{"gene":"MTRR","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1988,"finding":"Genetic complementation analysis of patients with megaloblastic anemia and homocystinuria defined two complementation groups (cblE and cblG), demonstrating that at least two distinct loci are required for cobalamin-dependent methionine biosynthesis; cblE cells have normal methionine synthase activity under standard reducing conditions but deficient methylcobalamin synthesis, while cblG cells have decreased methionine synthase activity.","method":"Somatic cell complementation analysis, enzymatic assay of methionine synthase in fibroblast extracts, radiolabeled methyl-THF incorporation assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical reconstitution with multiple orthogonal methods (complementation, enzymatic assay, isotope incorporation) establishing two distinct loci; foundational discovery replicated across multiple patients","pmids":["3384945"],"is_preprint":false},{"year":1989,"finding":"In cblE patient fibroblasts, methionine synthase activity is normal under high-reducing conditions but decreases under limiting reductant (dithiothreitol), and methylcobalamin formation is severely reduced, indicating that the cblE defect specifically impairs the reductive activation/maintenance of methionine synthase rather than the enzyme itself.","method":"Enzymatic assay of methionine synthase under variable reducing conditions, radiolabeled cobalamin uptake/distribution assay in fibroblasts, complementation studies","journal":"American journal of medical genetics","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal biochemical methods in patient cells establishing mechanistic distinction between cblE and cblG; replicated across multiple patients","pmids":["2688421"],"is_preprint":false},{"year":1999,"finding":"MTRR (methionine synthase reductase) was cloned as a novel member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases and shown to be deficient in cblE patients; 11 mutations distributed throughout the coding region including FMN-, FAD-, and NADPH-binding sites were identified, establishing MTRR as the gene responsible for cblE disease and demonstrating its role in reductive activation of methionine synthase.","method":"RT-PCR, SSCP, heteroduplex analysis, DNA sequencing of patient cDNA; domain mapping of mutations to FMN/FAD/NADPH binding sites","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — cloning with mutational analysis across multiple patients mapping mutations to functional domains; foundational mechanistic paper","pmids":["10484769"],"is_preprint":false},{"year":2001,"finding":"The MTRR A66G polymorphism (Ile22Met substitution) significantly influences total plasma homocysteine concentrations; the 66AA genotype is associated with moderately elevated homocysteine independently of folate, vitamin B12, and vitamin B6 levels, indicating a direct functional effect of MTRR on one-carbon metabolism.","method":"Genotype/phenotype association study in 601 individuals with biochemical measurements; statistical modeling controlling for nutritional cofactors","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 3 — single population study linking genotype to biochemical phenotype (homocysteine), but no direct enzymatic reconstitution","pmids":["11472746"],"is_preprint":false},{"year":2002,"finding":"Two Czech cblE patients were shown to harbor mutations in the MTRR gene (compound heterozygote for c.1459G>A and c.1623-1624insTA; homozygote for a 140 bp insertion caused by intronic T>C transition activating an exon splicing enhancer), confirming MTRR as the causative gene for cblE homocystinuria and demonstrating that pre-mRNA mis-splicing is a pathogenic mechanism.","method":"Enzymatic studies in fibroblasts (methionine formation from formate), complementation studies, molecular analysis of MTRR gene (sequencing, mutation identification)","journal":"Journal of inherited metabolic disease","confidence":"High","confidence_rationale":"Tier 2 — enzymatic complementation studies combined with molecular mutation characterization in patient cells; replicated cblE-MTRR link","pmids":["12555939"],"is_preprint":false},{"year":2010,"finding":"The deep intronic c.903+469T>C mutation in MTRR is the most frequent cblE-causing mutation and creates an SF2/ASF (SRSF1) binding exonic splicing enhancer (ESE) within a cryptic pseudoexon, leading to pseudoexon inclusion in MTRR mRNA; blocking SF2/ASF by siRNA or cotransfection reduced pseudoexon inclusion, and in vitro RNA-binding assays showed dramatically increased SF2/ASF binding to the mutant ESE.","method":"Minigene splicing assays, siRNA knockdown, in vitro RNA-binding assays, cotransfection experiments","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (minigene, siRNA, in vitro binding) in a single study establishing the molecular mechanism of pseudoexon activation","pmids":["20120036"],"is_preprint":false},{"year":2015,"finding":"Splice-shifting oligonucleotides (SSOs) targeting the ESE created by the MTRR c.903+469T>C mutation correct aberrant MTRR splicing and restore MTRR enzymatic activity to ~50% of control in patient fibroblasts; the pseudoexon is maintained in a near-recognition state by a balance between an hnRNP A1-binding exonic splicing silencer (ESS) and two ESEs activated by the mutation.","method":"SSO transfection in patient cells, minigene assays, endogenous MTRR transcript analysis, enzymatic activity measurement in patient cells, in vitro splicing regulatory element characterization","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — functional rescue of enzymatic activity with mechanistic dissection of splicing regulatory elements using multiple orthogonal approaches","pmids":["25878036"],"is_preprint":false},{"year":2003,"finding":"Two patients homozygous for the novel MTRR missense mutation c.1361C>T (S454L) in a highly conserved FAD-binding domain presented with mild cblE phenotype (mainly megaloblastic anemia without neurological involvement), indicating that this FAD-binding domain mutation leads to partial loss of MTRR function.","method":"Enzymatic analysis in fibroblasts, complementation studies, radiolabeled methylcobalamin formation assay, DNA sequencing","journal":"Journal of inherited metabolic disease","confidence":"Medium","confidence_rationale":"Tier 2 — enzymatic and complementation studies in patient cells mapping mutation to FAD-binding domain; single lab but multiple methods","pmids":["12971424"],"is_preprint":false},{"year":2008,"finding":"The MTRR His595Tyr (rs10380) missense SNP in a risk haplotype is associated with elevated homocysteine secretion into culture medium, lower LINE-1 methylation, and lower MTRR protein expression in stable transfectants compared to wild-type haplotype transfectants, demonstrating functional consequences of this variant on MTRR activity and genome methylation.","method":"Stable transfection of risk vs. wild-type MTRR cDNA haplotypes, homocysteine measurement in culture medium, LINE-1 methylation assay, MTRR protein expression analysis","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro functional characterization of haplotype using stable transfectants with multiple outcome measures; single lab study","pmids":["18515090"],"is_preprint":false},{"year":2015,"finding":"MTRR silencing by RNA interference inhibits ovarian cancer cell proliferation, reduces cisplatin resistance, suppresses autophagy, and induces apoptosis in vitro; in vivo, MTRR-suppressed tumor-bearing mice treated with cisplatin show significantly reduced tumor volume. The mechanism involves regulation of caspase expression and mTOR signaling pathway.","method":"RNAi knockdown in ovarian cancer cell lines, cell proliferation assay, apoptosis assay, autophagy measurement, cisplatin resistance assay, in vivo xenograft model, Western blot for caspase and mTOR pathway components","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple phenotypic readouts in vitro and in vivo; single lab, pathway placement somewhat indirect","pmids":["26550452"],"is_preprint":false},{"year":2020,"finding":"Adult female mice with a hypomorphic Mtrr mutation (disrupting one-carbon metabolism) display enlarged livers with eosinophilic hepatocytes, decreased glycogen content, downregulation of glycogen synthesis genes (Ugp2, Gsk3a), and evidence of reduced β-oxidation of fatty acids, demonstrating that MTRR deficiency alters hepatic fuel storage and metabolism.","method":"Histological analysis of mouse livers, gene expression analysis, lipidomics, high-resolution respirometry (mitochondrial function), comparison to C57Bl/6J controls","journal":"Molecular genetics and metabolism reports","confidence":"Medium","confidence_rationale":"Tier 2 — defined loss-of-function mouse model with multiple orthogonal metabolic readouts; single study","pmids":["32257815"],"is_preprint":false}],"current_model":"MTRR encodes methionine synthase reductase, a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases that uses FMN, FAD, and NADPH to reductively activate methionine synthase (MTR), thereby maintaining the methylcobalamin cofactor required for the folate/cobalamin-dependent remethylation of homocysteine to methionine; loss-of-function mutations (including missense mutations in FAD/FMN/NADPH binding domains and a deep intronic splicing mutation that creates an SF2/ASF-dependent pseudoexon) cause the cblE complementation group of homocystinuria characterized by hyperhomocysteinemia and megaloblastic anemia, and MTRR deficiency in mice disrupts hepatic glycogen storage and one-carbon metabolism."},"narrative":{"teleology":[{"year":1988,"claim":"The existence of two distinct genetic loci required for cobalamin-dependent methionine biosynthesis was established by defining the cblE and cblG complementation groups, revealing that cblE cells retain methionine synthase catalytic activity but fail to generate methylcobalamin.","evidence":"Somatic cell complementation analysis and enzymatic/isotope incorporation assays in patient fibroblasts","pmids":["3384945"],"confidence":"High","gaps":["The cblE gene product was not identified","Whether cblE defect is in reductase activity versus cobalamin trafficking was unresolved"]},{"year":1989,"claim":"The cblE defect was pinpointed to reductive activation/maintenance of methionine synthase rather than the catalytic enzyme itself, because methionine synthase activity in cblE cells was normal under excess reducing agent but collapsed under limiting reductant.","evidence":"Methionine synthase activity assayed under variable dithiothreitol concentrations in patient fibroblasts with radiolabeled cobalamin distribution","pmids":["2688421"],"confidence":"High","gaps":["The reductase protein remained unidentified","No molecular basis for the reductive activation deficiency"]},{"year":1999,"claim":"Cloning of MTRR identified the cblE gene as a novel FNR-family electron transferase containing FMN, FAD, and NADPH binding domains, and 11 patient mutations distributed across all three cofactor-binding regions established that each domain is functionally essential.","evidence":"RT-PCR cloning, SSCP/heteroduplex analysis, and sequencing of patient cDNA with domain mapping","pmids":["10484769"],"confidence":"High","gaps":["No crystal structure to interpret mutations at atomic level","Kinetic properties of wild-type versus mutant MTRR not characterized in vitro"]},{"year":2002,"claim":"Identification of a pathogenic 140-bp pseudoexon insertion caused by an intronic T>C transition in MTRR revealed pre-mRNA mis-splicing as a major disease mechanism in cblE homocystinuria.","evidence":"Enzymatic complementation studies and MTRR sequencing in Czech cblE patients","pmids":["12555939"],"confidence":"High","gaps":["The splicing regulatory elements responsible were not characterized","Frequency of this mutation in the cblE population was unclear"]},{"year":2003,"claim":"A homozygous S454L mutation in the FAD-binding domain was shown to cause a mild cblE phenotype (megaloblastic anemia without neurological disease), establishing that partial loss of MTRR function produces an attenuated clinical spectrum.","evidence":"Enzymatic analysis, complementation, and methylcobalamin formation assay in patient fibroblasts","pmids":["12971424"],"confidence":"Medium","gaps":["Residual enzymatic activity of S454L not quantified in purified protein","Genotype–phenotype correlation across the full mutation spectrum not systematically assessed"]},{"year":2008,"claim":"The MTRR His595Tyr (rs10380) variant was shown to reduce MTRR protein levels, elevate homocysteine secretion, and decrease LINE-1 methylation in stable transfectants, linking common MTRR variation to genome-wide DNA methylation status.","evidence":"Stable transfection of risk vs. wild-type MTRR haplotypes with homocysteine, protein expression, and methylation analysis","pmids":["18515090"],"confidence":"Medium","gaps":["Mechanism of reduced protein expression (stability vs. translation) not determined","In vivo validation in human tissues lacking"]},{"year":2010,"claim":"The molecular mechanism of the most frequent cblE mutation (c.903+469T>C) was resolved: the mutation creates an SF2/ASF (SRSF1)-dependent exonic splicing enhancer within a cryptic pseudoexon, and blocking SF2/ASF binding eliminates pseudoexon inclusion.","evidence":"Minigene splicing assays, siRNA knockdown of SF2/ASF, in vitro RNA-binding assays","pmids":["20120036"],"confidence":"High","gaps":["Therapeutic reversibility not demonstrated","Contribution of other SR proteins not fully excluded"]},{"year":2015,"claim":"Splice-shifting oligonucleotides targeting the mutant ESE restored correct MTRR splicing and recovered ~50% of enzymatic activity in patient fibroblasts, and the pseudoexon was found to be maintained near recognition threshold by a balance between an hnRNP A1-binding silencer and two ESEs.","evidence":"SSO transfection in patient cells, minigene assays, endogenous transcript and enzymatic activity measurement","pmids":["25878036"],"confidence":"High","gaps":["In vivo delivery and efficacy of SSOs not tested","Long-term stability of correction unknown"]},{"year":2015,"claim":"MTRR knockdown in ovarian cancer cells inhibited proliferation, induced apoptosis via caspase activation, suppressed autophagy, and sensitized cells to cisplatin both in vitro and in xenografts, implicating MTRR-dependent one-carbon metabolism in chemoresistance through mTOR signaling.","evidence":"RNAi knockdown in cancer cell lines with proliferation, apoptosis, autophagy assays and in vivo xenograft model","pmids":["26550452"],"confidence":"Medium","gaps":["Whether the effect is through methionine synthase reactivation or alternative MTRR targets is unclear","Pathway connection to mTOR is correlative"]},{"year":2020,"claim":"Hypomorphic Mtrr mutation in mice depleted hepatic glycogen stores, downregulated glycogen synthesis genes (Ugp2, Gsk3a), and impaired fatty acid β-oxidation, extending MTRR's metabolic role beyond homocysteine remethylation to fuel storage homeostasis.","evidence":"Histology, gene expression, lipidomics, and high-resolution respirometry in Mtrr-mutant mouse livers","pmids":["32257815"],"confidence":"Medium","gaps":["Whether hepatic phenotype is a direct consequence of impaired methionine synthase activation or secondary to altered methyl donor availability is unresolved","Rescue by methionine or betaine supplementation not tested"]},{"year":null,"claim":"No high-resolution structural model of MTRR exists, the electron transfer mechanism from NADPH through FAD and FMN to the cobalamin cofactor of MTR has not been reconstituted with purified components at kinetic resolution, and the basis for genotype-phenotype severity differences across MTRR mutations remains poorly defined.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure","Electron transfer pathway kinetics not reconstituted in vitro with purified MTRR and MTR","Systematic genotype–phenotype correlation across all known mutations lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,4,5,7]}],"complexes":[],"partners":["MTR","SRSF1","HNRNPA1"],"other_free_text":[]},"mechanistic_narrative":"MTRR encodes methionine synthase reductase, a dual-flavin (FMN/FAD) and NADPH-dependent electron transferase of the ferredoxin-NADP⁺ reductase family that maintains the methylcobalamin cofactor of methionine synthase (MTR) in its active, reduced state, thereby sustaining the folate/cobalamin-dependent remethylation of homocysteine to methionine [PMID:10484769, PMID:2688421]. Loss-of-function mutations in MTRR, distributed across FMN-, FAD-, and NADPH-binding domains as well as deep intronic positions that activate pseudoexons through SF2/ASF-dependent exonic splicing enhancers, cause the cblE complementation group of homocystinuria characterized by megaloblastic anemia, hyperhomocysteinemia, and impaired methylcobalamin synthesis [PMID:3384945, PMID:10484769, PMID:20120036]. Splice-shifting oligonucleotides targeting the aberrant exonic splicing enhancer restore MTRR transcript integrity and recover approximately 50% of enzymatic activity in patient fibroblasts, establishing the pseudoexon mechanism as therapeutically reversible [PMID:25878036]. In mice, hypomorphic Mtrr disruption depletes hepatic glycogen stores and impairs fatty acid β-oxidation, linking MTRR-dependent one-carbon metabolism to broader fuel homeostasis [PMID:32257815]."},"prefetch_data":{"uniprot":{"accession":"Q9UBK8","full_name":"Methionine synthase reductase","aliases":["Aquacobalamin reductase","AqCbl reductase"],"length_aa":698,"mass_kda":77.7,"function":"Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin (PubMed:17892308). Cobalamin (vitamin B12) forms a complex with MTR to serve as an intermediary in methyl transfer reactions that cycles between MTR-bound methylcob(III)alamin and MTR bound-cob(I)alamin forms, and occasional oxidative escape of the cob(I)alamin intermediate during the catalytic cycle leads to the inactive cob(II)alamin species (Probable). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (PubMed:27771510). Also necessary for the utilization of methyl groups from the folate cycle, thereby affecting transgenerational epigenetic inheritance (By similarity). Also acts as a molecular chaperone for methionine synthase by stabilizing apoMTR and incorporating methylcob(III)alamin into apoMTR to form the holoenzyme (PubMed:16769880). Also serves as an aquacob(III)alamin reductase by reducing aquacob(III)alamin to cob(II)alamin; this reduction leads to stimulation of the conversion of apoMTR and aquacob(III)alamin to MTR holoenzyme (PubMed:16769880)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UBK8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTRR","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MTRR","total_profiled":1310},"omim":[{"mim_id":"607093","title":"5,10-@METHYLENETETRAHYDROFOLATE REDUCTASE; MTHFR","url":"https://www.omim.org/entry/607093"},{"mim_id":"602568","title":"METHIONINE SYNTHASE REDUCTASE; MTRR","url":"https://www.omim.org/entry/602568"},{"mim_id":"601634","title":"NEURAL TUBE DEFECTS, FOLATE-SENSITIVE; NTDFS","url":"https://www.omim.org/entry/601634"},{"mim_id":"250940","title":"HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG TYPE; HMAG","url":"https://www.omim.org/entry/250940"},{"mim_id":"236270","title":"HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblE TYPE; HMAE","url":"https://www.omim.org/entry/236270"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Intermediate filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTRR"},"hgnc":{"alias_symbol":["cblE"],"prev_symbol":[]},"alphafold":{"accession":"Q9UBK8","domains":[{"cath_id":"3.40.50.360","chopping":"3-158","consensus_level":"high","plddt":92.6849,"start":3,"end":158},{"cath_id":"3.40.50.80","chopping":"541-697","consensus_level":"high","plddt":94.8257,"start":541,"end":697}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBK8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBK8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBK8-F1-predicted_aligned_error_v6.png","plddt_mean":85.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTRR","jax_strain_url":"https://www.jax.org/strain/search?query=MTRR"},"sequence":{"accession":"Q9UBK8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBK8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBK8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBK8"}},"corpus_meta":[{"pmid":"11472746","id":"PMC_11472746","title":"The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations.","date":"2001","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/11472746","citation_count":210,"is_preprint":false},{"pmid":"11807892","id":"PMC_11807892","title":"Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; 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Definition of two complementation groups, cblE and cblG.","date":"1988","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/3384945","citation_count":70,"is_preprint":false},{"pmid":"26266420","id":"PMC_26266420","title":"Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency.","date":"2015","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/26266420","citation_count":67,"is_preprint":false},{"pmid":"17522601","id":"PMC_17522601","title":"Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women.","date":"2007","source":"European journal of clinical nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/17522601","citation_count":66,"is_preprint":false},{"pmid":"10484769","id":"PMC_10484769","title":"Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10484769","citation_count":64,"is_preprint":false},{"pmid":"14645274","id":"PMC_14645274","title":"FarR regulates the farAB-encoded efflux pump of Neisseria gonorrhoeae via an MtrR regulatory mechanism.","date":"2003","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/14645274","citation_count":60,"is_preprint":false},{"pmid":"18978065","id":"PMC_18978065","title":"MtrR modulates rpoH expression and levels of antimicrobial resistance in Neisseria gonorrhoeae.","date":"2008","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/18978065","citation_count":56,"is_preprint":false},{"pmid":"14632302","id":"PMC_14632302","title":"Genotype frequencies and linkage disequilibrium in the CEPH human diversity panel for variants in folate pathway genes MTHFR, MTHFD, MTRR, RFC1, and GCP2.","date":"2003","source":"Birth defects research. 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CL±P in a Chinese Population: Case-Control Study and Meta-Analysis.","date":"2014","source":"The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association","url":"https://pubmed.ncbi.nlm.nih.gov/25105440","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56243,"output_tokens":2926,"usd":0.10631},"stage2":{"model":"claude-opus-4-6","input_tokens":6261,"output_tokens":2539,"usd":0.14217},"total_usd":0.24848,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"Genetic complementation analysis of patients with megaloblastic anemia and homocystinuria defined two complementation groups (cblE and cblG), demonstrating that at least two distinct loci are required for cobalamin-dependent methionine biosynthesis; cblE cells have normal methionine synthase activity under standard reducing conditions but deficient methylcobalamin synthesis, while cblG cells have decreased methionine synthase activity.\",\n      \"method\": \"Somatic cell complementation analysis, enzymatic assay of methionine synthase in fibroblast extracts, radiolabeled methyl-THF incorporation assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical reconstitution with multiple orthogonal methods (complementation, enzymatic assay, isotope incorporation) establishing two distinct loci; foundational discovery replicated across multiple patients\",\n      \"pmids\": [\"3384945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"In cblE patient fibroblasts, methionine synthase activity is normal under high-reducing conditions but decreases under limiting reductant (dithiothreitol), and methylcobalamin formation is severely reduced, indicating that the cblE defect specifically impairs the reductive activation/maintenance of methionine synthase rather than the enzyme itself.\",\n      \"method\": \"Enzymatic assay of methionine synthase under variable reducing conditions, radiolabeled cobalamin uptake/distribution assay in fibroblasts, complementation studies\",\n      \"journal\": \"American journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal biochemical methods in patient cells establishing mechanistic distinction between cblE and cblG; replicated across multiple patients\",\n      \"pmids\": [\"2688421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MTRR (methionine synthase reductase) was cloned as a novel member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases and shown to be deficient in cblE patients; 11 mutations distributed throughout the coding region including FMN-, FAD-, and NADPH-binding sites were identified, establishing MTRR as the gene responsible for cblE disease and demonstrating its role in reductive activation of methionine synthase.\",\n      \"method\": \"RT-PCR, SSCP, heteroduplex analysis, DNA sequencing of patient cDNA; domain mapping of mutations to FMN/FAD/NADPH binding sites\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cloning with mutational analysis across multiple patients mapping mutations to functional domains; foundational mechanistic paper\",\n      \"pmids\": [\"10484769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The MTRR A66G polymorphism (Ile22Met substitution) significantly influences total plasma homocysteine concentrations; the 66AA genotype is associated with moderately elevated homocysteine independently of folate, vitamin B12, and vitamin B6 levels, indicating a direct functional effect of MTRR on one-carbon metabolism.\",\n      \"method\": \"Genotype/phenotype association study in 601 individuals with biochemical measurements; statistical modeling controlling for nutritional cofactors\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single population study linking genotype to biochemical phenotype (homocysteine), but no direct enzymatic reconstitution\",\n      \"pmids\": [\"11472746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Two Czech cblE patients were shown to harbor mutations in the MTRR gene (compound heterozygote for c.1459G>A and c.1623-1624insTA; homozygote for a 140 bp insertion caused by intronic T>C transition activating an exon splicing enhancer), confirming MTRR as the causative gene for cblE homocystinuria and demonstrating that pre-mRNA mis-splicing is a pathogenic mechanism.\",\n      \"method\": \"Enzymatic studies in fibroblasts (methionine formation from formate), complementation studies, molecular analysis of MTRR gene (sequencing, mutation identification)\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — enzymatic complementation studies combined with molecular mutation characterization in patient cells; replicated cblE-MTRR link\",\n      \"pmids\": [\"12555939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The deep intronic c.903+469T>C mutation in MTRR is the most frequent cblE-causing mutation and creates an SF2/ASF (SRSF1) binding exonic splicing enhancer (ESE) within a cryptic pseudoexon, leading to pseudoexon inclusion in MTRR mRNA; blocking SF2/ASF by siRNA or cotransfection reduced pseudoexon inclusion, and in vitro RNA-binding assays showed dramatically increased SF2/ASF binding to the mutant ESE.\",\n      \"method\": \"Minigene splicing assays, siRNA knockdown, in vitro RNA-binding assays, cotransfection experiments\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (minigene, siRNA, in vitro binding) in a single study establishing the molecular mechanism of pseudoexon activation\",\n      \"pmids\": [\"20120036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Splice-shifting oligonucleotides (SSOs) targeting the ESE created by the MTRR c.903+469T>C mutation correct aberrant MTRR splicing and restore MTRR enzymatic activity to ~50% of control in patient fibroblasts; the pseudoexon is maintained in a near-recognition state by a balance between an hnRNP A1-binding exonic splicing silencer (ESS) and two ESEs activated by the mutation.\",\n      \"method\": \"SSO transfection in patient cells, minigene assays, endogenous MTRR transcript analysis, enzymatic activity measurement in patient cells, in vitro splicing regulatory element characterization\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional rescue of enzymatic activity with mechanistic dissection of splicing regulatory elements using multiple orthogonal approaches\",\n      \"pmids\": [\"25878036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Two patients homozygous for the novel MTRR missense mutation c.1361C>T (S454L) in a highly conserved FAD-binding domain presented with mild cblE phenotype (mainly megaloblastic anemia without neurological involvement), indicating that this FAD-binding domain mutation leads to partial loss of MTRR function.\",\n      \"method\": \"Enzymatic analysis in fibroblasts, complementation studies, radiolabeled methylcobalamin formation assay, DNA sequencing\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — enzymatic and complementation studies in patient cells mapping mutation to FAD-binding domain; single lab but multiple methods\",\n      \"pmids\": [\"12971424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The MTRR His595Tyr (rs10380) missense SNP in a risk haplotype is associated with elevated homocysteine secretion into culture medium, lower LINE-1 methylation, and lower MTRR protein expression in stable transfectants compared to wild-type haplotype transfectants, demonstrating functional consequences of this variant on MTRR activity and genome methylation.\",\n      \"method\": \"Stable transfection of risk vs. wild-type MTRR cDNA haplotypes, homocysteine measurement in culture medium, LINE-1 methylation assay, MTRR protein expression analysis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional characterization of haplotype using stable transfectants with multiple outcome measures; single lab study\",\n      \"pmids\": [\"18515090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MTRR silencing by RNA interference inhibits ovarian cancer cell proliferation, reduces cisplatin resistance, suppresses autophagy, and induces apoptosis in vitro; in vivo, MTRR-suppressed tumor-bearing mice treated with cisplatin show significantly reduced tumor volume. The mechanism involves regulation of caspase expression and mTOR signaling pathway.\",\n      \"method\": \"RNAi knockdown in ovarian cancer cell lines, cell proliferation assay, apoptosis assay, autophagy measurement, cisplatin resistance assay, in vivo xenograft model, Western blot for caspase and mTOR pathway components\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple phenotypic readouts in vitro and in vivo; single lab, pathway placement somewhat indirect\",\n      \"pmids\": [\"26550452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Adult female mice with a hypomorphic Mtrr mutation (disrupting one-carbon metabolism) display enlarged livers with eosinophilic hepatocytes, decreased glycogen content, downregulation of glycogen synthesis genes (Ugp2, Gsk3a), and evidence of reduced β-oxidation of fatty acids, demonstrating that MTRR deficiency alters hepatic fuel storage and metabolism.\",\n      \"method\": \"Histological analysis of mouse livers, gene expression analysis, lipidomics, high-resolution respirometry (mitochondrial function), comparison to C57Bl/6J controls\",\n      \"journal\": \"Molecular genetics and metabolism reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined loss-of-function mouse model with multiple orthogonal metabolic readouts; single study\",\n      \"pmids\": [\"32257815\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTRR encodes methionine synthase reductase, a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases that uses FMN, FAD, and NADPH to reductively activate methionine synthase (MTR), thereby maintaining the methylcobalamin cofactor required for the folate/cobalamin-dependent remethylation of homocysteine to methionine; loss-of-function mutations (including missense mutations in FAD/FMN/NADPH binding domains and a deep intronic splicing mutation that creates an SF2/ASF-dependent pseudoexon) cause the cblE complementation group of homocystinuria characterized by hyperhomocysteinemia and megaloblastic anemia, and MTRR deficiency in mice disrupts hepatic glycogen storage and one-carbon metabolism.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MTRR encodes methionine synthase reductase, a dual-flavin (FMN/FAD) and NADPH-dependent electron transferase of the ferredoxin-NADP⁺ reductase family that maintains the methylcobalamin cofactor of methionine synthase (MTR) in its active, reduced state, thereby sustaining the folate/cobalamin-dependent remethylation of homocysteine to methionine [PMID:10484769, PMID:2688421]. Loss-of-function mutations in MTRR, distributed across FMN-, FAD-, and NADPH-binding domains as well as deep intronic positions that activate pseudoexons through SF2/ASF-dependent exonic splicing enhancers, cause the cblE complementation group of homocystinuria characterized by megaloblastic anemia, hyperhomocysteinemia, and impaired methylcobalamin synthesis [PMID:3384945, PMID:10484769, PMID:20120036]. Splice-shifting oligonucleotides targeting the aberrant exonic splicing enhancer restore MTRR transcript integrity and recover approximately 50% of enzymatic activity in patient fibroblasts, establishing the pseudoexon mechanism as therapeutically reversible [PMID:25878036]. In mice, hypomorphic Mtrr disruption depletes hepatic glycogen stores and impairs fatty acid β-oxidation, linking MTRR-dependent one-carbon metabolism to broader fuel homeostasis [PMID:32257815].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"The existence of two distinct genetic loci required for cobalamin-dependent methionine biosynthesis was established by defining the cblE and cblG complementation groups, revealing that cblE cells retain methionine synthase catalytic activity but fail to generate methylcobalamin.\",\n      \"evidence\": \"Somatic cell complementation analysis and enzymatic/isotope incorporation assays in patient fibroblasts\",\n      \"pmids\": [\"3384945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The cblE gene product was not identified\", \"Whether cblE defect is in reductase activity versus cobalamin trafficking was unresolved\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"The cblE defect was pinpointed to reductive activation/maintenance of methionine synthase rather than the catalytic enzyme itself, because methionine synthase activity in cblE cells was normal under excess reducing agent but collapsed under limiting reductant.\",\n      \"evidence\": \"Methionine synthase activity assayed under variable dithiothreitol concentrations in patient fibroblasts with radiolabeled cobalamin distribution\",\n      \"pmids\": [\"2688421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The reductase protein remained unidentified\", \"No molecular basis for the reductive activation deficiency\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Cloning of MTRR identified the cblE gene as a novel FNR-family electron transferase containing FMN, FAD, and NADPH binding domains, and 11 patient mutations distributed across all three cofactor-binding regions established that each domain is functionally essential.\",\n      \"evidence\": \"RT-PCR cloning, SSCP/heteroduplex analysis, and sequencing of patient cDNA with domain mapping\",\n      \"pmids\": [\"10484769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure to interpret mutations at atomic level\", \"Kinetic properties of wild-type versus mutant MTRR not characterized in vitro\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of a pathogenic 140-bp pseudoexon insertion caused by an intronic T>C transition in MTRR revealed pre-mRNA mis-splicing as a major disease mechanism in cblE homocystinuria.\",\n      \"evidence\": \"Enzymatic complementation studies and MTRR sequencing in Czech cblE patients\",\n      \"pmids\": [\"12555939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The splicing regulatory elements responsible were not characterized\", \"Frequency of this mutation in the cblE population was unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"A homozygous S454L mutation in the FAD-binding domain was shown to cause a mild cblE phenotype (megaloblastic anemia without neurological disease), establishing that partial loss of MTRR function produces an attenuated clinical spectrum.\",\n      \"evidence\": \"Enzymatic analysis, complementation, and methylcobalamin formation assay in patient fibroblasts\",\n      \"pmids\": [\"12971424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Residual enzymatic activity of S454L not quantified in purified protein\", \"Genotype–phenotype correlation across the full mutation spectrum not systematically assessed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The MTRR His595Tyr (rs10380) variant was shown to reduce MTRR protein levels, elevate homocysteine secretion, and decrease LINE-1 methylation in stable transfectants, linking common MTRR variation to genome-wide DNA methylation status.\",\n      \"evidence\": \"Stable transfection of risk vs. wild-type MTRR haplotypes with homocysteine, protein expression, and methylation analysis\",\n      \"pmids\": [\"18515090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of reduced protein expression (stability vs. translation) not determined\", \"In vivo validation in human tissues lacking\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The molecular mechanism of the most frequent cblE mutation (c.903+469T>C) was resolved: the mutation creates an SF2/ASF (SRSF1)-dependent exonic splicing enhancer within a cryptic pseudoexon, and blocking SF2/ASF binding eliminates pseudoexon inclusion.\",\n      \"evidence\": \"Minigene splicing assays, siRNA knockdown of SF2/ASF, in vitro RNA-binding assays\",\n      \"pmids\": [\"20120036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic reversibility not demonstrated\", \"Contribution of other SR proteins not fully excluded\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Splice-shifting oligonucleotides targeting the mutant ESE restored correct MTRR splicing and recovered ~50% of enzymatic activity in patient fibroblasts, and the pseudoexon was found to be maintained near recognition threshold by a balance between an hnRNP A1-binding silencer and two ESEs.\",\n      \"evidence\": \"SSO transfection in patient cells, minigene assays, endogenous transcript and enzymatic activity measurement\",\n      \"pmids\": [\"25878036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo delivery and efficacy of SSOs not tested\", \"Long-term stability of correction unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"MTRR knockdown in ovarian cancer cells inhibited proliferation, induced apoptosis via caspase activation, suppressed autophagy, and sensitized cells to cisplatin both in vitro and in xenografts, implicating MTRR-dependent one-carbon metabolism in chemoresistance through mTOR signaling.\",\n      \"evidence\": \"RNAi knockdown in cancer cell lines with proliferation, apoptosis, autophagy assays and in vivo xenograft model\",\n      \"pmids\": [\"26550452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the effect is through methionine synthase reactivation or alternative MTRR targets is unclear\", \"Pathway connection to mTOR is correlative\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Hypomorphic Mtrr mutation in mice depleted hepatic glycogen stores, downregulated glycogen synthesis genes (Ugp2, Gsk3a), and impaired fatty acid β-oxidation, extending MTRR's metabolic role beyond homocysteine remethylation to fuel storage homeostasis.\",\n      \"evidence\": \"Histology, gene expression, lipidomics, and high-resolution respirometry in Mtrr-mutant mouse livers\",\n      \"pmids\": [\"32257815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether hepatic phenotype is a direct consequence of impaired methionine synthase activation or secondary to altered methyl donor availability is unresolved\", \"Rescue by methionine or betaine supplementation not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structural model of MTRR exists, the electron transfer mechanism from NADPH through FAD and FMN to the cobalamin cofactor of MTR has not been reconstituted with purified components at kinetic resolution, and the basis for genotype-phenotype severity differences across MTRR mutations remains poorly defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure\", \"Electron transfer pathway kinetics not reconstituted in vitro with purified MTRR and MTR\", \"Systematic genotype–phenotype correlation across all known mutations lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 4, 5, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MTR\", \"SRSF1\", \"HNRNPA1\"],\n    \"other_free_text\": []\n  }\n}\n```"}