.org/entry/601540"},{"mim_id":"142920","title":"HLA-DO HISTOCOMPATIBILITY TYPE; HLA-DO","url":"https://www.omim.org/entry/142920"},{"mim_id":"142856","title":"MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS II, DM BETA; HLA-DMB","url":"https://www.omim.org/entry/142856"},{"mim_id":"142855","title":"MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS II, DM ALPHA; HLA-DMA","url":"https://www.omim.org/entry/142855"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":119.3}],"url":"https://www.proteinatlas.org/search/HLA-DMA"},"hgnc":{"alias_symbol":["D6S222E","RING6"],"prev_symbol":[]},"alphafold":{"accession":"P28067","domains":[{"cath_id":"3.10.320.10","chopping":"45-117","consensus_level":"high","plddt":95.9249,"start":45,"end":117},{"cath_id":"2.60.40.10","chopping":"129-218","consensus_level":"high","plddt":96.7667,"start":129,"end":218}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P28067","model_url":"https://alphafold.ebi.ac.uk/files/AF-P28067-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P28067-F1-predicted_aligned_error_v6.png","plddt_mean":88.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HLA-DMA","jax_strain_url":"https://www.jax.org/strain/search?query=HLA-DMA"},"sequence":{"accession":"P28067","fasta_url":"https://rest.uniprot.org/uniprotkb/P28067.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P28067/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P28067"}},"corpus_meta":[{"pmid":"8139690","id":"PMC_8139690","title":"HLA-DMA and -DMB genes are both required for MHC class II/peptide complex formation in antigen-presenting cells.","date":"1994","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8139690","citation_count":289,"is_preprint":false},{"pmid":"8034636","id":"PMC_8034636","title":"Genomic organization of HLA-DMA and HLA-DMB. Comparison of the gene organization of all six class II families in the human major histocompatibility complex.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8034636","citation_count":42,"is_preprint":false},{"pmid":"25505276","id":"PMC_25505276","title":"HLA-DMA polymorphisms differentially affect MHC class II peptide loading.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25505276","citation_count":28,"is_preprint":false},{"pmid":"35543859","id":"PMC_35543859","title":"Expression of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA is synergistically associated with T cell exclusion, immune checkpoint blockade efficacy and recurrence risk in ER-negative breast cancer.","date":"2022","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/35543859","citation_count":21,"is_preprint":false},{"pmid":"9271826","id":"PMC_9271826","title":"Idiopathic and secondary membranous nephropathy and polymorphism at TAP1 and HLA-DMA loci.","date":"1997","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/9271826","citation_count":13,"is_preprint":false},{"pmid":"12858445","id":"PMC_12858445","title":"Polymorphism of HLA-DMA and DMB alleles in patients with systemic lupus erythematosus.","date":"2003","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/12858445","citation_count":9,"is_preprint":false},{"pmid":"10427471","id":"PMC_10427471","title":"Implication of HLA-DMA alleles in corsican IDDM.","date":"1998","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/10427471","citation_count":8,"is_preprint":false},{"pmid":"35077766","id":"PMC_35077766","title":"Role of Ring6 in the Function of the E. coli MCE Protein LetB.","date":"2022","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35077766","citation_count":6,"is_preprint":false},{"pmid":"9757947","id":"PMC_9757947","title":"Impact of the MHC-encoded HLA-DMA, DMB, and LMP2 gene polymorphisms on kidney graft outcome.","date":"1998","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9757947","citation_count":5,"is_preprint":false},{"pmid":"40347049","id":"PMC_40347049","title":"Extensive Analysis of Genetic Diversity in HLA-DMA, HLA-DMB, HLA-DOA and HLA-DOB: Characterisation of 236 Novel Alleles.","date":"2025","source":"HLA","url":"https://pubmed.ncbi.nlm.nih.gov/40347049","citation_count":5,"is_preprint":false},{"pmid":"10575273","id":"PMC_10575273","title":"HLA-DMA alleles are possible new markers of rheumatoid arthritis: study of a Corsican group.","date":"1999","source":"Experimental and clinical immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/10575273","citation_count":5,"is_preprint":false},{"pmid":"29382430","id":"PMC_29382430","title":"[Genetic polymorphisms of ARL15 and HLA-DMA are associated with rheumatoid arthritis in Han population from northwest China].","date":"2017","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29382430","citation_count":3,"is_preprint":false},{"pmid":"10689127","id":"PMC_10689127","title":"HLA-DMA allele polymorphism: no impact on kidney allograft outcome.","date":"2000","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10689127","citation_count":2,"is_preprint":false},{"pmid":"16737583","id":"PMC_16737583","title":"[Relationship of trichloroethylene-induced medicamentosa like dermatitis to HLA-DMA and HLA-DMB].","date":"2006","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/16737583","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7897,"output_tokens":850,"usd":0.018221},"stage2":{"model":"claude-opus-4-6","input_tokens":4032,"output_tokens":1129,"usd":0.072578},"total_usd":0.090799,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"HLA-DMA and HLA-DMB are both required for MHC class II/peptide complex formation in antigen-presenting cells. Somatic cell mutants with mutations in HLA-DMA showed defective class II/peptide assembly, and transfection of DMA cDNA reversed the mutant phenotype, demonstrating that HLA-DMA encodes a subunit of a functional heterodimer critical for peptide loading onto MHC class II molecules.\",\n      \"method\": \"Somatic cell mutagenesis, complementation by cDNA transfection, functional rescue assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined phenotype, genetic complementation, replicated across multiple mutant lines\",\n      \"pmids\": [\"8139690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HLA-DMA polymorphic residues directly affect the catalytic activity of the HLA-DM heterodimer as a peptide exchange catalyst for MHC class II. The DMA*0103 variant (carrying G155A substitution) attenuates peptide release velocity, resulting in ~2-fold increased half-life of preloaded peptide-MHCII complexes compared to DMA*0101, and leads to greater persistence of autoimmunity-related antigens in competition with high-affinity peptides.\",\n      \"method\": \"In vitro peptide exchange assay, peptide dissociation kinetics, direct interaction assays with HLA-DR/peptide complexes, site-specific variant comparison\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted enzymatic assay with multiple orthogonal methods (exchange, dissociation, binding) and defined mutagenesis\",\n      \"pmids\": [\"25505276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"HLA-DMA and HLA-DMB genes have a conserved genomic organization (5 exons for alpha, 6 exons for beta) shared with other class II genes, but with a unique deletion/insertion in exon 3 (membrane-proximal domain), suggesting DM genes originate from a time prior to divergence of classical class II genes.\",\n      \"method\": \"Genomic sequencing and comparative gene organization analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — structural/genomic characterization without direct functional assay\",\n      \"pmids\": [\"8034636\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HLA-DMA encodes the alpha subunit of the HLA-DM heterodimer (with HLA-DMB), a non-classical MHC class II molecule that functions as a peptide exchange catalyst in antigen-presenting cells, facilitating the removal of CLIP and loading of antigenic peptides onto classical MHC class II molecules; polymorphisms in the DMA chain (e.g., G155A in DMA*0103) directly modulate the catalytic rate of peptide exchange, altering the peptide repertoire presented to CD4+ T cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HLA-DMA encodes the alpha subunit of the HLA-DM heterodimer, a non-classical MHC class II molecule essential for peptide loading onto classical MHC class II molecules in antigen-presenting cells [PMID:8139690]. HLA-DMA and HLA-DMB are both required for MHC class II/peptide complex formation; somatic cell mutants lacking functional DMA show defective class II/peptide assembly that is reversed by DMA cDNA transfection [PMID:8139690]. Polymorphic residues in HLA-DMA directly modulate the catalytic rate of DM-mediated peptide exchange: the DMA*0103 variant (G155A) attenuates peptide release from MHC class II, increasing the half-life of preloaded peptide complexes and altering the antigenic peptide repertoire [PMID:25505276].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"The fundamental question of whether HLA-DMA encodes a functional gene product required for antigen presentation was resolved: DMA is an essential subunit of a heterodimer needed for MHC class II peptide loading.\",\n      \"evidence\": \"Somatic cell mutagenesis and cDNA complementation/rescue in antigen-presenting cell lines\",\n      \"pmids\": [\"8139690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Catalytic mechanism of DM-mediated peptide exchange not yet defined\",\n        \"Functional significance of DMA polymorphisms unknown\",\n        \"Subcellular site of DM action not resolved in this study\"\n      ]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Genomic characterization established that HLA-DMA shares the exon-intron organization of classical MHC class II genes but carries unique structural features in the membrane-proximal domain, positioning DM as an ancient divergent class II family member.\",\n      \"evidence\": \"Genomic sequencing and comparative gene organization analysis\",\n      \"pmids\": [\"8034636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Evolutionary timing of DM divergence from classical class II loci not precisely dated\",\n        \"Functional consequence of the exon 3 deletion/insertion not tested experimentally\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The open question of whether natural DMA polymorphisms affect DM catalytic function was answered: the DMA*0103 allele (G155A) reduces peptide exchange velocity approximately twofold, demonstrating that DMA variation tunes the peptide repertoire presented to CD4+ T cells.\",\n      \"evidence\": \"In vitro reconstituted peptide exchange and dissociation kinetics assays with site-specific DMA variants and HLA-DR/peptide complexes\",\n      \"pmids\": [\"25505276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how G155A attenuates catalytic activity not determined\",\n        \"In vivo impact of DMA polymorphisms on CD4+ T cell responses and autoimmunity susceptibility not directly demonstrated\",\n        \"Whether DMA polymorphisms affect interactions with HLA-DO (the endogenous DM inhibitor) is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A structural mechanism explaining how DMA polymorphisms modulate the conformational rearrangement of MHC class II molecules during peptide exchange remains undefined, and the in vivo immunological consequences of DMA allelic variation have not been established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of DMA variant heterodimers in complex with MHC class II\",\n        \"No in vivo studies linking DMA allelic variation to altered immune repertoire or disease susceptibility\",\n        \"Interplay between DMA polymorphisms and HLA-DO regulation unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"HLA-DM (DMA/DMB heterodimer)\"],\n    \"partners\": [\"HLA-DMB\"],\n    \"other_free_text\": []\n  }\n}\n```"}