{"gene":"MTR","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1996,"finding":"Human methionine synthase (MTR) was cloned as a 1265 amino-acid methylcobalamin-dependent enzyme that catalyzes remethylation of homocysteine to methionine; the gene was localized to chromosome 1q43 and contains the seven-residue structure-based sequence fingerprint for cobalamin-containing enzymes.","method":"RT-PCR cloning, inverse PCR, FISH chromosomal localization, SSCP and sequence analysis of patient mutations","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 — direct cDNA cloning with functional characterization, mutation identification in patients, chromosomal mapping","pmids":["8968737"],"is_preprint":false},{"year":1988,"finding":"Functional methionine synthase deficiency was shown to fall into two complementation classes (cblE and cblG); cblG is characterized by decreased methionine synthase activity in cell extracts, while cblE has normal synthase activity, both showing decreased methylcobalamin and impaired methionine biosynthesis.","method":"Genetic complementation analysis, enzyme activity assays in cultured fibroblasts, radiolabel incorporation from 5-[14C]methyl-tetrahydrofolate","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — complementation analysis plus biochemical assays, foundational study defining two complementation groups","pmids":["3384945"],"is_preprint":false},{"year":1989,"finding":"In cblG patients (MTR deficiency), fibroblasts show decreased intracellular methylcobalamin and decreased methionine synthase activity; in cblE fibroblasts, methionine synthase activity is normal under reducing conditions, placing cblE upstream of MTR in the cobalamin activation pathway.","method":"Enzyme activity assays in fibroblast extracts under standard reducing conditions, radiolabel incorporation","journal":"American journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple patient cell lines with biochemical assays, replicated across labs","pmids":["2688421"],"is_preprint":false},{"year":1996,"finding":"cblG patient mutations in MTR include a missense at conserved Pro1173 (P1173L) in the AdoMet-binding domain and a deletion of Ile881 in the B12-binding domain; P1173L is predicted by crystal structure of the E. coli homolog to disrupt reductive activation by disrupting contacts with AdoMet, establishing that the C-terminal domain houses the reductive activation function.","method":"Northern analysis, biochemical activity assays, SSCP, sequence analysis, structural inference from E. coli MS crystal structure","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical assays combined with structural modeling; mutations functionally characterized","pmids":["8968736"],"is_preprint":false},{"year":1998,"finding":"cblG-variant patients carry functionally null MTR mutations (frameshifts, intronic insertions creating cryptic splice sites) that produce premature stop codons, leading to mRNA instability and complete absence of methionine synthase protein and activity.","method":"Northern blotting, RT-PCR, SSCP, nucleotide sequence analysis, phosphorimage analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal molecular methods identifying null mutations, mRNA instability directly demonstrated","pmids":["9683607"],"is_preprint":false},{"year":1992,"finding":"Heterogeneity within cblG was demonstrated: a subset of cblG cell lines shows reduced accumulation of labeled cobalamin and virtually none associated with methionine synthase, indicating that the defect in these variant lines impairs the ability of methionine synthase to retain cobalamin.","method":"[57Co]CN-Cbl labeling of cultured fibroblasts, subcellular fractionation, enzyme activity assays","journal":"Biochemical medicine and metabolic biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct cobalamin-binding assay in multiple cell lines, single lab","pmids":["1627355"],"is_preprint":false},{"year":2002,"finding":"The structure of the MTR gene was fully characterized with 33 exons; P1173L was identified as a recurrent mutation arising on at least two separate genetic backgrounds (CpG island), and 13 novel loss-of-function mutations were described in cblG patients.","method":"Genomic exon amplification, sequencing, haplotype analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 — complete gene structure determination with functional mutation analysis in 24 patients","pmids":["12068375"],"is_preprint":false},{"year":2013,"finding":"Methionine synthase (MTR) physically interacts with MMACHC: co-immunoprecipitation and proximity ligation assays show a complex between full-size and truncated MTR and MMACHC; this interaction is reduced in cblC cells and is proposed to regulate cellular processing of cobalamins for cofactor synthesis.","method":"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown, 3D modelling and docking","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus proximity ligation assay plus structural docking, multiple orthogonal methods","pmids":["23825108"],"is_preprint":false},{"year":2017,"finding":"Decreased MTR expression and reduced serum S-adenosylmethionine levels were found in ovaries of prenatally androgenized (hyperandrogenic) mice and granulosa cells of women with hyperandrogenic PCOS, linking MTR-dependent one-carbon metabolism to the hyperandrogenic ovarian phenotype.","method":"Microarray analysis, qRT-PCR validation, serum SAM measurement","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 — expression/metabolite data without direct enzymatic or genetic rescue experiment","pmids":["29232372"],"is_preprint":false}],"current_model":"Human MTR encodes a 1265-amino-acid methylcobalamin-dependent enzyme that remethylates homocysteine to methionine; its C-terminal domain mediates reductive activation via AdoMet and cobalamin binding, it physically interacts with the cobalamin chaperone MMACHC to acquire its methylcobalamin cofactor, and loss-of-function mutations in MTR cause the cblG disorder characterized by hyperhomocysteinemia, megaloblastic anemia, and neurological defects."},"narrative":{"teleology":[{"year":1988,"claim":"Defining complementation groups resolved that functional methionine synthase deficiency comprises two genetically distinct disorders (cblE and cblG), with cblG mapping to the synthase itself and cblE to an upstream activating step.","evidence":"Genetic complementation analysis and enzyme activity assays in cultured patient fibroblasts","pmids":["3384945"],"confidence":"High","gaps":["The gene had not yet been cloned, so the molecular basis of cblG remained unknown","No structural information on the human enzyme was available"]},{"year":1992,"claim":"Demonstrating that a subset of cblG lines fail to accumulate cobalamin on methionine synthase revealed heterogeneity within cblG and implicated the cofactor-binding capacity of the enzyme as a distinct disease mechanism.","evidence":"Radiolabeled cobalamin binding and subcellular fractionation in patient fibroblasts","pmids":["1627355"],"confidence":"Medium","gaps":["Single-lab study; not independently confirmed at the time","Molecular identity of mutations causing impaired cofactor binding was unknown"]},{"year":1996,"claim":"Cloning of the full-length human MTR cDNA and mapping to 1q43 established the molecular identity of the enzyme and enabled genotype–phenotype correlation in cblG patients, while structure-based analysis of patient mutations (P1173L, ΔI881) located the reductive activation function to the C-terminal AdoMet-binding domain.","evidence":"RT-PCR cloning, FISH mapping, SSCP mutation screening, structural inference from E. coli methionine synthase crystal structure","pmids":["8968737","8968736"],"confidence":"High","gaps":["No crystal structure of the human enzyme existed; domain assignments relied on bacterial homolog","Mechanism of reductive activation was inferred from structural modeling rather than direct reconstitution"]},{"year":1998,"claim":"Identification of functionally null MTR alleles (frameshifts, splice-site disruptions) causing mRNA instability and complete loss of protein confirmed that absence of methionine synthase is compatible with survival but causes severe cblG disease.","evidence":"Northern blotting, RT-PCR, and sequence analysis of patient fibroblasts","pmids":["9683607"],"confidence":"High","gaps":["Residual in vivo methionine synthesis in null patients was not quantified","No rescue experiment demonstrated restoration of enzyme activity upon re-expression"]},{"year":2002,"claim":"Complete elucidation of the 33-exon MTR gene structure and identification of P1173L as a recurrent CpG-site mutation on independent haplotypes expanded the mutational spectrum and explained the high frequency of this allele in cblG.","evidence":"Genomic exon amplification, sequencing, and haplotype analysis in 24 cblG patients","pmids":["12068375"],"confidence":"High","gaps":["Functional impact of many novel missense variants was not biochemically validated","Genotype–phenotype severity correlations remained incomplete"]},{"year":2013,"claim":"Demonstrating a physical interaction between MTR and the cobalamin chaperone MMACHC established a direct cofactor-transfer mechanism and linked the cblC and cblG pathways at the protein level.","evidence":"Reciprocal co-immunoprecipitation, proximity ligation assay, and siRNA knockdown in human cells","pmids":["23825108"],"confidence":"High","gaps":["In vitro reconstitution of cofactor transfer from MMACHC to MTR has not been shown","Stoichiometry and kinetics of the MTR–MMACHC complex are undefined","Whether other chaperones participate in cofactor loading onto MTR is unknown"]},{"year":null,"claim":"A high-resolution structure of human MTR, the precise mechanism of cofactor transfer from MMACHC, and the structural basis for how specific patient mutations differentially affect cobalamin binding versus reductive activation remain to be determined.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of human methionine synthase","In vitro reconstitution of cofactor transfer from MMACHC to MTR is lacking","Quantitative genotype–phenotype model for cblG mutations is absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,4,6]}],"complexes":[],"partners":["MMACHC"],"other_free_text":[]},"mechanistic_narrative":"MTR encodes methionine synthase, a methylcobalamin-dependent enzyme that catalyzes the remethylation of homocysteine to methionine, linking one-carbon folate metabolism to the methionine cycle. The 1265-amino-acid protein contains a cobalamin-binding domain and a C-terminal S-adenosylmethionine (AdoMet)-binding domain that mediates reductive reactivation of the enzyme; patient mutations such as P1173L in the AdoMet domain disrupt this activation mechanism, while mutations in the cobalamin-binding domain impair cofactor retention [PMID:8968737, PMID:8968736, PMID:1627355]. MTR physically interacts with the cobalamin chaperone MMACHC to acquire its methylcobalamin cofactor, and this interaction is diminished in cblC-deficient cells [PMID:23825108]. Loss-of-function mutations in MTR cause cblG complementation group disease, characterized by hyperhomocysteinemia, megaloblastic anemia, and neurological impairment [PMID:3384945, PMID:9683607]."},"prefetch_data":{"uniprot":{"accession":"Q99707","full_name":"Methionine synthase","aliases":["5-methyltetrahydrofolate--homocysteine methyltransferase","Cobalamin-dependent methionine synthase","Vitamin-B12 dependent methionine synthase"],"length_aa":1265,"mass_kda":140.5,"function":"Catalyzes the transfer of a methyl group from methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound cob(I)alamin and methionine in the cytosol (PubMed:16769880, PubMed:17288554, PubMed:27771510). MeCbl is an active form of cobalamin (vitamin B12) used as a cofactor for methionine biosynthesis. Cob(I)alamin form is regenerated to MeCbl by a transfer of a methyl group from 5-methyltetrahydrofolate (PubMed:16769880, PubMed:17288554, PubMed:27771510). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (PubMed:16769880, PubMed:27771510)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q99707/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTR","classification":"Not Classified","n_dependent_lines":69,"n_total_lines":1208,"dependency_fraction":0.057119205298013245},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MTR","total_profiled":1310},"omim":[{"mim_id":"620940","title":"METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblL TYPE; MAHCL","url":"https://www.omim.org/entry/620940"},{"mim_id":"614857","title":"METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblJ TYPE; MAHCJ","url":"https://www.omim.org/entry/614857"},{"mim_id":"613888","title":"RAS HOMOLOG GENE FAMILY, MEMBER T1; RHOT1","url":"https://www.omim.org/entry/613888"},{"mim_id":"613355","title":"CHROMOSOME 17q23.1-q23.2 DELETION SYNDROME","url":"https://www.omim.org/entry/613355"},{"mim_id":"609831","title":"METABOLISM OF COBALAMIN ASSOCIATED C; MMACHC","url":"https://www.omim.org/entry/609831"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTR"},"hgnc":{"alias_symbol":["cblG"],"prev_symbol":[]},"alphafold":{"accession":"Q99707","domains":[{"cath_id":"3.20.20.330","chopping":"24-340","consensus_level":"medium","plddt":93.525,"start":24,"end":340},{"cath_id":"3.20.20.20","chopping":"358-651","consensus_level":"medium","plddt":93.3111,"start":358,"end":651},{"cath_id":"1.10.1240.10","chopping":"667-759","consensus_level":"high","plddt":77.1585,"start":667,"end":759},{"cath_id":"3.40.50.280","chopping":"774-925","consensus_level":"high","plddt":85.4639,"start":774,"end":925},{"cath_id":"3.10.196.10","chopping":"958-1232","consensus_level":"medium","plddt":89.6177,"start":958,"end":1232}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99707","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99707-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99707-F1-predicted_aligned_error_v6.png","plddt_mean":87.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTR","jax_strain_url":"https://www.jax.org/strain/search?query=MTR"},"sequence":{"accession":"Q99707","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99707.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99707/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99707"}},"corpus_meta":[{"pmid":"21145579","id":"PMC_21145579","title":"Short 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was localized to chromosome 1q43 and contains the seven-residue structure-based sequence fingerprint for cobalamin-containing enzymes.\",\n      \"method\": \"RT-PCR cloning, inverse PCR, FISH chromosomal localization, SSCP and sequence analysis of patient mutations\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct cDNA cloning with functional characterization, mutation identification in patients, chromosomal mapping\",\n      \"pmids\": [\"8968737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Functional methionine synthase deficiency was shown to fall into two complementation classes (cblE and cblG); cblG is characterized by decreased methionine synthase activity in cell extracts, while cblE has normal synthase activity, both showing decreased methylcobalamin and impaired methionine biosynthesis.\",\n      \"method\": \"Genetic complementation analysis, enzyme activity assays in cultured fibroblasts, radiolabel incorporation from 5-[14C]methyl-tetrahydrofolate\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — complementation analysis plus biochemical assays, foundational study defining two complementation groups\",\n      \"pmids\": [\"3384945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"In cblG patients (MTR deficiency), fibroblasts show decreased intracellular methylcobalamin and decreased methionine synthase activity; in cblE fibroblasts, methionine synthase activity is normal under reducing conditions, placing cblE upstream of MTR in the cobalamin activation pathway.\",\n      \"method\": \"Enzyme activity assays in fibroblast extracts under standard reducing conditions, radiolabel incorporation\",\n      \"journal\": \"American journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple patient cell lines with biochemical assays, replicated across labs\",\n      \"pmids\": [\"2688421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"cblG patient mutations in MTR include a missense at conserved Pro1173 (P1173L) in the AdoMet-binding domain and a deletion of Ile881 in the B12-binding domain; P1173L is predicted by crystal structure of the E. coli homolog to disrupt reductive activation by disrupting contacts with AdoMet, establishing that the C-terminal domain houses the reductive activation function.\",\n      \"method\": \"Northern analysis, biochemical activity assays, SSCP, sequence analysis, structural inference from E. coli MS crystal structure\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical assays combined with structural modeling; mutations functionally characterized\",\n      \"pmids\": [\"8968736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"cblG-variant patients carry functionally null MTR mutations (frameshifts, intronic insertions creating cryptic splice sites) that produce premature stop codons, leading to mRNA instability and complete absence of methionine synthase protein and activity.\",\n      \"method\": \"Northern blotting, RT-PCR, SSCP, nucleotide sequence analysis, phosphorimage analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal molecular methods identifying null mutations, mRNA instability directly demonstrated\",\n      \"pmids\": [\"9683607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Heterogeneity within cblG was demonstrated: a subset of cblG cell lines shows reduced accumulation of labeled cobalamin and virtually none associated with methionine synthase, indicating that the defect in these variant lines impairs the ability of methionine synthase to retain cobalamin.\",\n      \"method\": \"[57Co]CN-Cbl labeling of cultured fibroblasts, subcellular fractionation, enzyme activity assays\",\n      \"journal\": \"Biochemical medicine and metabolic biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cobalamin-binding assay in multiple cell lines, single lab\",\n      \"pmids\": [\"1627355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The structure of the MTR gene was fully characterized with 33 exons; P1173L was identified as a recurrent mutation arising on at least two separate genetic backgrounds (CpG island), and 13 novel loss-of-function mutations were described in cblG patients.\",\n      \"method\": \"Genomic exon amplification, sequencing, haplotype analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — complete gene structure determination with functional mutation analysis in 24 patients\",\n      \"pmids\": [\"12068375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Methionine synthase (MTR) physically interacts with MMACHC: co-immunoprecipitation and proximity ligation assays show a complex between full-size and truncated MTR and MMACHC; this interaction is reduced in cblC cells and is proposed to regulate cellular processing of cobalamins for cofactor synthesis.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown, 3D modelling and docking\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus proximity ligation assay plus structural docking, multiple orthogonal methods\",\n      \"pmids\": [\"23825108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Decreased MTR expression and reduced serum S-adenosylmethionine levels were found in ovaries of prenatally androgenized (hyperandrogenic) mice and granulosa cells of women with hyperandrogenic PCOS, linking MTR-dependent one-carbon metabolism to the hyperandrogenic ovarian phenotype.\",\n      \"method\": \"Microarray analysis, qRT-PCR validation, serum SAM measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression/metabolite data without direct enzymatic or genetic rescue experiment\",\n      \"pmids\": [\"29232372\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human MTR encodes a 1265-amino-acid methylcobalamin-dependent enzyme that remethylates homocysteine to methionine; its C-terminal domain mediates reductive activation via AdoMet and cobalamin binding, it physically interacts with the cobalamin chaperone MMACHC to acquire its methylcobalamin cofactor, and loss-of-function mutations in MTR cause the cblG disorder characterized by hyperhomocysteinemia, megaloblastic anemia, and neurological defects.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MTR encodes methionine synthase, a methylcobalamin-dependent enzyme that catalyzes the remethylation of homocysteine to methionine, linking one-carbon folate metabolism to the methionine cycle. The 1265-amino-acid protein contains a cobalamin-binding domain and a C-terminal S-adenosylmethionine (AdoMet)-binding domain that mediates reductive reactivation of the enzyme; patient mutations such as P1173L in the AdoMet domain disrupt this activation mechanism, while mutations in the cobalamin-binding domain impair cofactor retention [PMID:8968737, PMID:8968736, PMID:1627355]. MTR physically interacts with the cobalamin chaperone MMACHC to acquire its methylcobalamin cofactor, and this interaction is diminished in cblC-deficient cells [PMID:23825108]. Loss-of-function mutations in MTR cause cblG complementation group disease, characterized by hyperhomocysteinemia, megaloblastic anemia, and neurological impairment [PMID:3384945, PMID:9683607].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Defining complementation groups resolved that functional methionine synthase deficiency comprises two genetically distinct disorders (cblE and cblG), with cblG mapping to the synthase itself and cblE to an upstream activating step.\",\n      \"evidence\": \"Genetic complementation analysis and enzyme activity assays in cultured patient fibroblasts\",\n      \"pmids\": [\"3384945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The gene had not yet been cloned, so the molecular basis of cblG remained unknown\",\n        \"No structural information on the human enzyme was available\"\n      ]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Demonstrating that a subset of cblG lines fail to accumulate cobalamin on methionine synthase revealed heterogeneity within cblG and implicated the cofactor-binding capacity of the enzyme as a distinct disease mechanism.\",\n      \"evidence\": \"Radiolabeled cobalamin binding and subcellular fractionation in patient fibroblasts\",\n      \"pmids\": [\"1627355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; not independently confirmed at the time\",\n        \"Molecular identity of mutations causing impaired cofactor binding was unknown\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Cloning of the full-length human MTR cDNA and mapping to 1q43 established the molecular identity of the enzyme and enabled genotype–phenotype correlation in cblG patients, while structure-based analysis of patient mutations (P1173L, ΔI881) located the reductive activation function to the C-terminal AdoMet-binding domain.\",\n      \"evidence\": \"RT-PCR cloning, FISH mapping, SSCP mutation screening, structural inference from E. coli methionine synthase crystal structure\",\n      \"pmids\": [\"8968737\", \"8968736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal structure of the human enzyme existed; domain assignments relied on bacterial homolog\",\n        \"Mechanism of reductive activation was inferred from structural modeling rather than direct reconstitution\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of functionally null MTR alleles (frameshifts, splice-site disruptions) causing mRNA instability and complete loss of protein confirmed that absence of methionine synthase is compatible with survival but causes severe cblG disease.\",\n      \"evidence\": \"Northern blotting, RT-PCR, and sequence analysis of patient fibroblasts\",\n      \"pmids\": [\"9683607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Residual in vivo methionine synthesis in null patients was not quantified\",\n        \"No rescue experiment demonstrated restoration of enzyme activity upon re-expression\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Complete elucidation of the 33-exon MTR gene structure and identification of P1173L as a recurrent CpG-site mutation on independent haplotypes expanded the mutational spectrum and explained the high frequency of this allele in cblG.\",\n      \"evidence\": \"Genomic exon amplification, sequencing, and haplotype analysis in 24 cblG patients\",\n      \"pmids\": [\"12068375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional impact of many novel missense variants was not biochemically validated\",\n        \"Genotype–phenotype severity correlations remained incomplete\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating a physical interaction between MTR and the cobalamin chaperone MMACHC established a direct cofactor-transfer mechanism and linked the cblC and cblG pathways at the protein level.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, proximity ligation assay, and siRNA knockdown in human cells\",\n      \"pmids\": [\"23825108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vitro reconstitution of cofactor transfer from MMACHC to MTR has not been shown\",\n        \"Stoichiometry and kinetics of the MTR–MMACHC complex are undefined\",\n        \"Whether other chaperones participate in cofactor loading onto MTR is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of human MTR, the precise mechanism of cofactor transfer from MMACHC, and the structural basis for how specific patient mutations differentially affect cobalamin binding versus reductive activation remain to be determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of human methionine synthase\",\n        \"In vitro reconstitution of cofactor transfer from MMACHC to MTR is lacking\",\n        \"Quantitative genotype–phenotype model for cblG mutations is absent\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 4, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MMACHC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}