Affinage

RFC1

Replication factor C subunit 1 · UniProt P35251

Length
1148 aa
Mass
128.3 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RFC1 encodes the large subunit of the replication factor C (RFC) clamp loader, an ATP-utilizing complex that loads the PCNA sliding clamp onto DNA and thereby underpins DNA replication fidelity, repair, and telomere maintenance (PMID:9521689, PMID:9927446). It was first cloned as a GA-rich DNA-binding protein carrying an ATP/ADP-binding motif and nuclear localization signal, and assigned as the human ortholog of the mouse RFC large subunit (PMID:8512577, PMID:7914507). Yeast genetics establishes the mechanistic core: RFC1 mutation produces DNA replication defects, DNA-damage sensitivity, elongated telomeres and a mutator/repeat-instability phenotype, and RFC1 is synthetically lethal with PCNA, DNA Pol δ and Fen1, with destabilized PCNA trimers suppressing its replication defect — directly coupling RFC1 to PCNA clamp loading (PMID:9521689, PMID:9927446); allele-specific interactions with RFC5 further partition RFC1's roles in telomere maintenance, repair and viability from checkpoint signaling (PMID:11129041). RFC1 RNA peaks at the G1-to-S transition under control of dual GC-rich, Sp1-dependent promoters, a cell-cycle program conserved through the Drosophila DRE-DREF pathway (PMID:10375617, PMID:10231581, PMID:17381512). Within the clamp-loader family, RFC1-RFC selectively drives PCNA-CRL4(Cdt2)-mediated Cdt1 degradation after UV damage, whereas Ctf18-RFC handles Cdt1 turnover during S phase (PMID:22493068). Independently, the same locus (SLC19A1) encodes the reduced folate carrier, a bidirectional, equilibrating anion exchanger at the plasma membrane that mediates uptake of reduced folates and antifolates including methotrexate; its first transmembrane domain (E45) determines substrate selectivity and anion dependence, and a residue near helices 7-8 (codon 297) tunes the influx Km for N10-substituted folates (PMID:7641195, PMID:9261128, PMID:9668089, PMID:9446553). Biallelic intronic AAGGG repeat expansions in RFC1 cause CANVAS and late-onset ataxia without altering RFC1 expression (PMID:30926972); iPSC-neuron work shows the synaptic and developmental deficits are rescued by CRISPR deletion of the expanded allele but not reproduced by RFC1 knockdown or rescued by RFC1 reprovision, establishing a repeat-dependent, RFC1-protein-independent mechanism (PMID:39231235), with pathogenic motifs forming G-quadruplex and triplex structures in vitro (PMID:37660923). In compound heterozygosity with the expansion, truncating variants cause disease through partial loss of function via nonsense-mediated mRNA decay (PMID:36289003, PMID:35883251, PMID:36524104, PMID:36250766).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1994 Medium

    Establishing that the cloned GA-rich DNA-binding protein PO-GA is the human RFC large subunit answered what this protein is and pointed toward replication/repair function via its ATP-binding motif.

    Evidence cDNA expression cloning by DNA-binding, sequence comparison to mouse RFC, Northern blot of human tissues

    PMID:7914507 PMID:8512577

    Open questions at the time
    • DNA-binding specificity not linked to a defined replication step
    • No reconstitution of clamp-loading activity
  2. 1997 High

    Demonstrating that the same locus encodes the reduced folate carrier resolved its second identity as a membrane transporter and explained methotrexate uptake and resistance.

    Evidence cDNA transfection rescue of transport-deficient cells, MTX influx/efflux kinetics, uptake competition assays

    PMID:7641195 PMID:9261128

    Open questions at the time
    • Transport mechanism (equilibrating vs concentrative) defined functionally but not structurally
    • Relationship between transporter role and RFC clamp-loader role unexplained
  3. 1998 High

    Site-directed and natural variant analysis mapped the structural determinants of folate/antifolate substrate selectivity, showing specific transmembrane residues set substrate spectrum and anion dependence.

    Evidence E45K and codon-297 mutants reconstituted in carrier-null cells with substrate influx Km/Vmax and anion-substitution kinetics

    PMID:9446553 PMID:9668089

    Open questions at the time
    • No high-resolution structure of the carrier
    • Full transport cycle not modeled
  4. 1999 High

    Yeast genetics placed RFC1 mechanistically within PCNA clamp loading and replication-error suppression, defining its epistatic relationships with PCNA, Pol δ, Fen1 and mismatch repair and separating its functions from checkpoint signaling.

    Evidence Yeast rfc1 mutants/Tn3 alleles, in vitro replication assays with PCNA suppressors, synthetic lethality and mutation-frequency epistasis, allele-specific RFC5 suppression

    PMID:11129041 PMID:9521689 PMID:9927446

    Open questions at the time
    • Human RFC1 clamp-loading not directly reconstituted in these studies
    • Telomere maintenance role mechanistically undefined
  5. 1999 Medium

    Promoter and cell-cycle expression analysis showed RFC1 transcription is coordinated with the G1/S transition through Sp1-dependent dual promoters, a regulatory logic conserved to the Drosophila DRE-DREF pathway.

    Evidence RT-PCR across cell cycle, reporter/footprinting promoter dissection, EMSA/ChIP/RNAi in Drosophila S2 cells

    PMID:10231581 PMID:10375617 PMID:11162445 PMID:17381512 PMID:9602167

    Open questions at the time
    • Upstream signals coupling RFC1 transcription to cell-cycle machinery not fully defined
    • MTX-induced down-regulation mechanism (non-methylation) incomplete
  6. 2012 High

    Distinguishing RFC1-RFC from Ctf18-RFC in CRL4(Cdt2)-dependent Cdt1 proteolysis defined a context-specific role for canonical RFC in coupling PCNA loading to ubiquitin-mediated degradation after UV damage rather than during S phase.

    Evidence siRNA depletion of RFC1 vs Ctf18 in human cells, Cdt1 stability by Western/flow, chromatin fractionation, re-replication assay

    PMID:22493068

    Open questions at the time
    • Molecular basis of why RFC1-RFC acts only in repair context unknown
    • Direct interaction with CRL4(Cdt2) not structurally resolved
  7. 2019 High

    Linkage and genome sequencing identified biallelic intronic AAGGG repeat expansion as the cause of CANVAS, and the absence of expression change reframed the question away from simple RFC1 loss.

    Evidence Non-parametric linkage, genome sequencing, repeat-primed PCR/Southern, expression analysis in patient tissues

    PMID:30926972

    Open questions at the time
    • Pathogenic mechanism of the repeat not established
    • Cell type and pathway driving neurodegeneration unknown
  8. 2022 High

    Identification of truncating variants in trans with the expansion, with NMD and reduced transcript/protein, established that a partial loss-of-function mechanism contributes to RFC1-related CANVAS.

    Evidence Exome/genome sequencing across families, RT-PCR transcript quantification, Western blot in patient fibroblasts and blood

    PMID:35883251 PMID:36250766 PMID:36289003 PMID:36524104

    Open questions at the time
    • Reconciliation of loss-of-function with normal expression in biallelic-expansion patients incomplete
    • Quantitative dosage threshold for disease unknown
  9. 2023 Medium

    Biophysical and neuropathological work characterized the molecular nature of the repeat, showing pathogenic motifs uniquely form G-quadruplex/triplex structures and produce nuclear RNA foci, supporting toxic-DNA/RNA modes.

    Evidence In vitro G-quadruplex/triplex assays on synthetic oligonucleotides, RNA FISH on autopsy tissue

    PMID:37660923 PMID:38062616

    Open questions at the time
    • Causal link between secondary structures and neuronal toxicity not established in vivo
    • RNA foci finding limited to two autopsy cases
  10. 2024 High

    iPSC-neuron modeling resolved the CANVAS mechanism as repeat-dependent but RFC1-protein-independent, since allele deletion rescued synaptic deficits while RFC1 knockdown failed to phenocopy and reprovision failed to rescue.

    Evidence Patient iPSC-derived neurons, calcium imaging, transcriptomics, CRISPR allele deletion, RFC1 knockdown and overexpression, DNA-repair assays

    PMID:39231235

    Open questions at the time
    • Identity of the toxic species (DNA vs RNA vs RAN product) not pinned down
    • How repeat toxicity converges on synaptic connectivity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the repeat-dependent toxic mechanism mechanistically reconciles with the loss-of-function contribution of truncating variants, and what the toxic molecular species is.
  • No unified model linking expansion toxicity and partial loss-of-function
  • Toxic species and its cellular target not identified
  • No structural model of human RFC1 clamp-loader function in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140657 ATP-dependent activity 2 GO:0003677 DNA binding 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 3 R-HSA-69306 DNA Replication 2 R-HSA-73894 DNA Repair 2
Partners
CDT1PCNARFC5
Complex memberships
Replication factor C (RFC) clamp loader

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 PO-GA (RFC1) was identified as a human DNA-binding protein that selectively binds GA-rich double-stranded DNA sequences and certain single-stranded DNA sequences. The protein has regions of homology to E. coli and yeast DNA ligases and to proteins involved in DNA repair, suggesting roles in transcription, DNA repair, or replication. HeLa cDNA expression library screening with cognate DNA binding site; E. coli expression and DNA-binding assay; Northern blot Biochemical and biophysical research communications Medium 8512577
1994 PO-GA was shown to be 80% identical at the amino-acid level to the large subunit of mouse replication factor C (RFC), establishing it as the human RFC1 large subunit. The protein contains a nuclear translocation signal and an ATP/ADP-binding motif. Two mRNA species (5.3 kb and 4.5 kb) arise from alternate use of poly(A)-addition sites, with expression levels varying by tissue. DNA sequence database comparison; Northern blot of human tissues; cDNA sequence analysis of 3'-UTR Gene Medium 7914507
1995 RFC1 encodes the reduced folate carrier protein responsible for methotrexate (MTX) uptake in human breast cancer cells. Decreased RFC1 expression was the molecular mechanism of decreased MTX uptake in MTX-resistant ZR-75-1 cells; transfection with RFC1 restored MTX uptake with folinic acid competition preference over folic acid. Northern blot; Western blot with anti-RFC1 peptide antibody; cDNA transfection into transport-deficient cells; MTX uptake competition assay; FISH chromosomal mapping Cancer research High 7641195
1997 RFC1 functions as a bidirectional anion exchanger/reduced folate carrier. High-level RFC1 overexpression via transfection increased MTX influx ~9-fold and efflux ~5-fold but produced only a modest (~2-fold) increase in steady-state intracellular MTX, consistent with RFC1 being intrinsically equilibrating rather than concentrative. Free intracellular folate levels, not influx rate, determined antifolate activity. cDNA transfection of RFC1 into MTXrA carrier-null cells; radiolabeled MTX influx/efflux kinetics; intracellular MTX concentration measurement; IC50 determination The Journal of biological chemistry High 9261128
1997 The murine RFC-1 gene spans 10.4 kb and is distributed in eight exons including alternates of exon 1 and exon 5. Splice variants encoding polypeptides of 58, 53.6, and 43.4 kDa arise from alternate exon usage. A GC-rich region 5' of exon 1 contains promoter-like elements. Two distinct promoters drive RFC-1 transcription. Genomic DNA sequencing; cDNA library screening; splice variant identification; gene structure mapping Gene Medium 9161403
1998 A glutamate-to-lysine mutation at amino acid 45 (E45K) in the first predicted transmembrane domain of murine RFC1 markedly altered substrate specificity: folic acid influx doubled while MTX and 5-CHO-THF influx decreased. The E45K mutant carrier required small inorganic anions (chloride, fluoride, nitrate) for transport function, whereas the wild-type did not show this obligatory anion requirement. This indicates that the first transmembrane domain is critical for determining the spectrum of substrate affinities and carrier mobility. cDNA transfection of RFC1-E45K into carrier-null MTXrA cells; radiolabeled substrate influx assays; anion substitution experiments; inhibition kinetics The Journal of biological chemistry High 9668089
1998 A single amino acid difference at codon 297 (Ser in L1210 vs. Asn in S180 cells), located between transmembrane helices 7 and 8, accounts for a 4-fold higher influx Km for MTX in S180 cells without affecting Vmax or efflux. This residue is on or near the external substrate-binding site and selectively affects N1O-substituted folate analogues. The topology analysis places the codon-297 region on the external plasma membrane surface. Nucleotide sequencing of cDNA and genomic DNA; cDNA transfection of S180 vs. L1210 RFC-1 cDNAs into carrier-null L1210 variant; radiolabeled MTX/aminopterin influx Km measurements; Western blot; topology analysis The Journal of biological chemistry High 9446553
1998 The human RFC-1 gene spans 22.5 kb and contains eight exons including three alternatives of exon 1 (1a, 1b, 1c). Two distinct promoters were identified upstream of exons 1a/1c and 1b respectively by functional deletion analysis. Promoter 1 (upstream of exon 1a) had ~3-fold lower basal activity than promoter 2 (upstream of exon 1b), but was enhanced up to 9-fold with an SV40 enhancer. Promoter 2 contains a GC-rich direct repeat with Sp1 and MZF1 sites. Genomic DNA sequencing; primer extension analysis; luciferase reporter gene transient transfection in two human cell types; functional deletion analysis Gene Medium 9602167
1998 A mutation in the large subunit of yeast RFC (rfc1-1, D513N) within the conserved RFC box VIII sequence causes DNA replication defects, increased sensitivity to DNA-damaging agents, elongated telomeres, and in vitro DNA replication defects. Destabilized PCNA trimers (mutant PCNA) suppress the in vitro replication defects of rfc1-1 mutant complexes in an ATP-concentration-sensitive manner, suggesting that RFC1-PCNA interaction and PCNA clamp loading are mechanistically linked. Yeast genetics; in vitro DNA replication assay; PCNA mutant suppressor analysis; DNA damage sensitivity assay; telomere length analysis Biochemistry High 9521689
1998 RFC1 gene copy number amplification at a homogeneously staining region (HSR) in a chromosome 10 locus in the L1210/R83 variant underlies a 30-35-fold increase in RFC-1 mRNA and a 35-fold increase in MTX transport Vmax. Chromosomal localization of murine RFC-1 gene is on chromosome 10B3 in association with the Col18a1 collagen gene. Southern blot (gene copy number); Northern blot (mRNA levels); FISH (chromosomal localization and HSR identification); MTX influx Vmax measurement; karyotype analysis Cancer genetics and cytogenetics Medium 9689927
1999 The rfc1::Tn3 (large subunit of yeast clamp loader RFC) mutant displays a mutator phenotype and repeat-tract instability. Genetic epistasis analysis shows that rfc1::Tn3 is synthetically lethal with pol30 (PCNA), pol3 (DNA Pol δ), and rad27 (Fen1) mutations. The rfc1::Tn3 forward mutation frequency is nearly multiplicative with mismatch repair mutants (msh2Δ, pms1Δ), but its repeat-tract instability phenotype is epistatic to mismatch repair mutants, indicating RFC1 generates replication errors that are partially corrected by MMR. Yeast genetic screen; forward mutation assay; repeat-tract instability assay; double and triple mutant analysis with msh2Δ, pms1Δ, rad52, pol3-01, pol30-52, rth1Δ/rad27Δ; synthetic lethality testing Genetics High 9927446
1999 RFC1 RNA levels are cell-cycle regulated and peak at the G1-to-S transition. Differential transcription from multiple RFC1 5' non-coding exons occurs in different tissues, during development, and in MTX-resistant cells. Genomic sequences upstream of exons 1b and 1c contain functional promoter elements, identified by promoter-reporter fusion constructs. Semi-quantitative RT-PCR with exon-specific primers; RFC1 promoter-reporter fusion constructs; Northern blot Gene Medium 10375617
1999 Two promoters regulating mouse RFC-1 gene expression were functionally characterized. The promoter upstream of exon 1 (stronger) and the promoter upstream of exon 1a (weaker) each rely on closely spaced tandem Sp1 sites for basal promoter activity, as demonstrated by site-directed mutagenesis and DNase I footprinting. A poly(GT)21 dinucleotide repeat upstream of the Sp1 sites suppresses transcription when deleted. Luciferase reporter gene transient transfection in NIH3T3 cells; site-directed mutagenesis of Sp1 sites; DNase I footprinting analysis Gene Medium 10231581
2000 Exposure of ZR-75-1 breast cancer cells to low-dose MTX caused transcriptional down-regulation of RFC1: RFC1 RNA and protein levels decreased to ~22% of baseline, and promoter-reporter assays showed decreased activity of RFC1 promoter elements. This down-regulation was not due to DNA methylation of the RFC1 promoter (5-azacytidine pretreatment did not restore RFC1 activity). Western blot; Northern blot; RT-PCR with exon-specific primers; promoter-reporter construct assays; MTX uptake measurement; 5-azacytidine pretreatment experiment Biochemical and biophysical research communications Medium 11162445
2000 Allele-specific genetic interactions between yeast RFC1 and RFC5 genes were identified: RFC5 mutations in conserved RFC box motifs IV-VII suppress the cold-sensitive growth phenotype of rfc1-1 mutants but cannot suppress its elongated telomere, DNA-damage sensitivity, or mutator phenotypes. RFC5 suppressor mutations do not interfere with checkpoint signaling (Rad53p phosphorylation). This defines distinct functional contributions of RFC1 and RFC5 to telomere maintenance, DNA repair, and viability versus checkpoint function. Yeast genetics; allele-specific suppressor isolation; phenotypic analysis (growth, DNA damage sensitivity, telomere length, mutation frequency); Rad53p phosphorylation assay (Western blot) Molecular & general genetics Medium 11129041
2007 Drosophila rfc1 gene (encoding dRFC140, the large RFC subunit) is transcriptionally regulated by the DRE-DREF pathway. Three DRE-like sequences in the rfc1 promoter bind DREF in vitro (EMSA with nuclear extracts) and in vivo (chromatin immunoprecipitation). Luciferase reporter assays confirm that DREs are required for full rfc1 promoter activity in S2 cells; DREF dsRNA knockdown reduced rfc1 promoter activity by 38%. Immunostaining shows rfc1 expression correlates with cell-cycle stage. Band-mobility shift assay (EMSA); chromatin immunoprecipitation; luciferase transient expression assay in S2 cells; DREF dsRNA knockdown; immunostaining of polytene chromosomes and larval tissues The FEBS journal Medium 17381512
2012 RFC1-RFC (the canonical clamp loader) is required for PCNA-CRL4(Cdt2)-mediated Cdt1 degradation specifically after UV irradiation (during nucleotide excision repair), but not during S phase. A distinct RFC complex, Ctf18-RFC, is required for Cdt1 degradation during S phase. Thus, different RFC complexes differentially control CRL4(Cdt2)-dependent proteolysis of Cdt1 during replication versus repair. siRNA depletion of RFC1 and Ctf18 in human cells; flow cytometry and Western blot of Cdt1 stability; chromatin fractionation for PCNA loading; re-replication assay; Cdt1 degron mutant constructs Molecular and cellular biology High 22493068
2019 Biallelic intronic AAGGG repeat expansion in RFC1 intron 2 (within the poly(A) tail of an AluSx3 element) is the genetic cause of CANVAS and late-onset ataxia. Critically, the expansion does not affect RFC1 expression in patient peripheral and brain tissue, suggesting the pathogenic mechanism is not simple loss of RFC1 protein function. Non-parametric linkage analysis; genome sequencing; quantitative expression analysis in patient peripheral and brain tissue; repeat-primed PCR; Southern blot Nature genetics High 30926972
2022 Truncating variants (nonsense and frameshift) in RFC1, when compound heterozygous with the AAGGG repeat expansion, cause CANVAS. Patient fibroblasts with truncating variants show nonsense-mediated mRNA decay and reduced RFC1 transcript and protein levels, providing evidence that a loss-of-function mechanism underlies RFC1-related CANVAS. Whole-genome/exome sequencing; RT-PCR quantification of RFC1 transcript; Western blot of RFC1 protein in patient fibroblasts; nonsense-mediated decay assessment Neurology High 35883251 36250766 36289003 36524104
2022 RFC1 expression studies in whole blood from CANVAS patients compound heterozygous for truncating variants and AAGGG expansion showed significantly reduced RFC1 mRNA compared with patients carrying biallelic RFC1 expansions alone, providing additional evidence for conditional loss-of-function as a disease mechanism. Quantitative RT-PCR of RFC1 mRNA in patient whole blood; clinical exome sequencing; repeat-primed PCR for expansion identification Brain Medium 35883251
2023 Pathogenic CANVAS-causing RFC1 repeat motifs (AAGGG and ACAGG) but not nonpathogenic motifs (AAAAG) form G-quadruplex structures (in potassium solution) and triple-stranded structures. The pathogenic motif r(AAGGG)4 forms G-quadruplexes detectable with the ligand TMPyP4. Nonpathogenic repeats do not form these structures. This supports toxic-DNA and toxic-RNA modes of pathogenesis via unusual nucleic acid secondary structures. In vitro biophysical characterization of synthetic DNA/RNA oligonucleotides; G-quadruplex detection in potassium solution; triplex structure formation assays; TMPyP4 ligand-binding assay; computational analysis of hydrogen bonds and pi-stacking The Journal of biological chemistry Medium 37660923
2024 CCCTT/AAGGG repeat expansions in CANVAS patient iPSC-derived neurons do not alter RFC1 splicing, expression, or DNA repair pathway function. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded AAGGG allele. These neuronal deficits were NOT replicated by RFC1 knockdown in control neurons and were NOT rescued by RFC1 reprovision, establishing that the pathogenic mechanism is repeat-dependent but RFC1 protein-independent. Patient iPSC-derived neuron generation; calcium imaging; transcriptomics; CRISPR allele deletion; RFC1 knockdown (siRNA/shRNA); RFC1 overexpression/reprovision; RT-PCR for RFC1 splicing; DNA repair pathway functional assays Science advances High 39231235
2023 CCCTT- and CCCGT-containing RNA foci were detected by RNA FISH in neuronal nuclei of tissues with neuronal loss in two autopsy CANVAS patients with biallelic ACAGG and AAGGG expansions, respectively. This suggests that RNA toxicity (toxic RNA gain-of-function) may contribute to CANVAS pathogenesis. RNA fluorescence in situ hybridization (FISH) on autopsy tissue; neuropathological analysis Annals of neurology Low 38062616

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nature genetics 432 30926972
2019 Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS. American journal of human genetics 192 31230722
1995 Isolation of a gene encoding a human reduced folate carrier (RFC1) and analysis of its expression in transport-deficient, methotrexate-resistant human breast cancer cells. Cancer research 187 7641195
2020 A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families. Brain : a journal of neurology 80 33103729
2020 A Māori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele. Brain : a journal of neurology 65 32851396
1998 A mutated murine reduced folate carrier (RFC1) with increased affinity for folic acid, decreased affinity for methotrexate, and an obligatory anion requirement for transport function. The Journal of biological chemistry 65 9668089
2019 Investigation of the RFC1 Repeat Expansion in a Canadian and a Brazilian Ataxia Cohort: Identification of Novel Conformations. Frontiers in genetics 64 31824583
2023 Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis. Brain : a journal of neurology 61 37450567
1997 Impact of overexpression of the reduced folate carrier (RFC1), an anion exchanger, on concentrative transport in murine L1210 leukemia cells. The Journal of biological chemistry 58 9261128
2003 Genotype frequencies and linkage disequilibrium in the CEPH human diversity panel for variants in folate pathway genes MTHFR, MTHFD, MTRR, RFC1, and GCP2. Birth defects research. Part A, Clinical and molecular teratology 56 14632302
2020 Biallelic Intronic AAGGG Expansion of RFC1 is Related to Multiple System Atrophy. Annals of neurology 53 32939785
1998 A single amino acid difference within the folate transporter encoded by the murine RFC-1 gene selectively alters its interaction with folate analogues. Implications for intrinsic antifolate resistance and directional orientation of the transporter within the plasma membrane of tumor cells. The Journal of biological chemistry 53 9446553
2020 Prevalence of RFC1-mediated spinocerebellar ataxia in a North American ataxia cohort. Neurology. Genetics 51 32582864
2008 Influence of MTHFR and RFC1 polymorphisms on toxicities during maintenance chemotherapy for childhood acute lymphoblastic leukemia or lymphoma. Journal of pediatric hematology/oncology 49 18458567
1998 Structural analysis of the human RFC-1 gene encoding a folate transporter reveals multiple promoters and alternatively spliced transcripts with 5' end heterogeneity. Gene 49 9602167
2018 Removal and biodegradation of different petroleum hydrocarbons using the filamentous fungus Aspergillus sp. RFC-1. MicrobiologyOpen 46 29577679
2022 Truncating Variants in RFC1 in Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome. Neurology 44 36289003
2011 Association of MTHFR, MTR, MTRR, RFC1, and DHFR gene polymorphisms with susceptibility to sporadic colon cancer. DNA and cell biology 44 21438757
2020 Clinical spectrum of the pentanucleotide repeat expansion in the RFC1 gene in ataxia syndromes. Neurology 42 32873692
2003 Effects of the glutamate carboxypeptidase II (GCP2 1561C>T) and reduced folate carrier (RFC1 80G>A) allelic variants on folate and total homocysteine levels in kidney transplant patients. Kidney international 42 12753319
2020 RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia. Journal of human genetics 41 32694621
2014 RFC1 80G>A is a genetic determinant of methotrexate efficacy in rheumatoid arthritis: a human genome epidemiologic review and meta-analysis of observational studies. Arthritis & rheumatology (Hoboken, N.J.) 41 24782176
2011 Association of MTHFR and RFC1 gene polymorphism with hyperhomocysteinemia and its modulation by vitamin B12 and folic acid in an Indian population. European journal of clinical nutrition 41 21878957
1999 Characterization of the repeat-tract instability and mutator phenotypes conferred by a Tn3 insertion in RFC1, the large subunit of the yeast clamp loader. Genetics 40 9927446
2008 Association of RFC1 A80G and MTHFR C677T polymorphisms with Alzheimer's disease. Neurobiology of aging 39 18258338
2022 RFC1-Related Disease: Molecular and Clinical Insights. Neurology. Genetics 38 36046423
2011 The role of MTHFR and RFC1 polymorphisms on toxicity and outcome of adult patients with hematological malignancies treated with high-dose methotrexate followed by leucovorin rescue. Cancer chemotherapy and pharmacology 37 21984221
2022 RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology. Brain : a journal of neurology 36 35883251
2021 RFC1 AAGGG repeat expansion masquerading as Chronic Idiopathic Axonal Polyneuropathy. Journal of neurology 36 33884451
2015 Impact of genetic variants of RFC1, DHFR and MTHFR in osteosarcoma patients treated with high-dose methotrexate. The pharmacogenomics journal 36 25778468
1997 Reduced folate carrier gene (RFC1) expression and anti-folate resistance in transfected and non-selected cell lines. International journal of cancer 35 9212241
2015 Associations between single-nucleotide polymorphisms of RFC-1, GGH, MTHFR , TYMS, and TCII genes and the efficacy and toxicity of methotrexate treatment in patients with rheumatoid arthritis. Polskie Archiwum Medycyny Wewnetrznej 33 25599563
2008 Correlation of polymorphism of MTHFRs and RFC-1 genes with neural tube defects in China. Birth defects research. Part A, Clinical and molecular teratology 33 18022874
2021 Biallelic RFC1-expansion in a French multicentric sporadic ataxia cohort. Journal of neurology 32 33666721
1993 Cloning and expression of a novel human DNA binding protein, PO-GA. Biochemical and biophysical research communications 30 8512577
1997 Organization, structure and alternate splicing of the murine RFC-1 gene encoding a folate transporter. Gene 29 9161403
2021 Brain Structural Signature of RFC1-Related Disorder. Movement disorders : official journal of the Movement Disorder Society 28 34241918
2022 Biallelic expansion in RFC1 as a rare cause of Parkinson's disease. NPJ Parkinson's disease 26 35013364
1999 Isolation and characterization of genomic sequences involved in the regulation of the human reduced folate carrier gene (RFC1). Gene 26 10375617
2007 Transcriptional regulation of the Drosophila rfc1 gene by the DRE-DREF pathway. The FEBS journal 24 17381512
2022 New Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome cases are caused by the presence of a nonsense variant in compound heterozygosity with the pathogenic repeat expansion in the RFC1 gene. Clinical genetics 21 36250766
2018 Biodegradation of n-hexadecane by Aspergillus sp. RFC-1 and its mechanism. Ecotoxicology and environmental safety 21 30142606
2016 The application of GBS markers for extending the dense genetic map of rye (Secale cereale L.) and the localization of the Rfc1 gene restoring male fertility in plants with the C source of sterility-inducing cytoplasm. Journal of applied genetics 21 27085345
2023 Association of biallelic RFC1 expansion with early-onset Parkinson's disease. European journal of neurology 20 36705320
2009 Investigation of CBS, MTR, RFC-1 and TC polymorphisms as maternal risk factors for Down syndrome. Disease markers 20 19729796
2008 Reduced folate carrier 1 (RFC1) is associated with cleft of the lip only. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 20 18797703
2008 A80G polymorphism of reduced folate carrier 1 (RFC1) and C776G polymorphism of transcobalamin 2 (TC2) genes in Down's syndrome etiology. Sao Paulo medical journal = Revista paulista de medicina 20 19274320
1998 Variable expression of RFC1 in human leukemia cell lines resistant to antifolates. Cancer letters 20 9500202
2013 Role of methotrexate polyglutamation and reduced folate carrier 1 (RFC1) gene polymorphisms in clinical assessment indexes. Drug metabolism and pharmacokinetics 19 23545592
2012 Two different replication factor C proteins, Ctf18 and RFC1, separately control PCNA-CRL4Cdt2-mediated Cdt1 proteolysis during S phase and following UV irradiation. Molecular and cellular biology 19 22493068
2023 RFC1 in an Australasian neurological disease cohort: extending the genetic heterogeneity and implications for diagnostics. Brain communications 18 37621409
2021 Biallelic RFC1 pentanucleotide repeat expansions in Greek patients with late-onset ataxia. Clinical genetics 17 33745133
2019 Polymorphisms in MTHFR, MTR, RFC1 and CßS genes involved in folate metabolism and thyroid cancer: a case-control study. Archives of medical science : AMS 17 30899306
2013 Epigenetic modulation of RFC1, MHC2TA and HLA-DR in systemic lupus erythematosus: association with serological markers and six functional polymorphisms of one-carbon metabolic pathway. Gene 17 24333266
2023 Pathogenic CANVAS-causing but not nonpathogenic RFC1 DNA/RNA repeat motifs form quadruplex or triplex structures. The Journal of biological chemistry 16 37660923
2022 Motor neuron involvement expands the neuropathological phenotype of late-onset ataxia in RFC1 mutation (CANVAS). Brain pathology (Zurich, Switzerland) 16 35001451
2022 Whole-Genome and Long-Read Sequencing Identify a Novel Mechanism in RFC1 Resulting in CANVAS Syndrome. Neurology. Genetics 16 36524104
2024 AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS neurons. Science advances 15 39231235
2024 Profiling complex repeat expansions in RFC1 in Parkinson's disease. NPJ Parkinson's disease 14 38789445
2022 Multi-type RFC1 repeat expansions as the most common cause of hereditary sensory and autonomic neuropathy. Frontiers in neurology 14 36061987
2019 Association of MTHFR and RFC1 gene polymorphisms with methotrexate efficacy and toxicity in Chinese Han patients with rheumatoid arthritis. The Journal of international medical research 14 31617429
2013 The reduced folate carrier (RFC-1) 80A>G polymorphism and maternal risk of having a child with Down syndrome: a meta-analysis. Nutrients 14 23857226
2000 Down-regulation of reduced folate carrier gene (RFC1) expression after exposure to methotrexate in ZR-75-1 breast cancer cells. Biochemical and biophysical research communications 14 11162445
2021 Investigating RFC1 expansions in sporadic amyotrophic lateral sclerosis. Journal of the neurological sciences 13 34537679
2016 The association between RFC1 G80A polymorphism and cancer susceptibility: Evidence from 33 studies. Journal of Cancer 13 26819637
2022 Cognitive Impairment in a Complex Family With AAGGG and ACAGG Repeat Expansions in RFC1 Detected by ExpansionHunter Denovo. Neurology. Genetics 12 36381255
2017 MTRR A66G, RFC1 G80A, and MTHFR C677T and A1298C Polymorphisms and Disease Activity in Mexicans with Rheumatoid Arthritis Treated with Methotrexate. Genetic testing and molecular biomarkers 12 28994615
2017 The study of association between reduced folate carrier 1 (RFC1) polymorphism and non-syndromic cleft lip/palate in Iranian population. BioImpacts : BI 12 29435434
2014 RFC1 and non-syndromic cleft lip with or without cleft palate: an association based study in Italy. Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery 12 24942095
2010 A80G polymorphism of reduced folate carrier 1 (RFC1) gene and head and neck squamous cell carcinoma etiology in Brazilian population. Molecular biology reports 12 20661649
1994 The human DNA-binding protein, PO-GA, is homologous to the large subunit of mouse replication factor C: regulation by alternate 3' processing of mRNA. Gene 12 7914507
2013 The influence of genetic RFC1, MS and MTHFR polymorphisms on the risk of acute lymphoblastic leukemia relapse in children and the adverse effects of methotrexate. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 11 23986219
2011 DArT markers tightly linked with the Rfc1 gene controlling restoration of male fertility in the CMS-C system in cultivated rye (Secale cereale L.). Journal of applied genetics 11 21559995
2022 Screening for RFC-1 pathological expansion in late-onset ataxias: a contribution to the differential diagnosis. Journal of neurology 10 35633373
2016 A Study of Single Nucleotide Polymorphisms of the SLC19A1/RFC1 Gene in Subjects with Autism Spectrum Disorder. International journal of molecular sciences 10 27213354
2015 Association of reduced folate carrier-1 (RFC-1) polymorphisms with ischemic stroke and silent brain infarction. PloS one 10 25659099
1998 Destabilized PCNA trimers suppress defective Rfc1 proteins in vivo and in vitro. Biochemistry 10 9521689
2025 Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson's disease. NPJ Parkinson's disease 9 39833204
2024 RFC1: Motifs and phenotypes. Revue neurologique 9 38627134
2016 The RFC1 80G>A, among Common One-Carbon Polymorphisms, Relates to Survival Rate According to DNA Global Methylation in Primary Liver Cancers. PloS one 9 27936032
2014 RFC-1 80G>A polymorphism in case-mother/control-mother dyads is associated with risk of nephroblastoma and neuroblastoma. Genetic testing and molecular biomarkers 9 25536437
2014 Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors. Clinical epigenetics 8 24401732
1999 Transcription of the mouse RFC-1 gene encoding a folate transporter. Multiplicity and properties of promoters with minimum requirements for their basal activity. Gene 8 10231581
2024 Chronic Cough and Cerebellar Ataxia With Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS): Screening for Mutations in Replication Factor C Subunit 1 (RFC1). Archivos de bronconeumologia 7 38755058
2023 Investigation of RFC1 tandem nucleotide repeat locus in diverse neurodegenerative outcomes in an Indian cohort. Neurogenetics 7 37917284
1998 Chromosomal localization of the murine RFC-1 gene encoding a folate transporter and its amplification in an antifolate resistant variant overproducing the transporter. Cancer genetics and cytogenetics 7 9689927
2025 Repeat expansions in RFC1 gene in refractory chronic cough. ERJ open research 6 39811557
2023 RNA Foci in Two bi-Allelic RFC1 Expansion Carriers. Annals of neurology 6 38062616
2020 Spasmodic cough preceding CANVAS phenotype in a family with biallelic repeat expansions in RFC1. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 6 33188504
2016 Association Between RFC1 G80A Polymorphism and Acute Lymphoblastic Leukemia: a Review and Meta-Analysis of 10 Studies. Iranian journal of pediatric hematology and oncology 6 27222703
2005 [Epidemiological study on reduced folate carrier gene(RFC1 A80G) polymorphism and other risk factors of neural tube defects]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 6 16086047
2004 [Study on reduced folate carrier gene (RFC1) polymorphism in the southern and northern Chinese population]. Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi 6 15231126
2024 RFC1 Repeat Distribution in the Cypriot Population: Study of a Large Cohort of Patients With Undiagnosed Ataxia and Non-Disease Controls. Neurology. Genetics 5 38685975
2023 AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons. bioRxiv : the preprint server for biology 5 38168171
2022 Expanding the Clinical Spectrum of RFC1 Gene Mutations. Journal of movement disorders 5 35306791
2022 Beyond canvas: behavioral onset of rfc1-expansion disease in an Italian family-causal or casual? Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 5 35585435
2021 Influence of RFC1 c.80A>G Polymorphism on Methotrexate-Mediated Toxicity and Therapeutic Efficacy in Rheumatoid Arthritis: A Meta-analysis. The Annals of pharmacotherapy 5 33749319
2009 [Relationship between genetic polymorphisms of RFC1 A80G and nonsymdromic cleft lip with or without palate]. Wei sheng yan jiu = Journal of hygiene research 5 19548564
2000 Allele-specific interactions between the yeast RFC1 and RFC5 genes suggest a basis for RFC subunit-subunit interactions. Molecular & general genetics : MGG 5 11129041
2024 An Updated Canvas of the RFC1-mediated CANVAS (Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome). Molecular neurobiology 4 38898197

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