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1
Amin, Neelam S., K. Michelle Tuffo, and Connie Holm. "Dominant Mutations in Three Different Subunits of Replication Factor C Suppress Replication Defects in Yeast PCNA Mutants." Genetics 153, no. 4 (December 1, 1999): 1617–28. http://dx.doi.org/10.1093/genetics/153.4.1617.
Abstract:
Abstract To identify proteins that interact with the yeast proliferating cell nuclear antigen (PCNA), we used a genetic approach to isolate mutations that compensate for the defects in cold-sensitive (Cs−) mutants of yeast PCNA (POL30). Because the cocrystal structure of human PCNA and a p21WAF1/CIP1 peptide shows that the interdomain region of PCNA is a site of p21 interaction, we specifically looked for new mutations that suppress mutations in the equivalent region of yeast PCNA. In independent screens using three different Cs− mutants, we identified spontaneously arising dominant suppressor mutations in the RFC3 gene. In addition, dominant suppressor mutations were identified in the RFC1 and RFC2 genes using a single pol30 mutant. An intimate association between PCNA and RFC1p, RFC2p, and RFC3p is suggested by the allele-restricted suppression of 10 different pol30 alleles by the RFC suppressors. RFC1, RFC2, and RFC3 encode three of the five subunits of the replication factor C complex, which is required to load PCNA onto DNA in reconstituted DNA replication reactions. Genomic sequencing reveals a common region in RFC1p, RFC2p, and RFC3p that is important for the functional interaction with PCNA. Biochemical analysis of the wild type and mutant PCNA and RFC3 proteins shows that mutant RFC3p enhances the production of long DNA products in pol δ-dependent DNA synthesis, which is consistent with an increase in processivity.
2
Cullmann, G., K. Fien, R. Kobayashi, and B. Stillman. "Characterization of the five replication factor C genes of Saccharomyces cerevisiae." Molecular and Cellular Biology 15, no. 9 (September 1995): 4661–71. http://dx.doi.org/10.1128/mcb.15.9.4661.
Abstract:
Replication factor C (RFC) is a five-subunit DNA polymerase accessory protein that functions as a structure-specific, DNA-dependent ATPase. The ATPase function of RFC is activated by proliferating cell nuclear antigen. RFC was originally purified from human cells on the basis of its requirement for simian virus 40 DNA replication in vitro. A functionally homologous protein complex from Saccharomyces cerevisiae, called ScRFC, has been identified. Here we report the cloning, by either peptide sequencing or by sequence similarity to the human cDNAs, of the S. cerevisiae genes RFC1, RFC2, RFC3, RFC4, and RFC5. The amino acid sequences are highly similar to the sequences of the homologous human RFC 140-, 37-, 36-, 40-, and 38-kDa subunits, respectively, and also show amino acid sequence similarity to functionally homologous proteins from Escherichia coli and the phage T4 replication apparatus. All five subunits show conserved regions characteristic of ATP/GTP-binding proteins and also have a significant degree of similarity among each other. We have identified eight segments of conserved amino acid sequences that define a family of related proteins. Despite their high degree of sequence similarity, all five RFC genes are essential for cell proliferation in S. cerevisiae. RFC1 is identical to CDC44, a gene identified as a cell division cycle gene encoding a protein involved in DNA metabolism. CDC44/RFC1 is known to interact genetically with the gene encoding proliferating cell nuclear antigen, confirming previous biochemical evidence of their functional interaction in DNA replication.
3
Cui, Kan, Lei Qin, Xianyu Tang, Jieying Nong, Jin Chen, Nan Wu, Xin Gong, Lixiong Yi, Chenghuizi Yang, and Shitou Xia. "A Single Amino Acid Substitution in RFC4 Leads to Endoduplication and Compromised Resistance to DNA Damage in Arabidopsis thaliana." Genes 13, no. 6 (June 9, 2022): 1037. http://dx.doi.org/10.3390/genes13061037.
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Replication factor C (RFC) is a heteropentameric ATPase associated with the diverse cellular activities (AAA+ATPase) protein complex, which is composed of one large subunit, known as RFC1, and four small subunits, RFC2/3/4/5. Among them, RFC1 and RFC3 were previously reported to mediate genomic stability and resistance to pathogens in Arabidopsis. Here, we generated a viable rfc4e (rfc4−1/RFC4G54E) mutant with a single amino acid substitution by site-directed mutagenesis. Three of six positive T2 mutants with the same amino acid substitution, but different insertion loci, were sequenced to identify homozygotes, and the three homozygote mutants showed dwarfism, early flowering, and a partially sterile phenotype. RNA sequencing revealed that genes related to DNA repair and replication were highly upregulated. Moreover, the frequency of DNA lesions was found to be increased in rfc4e mutants. Consistent with this, the rfc4e mutants were very sensitive to DSB-inducing genotoxic agents. In addition, the G54E amino acid substitution in AtRFC4 delayed cell cycle progression and led to endoduplication. Overall, our study provides evidence supporting the notion that RFC4 plays an important role in resistance to genotoxicity and cell proliferation by regulating DNA damage repair in Arabidopsis thaliana.
4
Gong, Maokai, James Yess, Tatiana Connolly, S. Percy Ivy, Takao Ohnuma, Kenneth H. Cowan, and Jeffrey A. Moscow. "Molecular Mechanism of Antifolate Transport-Deficiency in a Methotrexate-Resistant MOLT-3 Human Leukemia Cell Line." Blood 89, no. 7 (April 1, 1997): 2494–99. http://dx.doi.org/10.1182/blood.v89.7.2494.
Abstract:
Abstract Ohnuma et al reported a series of methotrexate-resistant MOLT-3 human T-cell acute lymphoblastic leukemia cell lines that showed decreasing methotrexate (MTX) uptake as the sublines acquired increasing MTX resistance (Cancer Res 45:1815, 1985). The alteration of MTX uptake kinetics in these cells, the intermediately resistant MOLT-3/MTX200 and the highly resistant MOLT-3/MTX10,000 cell lines, was attributed to a change in Vmax for methotrexate transport, without an apparent change in affinity of the transporter for MTX. We studied these cell lines to determine whether alteration of transcription or translation of the recently isolated reduced folate carrier gene (RFC1) was the cause of MTX transport deficiency in these cell lines. Reconstitution of RFC activity in MOLT-3/MTX10,000 cells by transduction with a murine RFC retroviral vector reversed MTX resistance and trimetrexate sensitivity. Although RFC1 RNA levels were unchanged in the resistant cell lines, FACS analysis using a polyclonal anti-RFCl antibody showed no detectable RFCl protein in the MOLT-3/MTX10,000 cells. Determination of the nucleotide sequence of RFC1 genes from MOLT-3/MTX10,000 cells revealed that this cell line contained 3 RFC1 alleles: a wild-type allele, an allele containing the premature stop codon at codon 40 and a third allele containing another mutation, which resulted in a premature stop codon at codon 25. We examined the relative expression of these alleles by determining the nucleotide sequence of 24 RFC1 cDNA subclones from MOLT-3/MTX10,000 cells and found that only one-third of these clones contained the wild-type sequence. Determination of the genomic sequence of RFC1 in MOLT-3/MTX200 cells demonstrated that these cells were heterozygous for a mutation at codon 40, but were homozygous for the wild-type sequence at codon 25. Thus, the acquisition of MTX transport-deficiency in MOLT-3/MTX10,000 cells results from inactivating mutations of RFC1 gene alleles.
5
Naiki, Takahiro, Tae Kondo, Daisuke Nakada, Kunihiro Matsumoto, and Katsunori Sugimoto. "Chl12 (Ctf18) Forms a Novel Replication Factor C-Related Complex and Functions Redundantly with Rad24 in the DNA Replication Checkpoint Pathway." Molecular and Cellular Biology 21, no. 17 (September 1, 2001): 5838–45. http://dx.doi.org/10.1128/mcb.21.17.5838-5845.2001.
Abstract:
ABSTRACT RAD24 has been identified as a gene essential for the DNA damage checkpoint in budding yeast. Rad24 is structurally related to subunits of the replication factor C (RFC) complex, and forms an RFC-related complex with Rfc2, Rfc3, Rfc4, and Rfc5. Therad24Δ mutation enhances the defect ofrfc5-1 in the DNA replication block checkpoint, implicating RAD24 in this checkpoint.CHL12 (also called CTF18) encodes a protein that is structurally related to the Rad24 and RFC proteins. We show here that although neither chl12Δ norrad24Δ single mutants are defective, chl12Δ rad24Δ double mutants become defective in the replication block checkpoint. We also show that Chl12 interacts physically with Rfc2, Rfc3, Rfc4, and Rfc5 and forms an RFC-related complex which is distinct from the RFC and RAD24 complexes. Our results suggest that Chl12 forms a novel RFC-related complex and functions redundantly with Rad24 in the DNA replication block checkpoint.
6
Panda, Debasis, Daniel J. Fernandez, Madhu Lal, Eugen Buehler, and Bernard Moss. "Triad of human cellular proteins, IRF2, FAM111A, and RFC3, restrict replication of orthopoxvirus SPI-1 host-range mutants." Proceedings of the National Academy of Sciences 114, no. 14 (March 20, 2017): 3720–25. http://dx.doi.org/10.1073/pnas.1700678114.
Abstract:
Viruses and their hosts can reach balanced states of evolution ensuring mutual survival, which makes it difficult to appreciate the underlying dynamics. To uncover hidden interactions, virus mutants that have lost defense genes may be used. Deletion of the gene that encodes serine protease inhibitor 1 (SPI-1) of rabbitpox virus and vaccinia virus, two closely related orthopoxviruses, prevents their efficient replication in human cells, whereas certain other mammalian cells remain fully permissive. Our high-throughput genome-wide siRNA screen identified host factors that prevent reproduction and spread of the mutant viruses in human cells. More than 20,000 genes were interrogated with individual siRNAs and those that prominently increased replication of the SPI-1 deletion mutant were subjected to a secondary screen. The top hits based on the combined data—replication factor C3 (RFC3), FAM111A, and interferon regulatory factor 2 (IRF2)—were confirmed by custom assays. The siRNAs to RFC1, RFC2, RFC4, and RFC5 mRNAs also enhanced spread of the mutant virus, strengthening the biological significance of the RFC complex as a host restriction factor for poxviruses. Whereas association with proliferating cell nuclear antigen and participation in processive genome replication are common features of FAM111A and RFC, IRF2 is a transcriptional regulator. Microarray analysis, quantitative RT-PCR, and immunoblotting revealed that IRF2 regulated the basal level expression of FAM111A, suggesting that the enhancing effect of depleting IRF2 on replication of the SPI-1 mutant was indirect. Thus, the viral SPI-1 protein and the host IRF2, FAM111A, and RFC complex likely form an interaction network that influences the ability of poxviruses to replicate in human cells.
7
Kai, Mihoko, Hiroyuki Tanaka, and Teresa S. F. Wang. "Fission Yeast Rad17 Associates with Chromatin in Response to Aberrant Genomic Structures." Molecular and Cellular Biology 21, no. 10 (May 15, 2001): 3289–301. http://dx.doi.org/10.1128/mcb.21.10.3289-3301.2001.
Abstract:
ABSTRACT Fission yeast checkpoint protein Rad17 is required for the DNA integrity checkpoint responses. A fraction of Rad17 is chromatin bound independent of the other checkpoint proteins throughout the cell cycle. Here we show that in response to DNA damage induced by either methyl methanesulfonate treatment or ionizing radiation, increased levels of Rad17 bind to chromatin. Following S-phase stall induced by hydroxyurea or a cdc22 mutation, the chromatin-bound Rad17 progressively dissociates from the chromatin. After S-phase arrest by hydroxyurea in cds1Δ or rad3Δ cells or by replication mutants, Rad17 remains chromatin bound. Rad17 is able to complex in vivo with an Rfc small subunit, Rfc2, but not with Rfc1. Furthermore, cells with rfc1Δ are checkpoint proficient, suggesting that Rfc1 does not have a role in checkpoint function. A checkpoint-defective mutant protein, Rad17(K118E), which has similar nuclear localization to that of the wild type, is unable to bind ATP and has reduced ability in chromatin binding. Mutant Rad17(K118E) protein also has reduced ability to complex with Rfc2, suggesting that Lys118 of Rad17 plays a role in Rad17-Rfc small-subunit complex formation and chromatin association. However, in therad17.K118E mutant cells, Cds1 can be activated by hydroxyurea. Together, these results suggest that Rad17 binds to chromatin in response to an aberrant genomic structure generated from DNA damage, replication mutant arrest, or hydroxyurea arrest in the absence of Cds1. Rad17 is not required to bind chromatin when genomic structures are protected by hydroxyurea-activated Cds1. The possible checkpoint events induced by chromatin-bound Rad17 are discussed.
8
Ma, David W. L., Richard H. Finnell, Laurie A. Davidson, Evelyn S. Callaway, Ofer Spiegelstein, Jorge A. Piedrahita, J. Michael Salbaum, et al. "Folate Transport Gene Inactivation in Mice Increases Sensitivity to Colon Carcinogenesis." Cancer Research 65, no. 3 (February 1, 2005): 887–97. http://dx.doi.org/10.1158/0008-5472.887.65.3.
Abstract:
Abstract Low dietary folate intake is associated with an increased risk for colon cancer; however, relevant genetic animal models are lacking. We therefore investigated the effect of targeted ablation of two folate transport genes, folate binding protein 1 (Folbp1) and reduced folate carrier 1 (RFC1), on folate homeostasis to elucidate the molecular mechanisms of folate action on colonocyte cell proliferation, gene expression, and colon carcinogenesis. Targeted deletion of Folbp1 (Folbp1+/− and Folbp1−/−) significantly reduced (P < 0.05) colonic Folbp1 mRNA, colonic mucosa, and plasma folate concentration. In contrast, subtle changes in folate homeostasis resulted from targeted deletion of RFC1 (RFC1+/−). These animals had reduced (P < 0.05) colonic RFC1 mRNA and exhibited a 2-fold reduction in the plasma S-adenosylmethionine/S-adenosylhomocysteine. Folbp1+/− and Folbp1−/− mice had larger crypts expressed as greater (P < 0.05) numbers of cells per crypt column relative to Folbp1+/+ mice. Colonic cell proliferation was increased in RFC1+/− mice relative to RFC1+/+ mice. Microarray analysis of colonic mucosa showed distinct changes in gene expression specific to Folbp1 or RFC1 ablation. The effect of folate transporter gene ablation on colon carcinogenesis was evaluated 8 and 38 weeks post-azoxymethane injection in wild-type and heterozygous mice. Relative to RFC1+/+ mice, RFC1+/− mice developed increased (P < 0.05) numbers of aberrant crypt foci at 8 weeks. At 38 weeks, RFC1+/− mice developed local inflammatory lesions with or without epithelial dysplasia as well as adenocarcinomas, which were larger relative to RFC1+/+ mice. In contrast, Folbp1+/− mice developed 4-fold (P < 0.05) more lesions relative to Folbp1+/+ mice. In conclusion, Folbp1 and RFC1 genetically modified mice exhibit distinct changes in colonocyte phenotype and therefore have utility as models to examine the role of folate homeostasis in colon cancer development.
9
Xie, Yali, Chris Counter, and Eric Alani. "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 151, no. 2 (February 1, 1999): 499–509. http://dx.doi.org/10.1093/genetics/151.2.499.
Abstract:
Abstract The RFC1 gene encodes the large subunit of the yeast clamp loader (RFC) that is a component of eukaryotic DNA polymerase holoenzymes. We identified a mutant allele of RFC1 (rfc1::Tn3) from a large collection of Saccharomyces cerevisiae mutants that were inviable when present in a rad52 null mutation background. Analysis of rfc1::Tn3 strains indicated that they displayed both a mutator and repeat-tract instability phenotype. Strains bearing this allele were characterized in combination with mismatch repair (msh2Δ, pms1Δ), double-strand break repair (rad52), and DNA replication (pol3-01, pol30-52, rth1Δ/rad27Δ) mutations in both forward mutation and repeat-tract instability assays. This analysis indicated that the rfc1::Tn3 allele displays synthetic lethality with pol30, pol3, and rad27 mutations. Measurement of forward mutation frequencies in msh2Δ rfc1:Tn3 and pms1Δ rfc1:Tn3 strains indicated that the rfc1::Tn3 mutant displayed a mutation frequency that appeared nearly multiplicative with the mutation frequency exhibited by mismatch-repair mutants. In repeat-tract instability assays, however, the rfc1::Tn3 mutant displayed a tract instability phenotype that appeared epistatic to the phenotype displayed by mismatch-repair mutants. From these data we propose that defects in clamp loader function result in DNA replication errors, a subset of which are acted upon by the mismatch-repair system.
10
Zhao, Rongbao, Feng Gao, and I. David Goldman. "Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells." American Journal of Physiology-Cell Physiology 282, no. 6 (June 1, 2002): C1512—C1517. http://dx.doi.org/10.1152/ajpcell.00547.2001.
Abstract:
Although the reduced folate carrier RFC1 and the thiamine transporters THTR-1 and THTR-2 share ∼40% of their identity in protein sequence, RFC1 does not transport thiamine and THTR-1 and THTR-2 do not transport folates. In the present study, we demonstrate that transport of thiamine monophosphate (TMP), an important thiamine metabolite present in plasma and cerebrospinal fluid, is mediated by RFC1 in L1210 murine leukemia cells. Transport of TMP was augmented by a factor of five in cells (R16) that overexpress RFC1 and was markedly inhibited by methotrexate, an RFC1 substrate, but not by thiamine. At a near-physiological concentration (50 nM), TMP influx mediated by RFC1 in wild-type L1210 cells was ∼50% of thiamine influx mediated by thiamine transporter(s). Within 1 min, the majority of TMP transported into R16 cells was hydrolyzed to thiamine with a component metabolized to thiamine pyrophosphate, the active enzyme cofactor. These data suggest that RFC1 may be one of the alternative transport routes available for TMP in some tissues when THTR-1 is mutated in the autosomal recessive disorder thiamine-responsive megaloblastic anemia.
11
Kim, Hee-Sook, and Steven J. Brill. "Rfc4 Interacts with Rpa1 and Is Required for Both DNA Replication and DNA Damage Checkpoints in Saccharomyces cerevisiae." Molecular and Cellular Biology 21, no. 11 (June 1, 2001): 3725–37. http://dx.doi.org/10.1128/mcb.21.11.3725-3737.2001.
Abstract:
ABSTRACT The large subunit of replication protein A (Rpa1) consists of three single-stranded DNA binding domains and an N-terminal domain (Rpa1N) of unknown function. To determine the essential role of this domain we searched for mutations that require wild-type Rpa1N for viability in yeast. A mutation in RFC4, encoding a small subunit of replication factor C (RFC), was found to display allele-specific interactions with mutations in the gene encoding Rpa1 (RFA1). Mutations that map to Rpa1N and confer sensitivity to the DNA synthesis inhibitor hydroxyurea, such asrfa1-t11, are lethal in combination withrfc4-2. The rfc4-2 mutant itself is sensitive to hydroxyurea, and like rfc2 and rfc5 strains, it exhibits defects in the DNA replication block and intra-S checkpoints. RFC4 and the DNA damage checkpoint geneRAD24 were found to be epistatic with respect to DNA damage sensitivity. We show that the rfc4-2 mutant is defective in the G1/S DNA damage checkpoint response and that both therfc4-2 and rfa1-t11 strains are defective in the G2/M DNA damage checkpoint. Thus, in addition to its essential role as part of the clamp loader in DNA replication, Rfc4 plays a role as a sensor in multiple DNA checkpoint pathways. Our results suggest that a physical interaction between Rfc4 and Rpa1N is required for both roles.
12
Traschütz, Andreas, Andrea Cortese, Selina Reich, Natalia Dominik, Jennifer Faber, Heike Jacobi, Annette M. Hartmann, et al. "Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease." Neurology 96, no. 9 (January 25, 2021): e1369-e1382. http://dx.doi.org/10.1212/wnl.0000000000011528.
Abstract:
ObjectiveTo delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).MethodsMultimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing–based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia.ResultsPrevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C–like progression (SARA points 2.5–5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression.ConclusionsRFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials.Classification of EvidenceThis study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.
13
Beckwith, W., and M. A. McAlear. "Allele-specific interactions between the yeast RFC1 and RFC5 genes suggest a basis for RFC subunit-subunit interactions." Molecular Genetics and Genomics 264, no. 4 (November 2000): 378–91. http://dx.doi.org/10.1007/s004380000339.
14
Thieme, Andreas, Christel Depienne, and Dagmar Timmann. "Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): from clinical diagnosis towards genetic testing." Medizinische Genetik 33, no. 4 (December 1, 2021): 301–10. http://dx.doi.org/10.1515/medgen-2021-2098.
Abstract:
Abstract The cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset and recessively inherited ataxia. For many years, CANVAS has been diagnosed based on the clinical phenotype. Only recently, a large biallelic pentanucleotide repeat expansion in the replication factor C subunit 1 (RFC1) gene has been identified as the underlying genetic cause for the large majority of CANVAS cases. Subsequently, other phenotypes such as ataxia with chronic cough, incomplete CANVAS and MSA-C-like phenotypes have been associated with biallelic RFC1 repeat expansions. Because of this heterogeneity it has been suggested to change the name of the disease to “RFC1 disease”. Chronic cough is characteristic and can precede neurological symptoms by years or decades. In the neurological examination signs of cerebellar, sensory, and vestibular ataxia are frequently observed. Nerve conduction studies usually show absent or markedly reduced sensory nerve action potentials. On brain MRI cerebellar degeneration and spinal cord alterations are common. In later disease stages more widespread neurodegeneration with additional involvement of the brainstem and basal ganglia is possible. As yet, the exact incidence of RFC1-associated neurological diseases remains uncertain although first studies suggest that RFC1-related ataxia is common. Moreover, the pathophysiological mechanisms caused by the large biallelic pentanucleotide repeat expansions in RFC1 remain elusive. Future molecular and genetic research as well as natural history studies are highly desirable to pave the way towards personalized treatment approaches.
15
Davies, Kayli, David J. Szmulewicz, Louise A. Corben, Martin Delatycki, and Paul J. Lockhart. "RFC1-Related Disease." Neurology Genetics 8, no. 5 (August 29, 2022): e200016. http://dx.doi.org/10.1212/nxg.0000000000200016.
Abstract:
In 2019, a biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 (RFC1) was reported as a cause of cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). In addition, biallelic expansions were shown to account for up to 22% of cases with late-onset ataxia. Since this discovery, the phenotypic spectrum reported to be associated with RFC1 expansions has extended beyond the initial conditions to include pure cerebellar ataxia, isolated somatosensory impairment, combinations of the 2, and parkinsonism, leading to a potentially broad differential diagnosis. Genetic studies suggest RFC1 expansions may be the most common genetic cause of ataxia and are likely underdiagnosed. This review summarizes the current molecular and clinical knowledge of RFC1-related disease, with a focus on the evaluation of recent phenotype associations and highlighting the current challenges in clinical pathways to diagnosis and molecular testing.
16
Currò, Riccardo, Alessandro Salvalaggio, Stefano Tozza, Chiara Gemelli, Natalia Dominik, Valentina Galassi Deforie, Francesca Magrinelli, et al. "RFC1 expansions are a common cause of idiopathic sensory neuropathy." Brain 144, no. 5 (May 1, 2021): 1542–50. http://dx.doi.org/10.1093/brain/awab072.
Abstract:
Abstract After extensive evaluation, one-third of patients affected by polyneuropathy remain undiagnosed and are labelled as having chronic idiopathic axonal polyneuropathy, which refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy of unknown origin. Since a sensory neuropathy/neuronopathy is identified in all patients with genetically confirmed RFC1 cerebellar ataxia, neuropathy, vestibular areflexia syndrome, we speculated that RFC1 expansions could underlie a fraction of idiopathic sensory neuropathies also diagnosed as chronic idiopathic axonal polyneuropathy. We retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy) from our general neuropathy clinics in Italy and the UK. All patients underwent full neurological evaluation and a blood sample was collected for RFC1 testing. Biallelic RFC1 expansions were identified in 43 patients (34%) with sensory neuropathy and in none with sensory-motor neuropathy. Forty-two per cent of RFC1-positive patients had isolated sensory neuropathy or sensory neuropathy with chronic cough, while vestibular and/or cerebellar involvement, often subclinical, were identified at examination in 58%. Although the sensory ganglia are the primary pathological target of the disease, the sensory impairment was typically worse distally and symmetric, while gait and limb ataxia were absent in two-thirds of the cases. Sensory amplitudes were either globally absent (26%) or reduced in a length-dependent (30%) or non-length dependent pattern (44%). A quarter of RFC1-positive patients had previously received an alternative diagnosis, including Sjögren’s syndrome, sensory chronic inflammatory demyelinating polyneuropathy and paraneoplastic neuropathy, while three cases had been treated with immune therapies.
17
de Jonge, Robert, Wim J. E. Tissing, Jan Hendrik Hooijberg, Gerrit Jansen, Gertjan J. L. Kaspers, Jan Lindemans, Godefridus J. Peters, and Rob Pieters. "Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia." Blood 113, no. 10 (March 5, 2009): 2284–89. http://dx.doi.org/10.1182/blood-2008-07-165928.
Abstract:
Abstract Polymorphisms in folate pathway genes may influence the susceptibility to acute lymphoblastic leukemia (ALL). DNA was isolated from 245 pediatric ALL patients (cases) and from 500 blood bank donors (controls). Polymorphisms in methylene-tetrahydrofolate reductase (MTHFR 677C>T, 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), nicotinamide N-methyltransferase (NNMT IVS −151C>T), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC1 80G>A) were detected. In ALL patients, an increased occurrence was observed of the RFC1 80AA variant (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.3-3.2; P = .002) and the RFC1 80A allele (OR = 1.5; 95% CI, 1.1-2.1; P = .02). Likewise, the NNMT IVS −151TT genotype showed a 2.2-fold increased ALL risk (OR = 2.2; 95% CI, 1.1-4.6; P = .04). A 1.4-fold reduction in ALL risk was observed for (heterozygous or homozygous) carriers of the TS 2R allele and the MTHFR 677T allele (OR = 0.7; 95% CI, 0.5-1.0; P < .05). Furthermore, interactions between NNMT and MTHFR 677C>T and RFC1 were observed. NNMT IVS −151CC/MTHFR 677CT + TT patients exhibited a 2-fold reduction in ALL risk whereas RFC1 80AA/NNMT IVS −151CT + TT subjects had a 4.2-fold increase in ALL risk (P = .001). For the first time, we associate the RFC1 80G>A and NNMT IVS −151C>T variants to an increased ALL susceptibility.
18
Aboud Syriani, Dona, Darice Wong, Sameer Andani, Claudio M. De Gusmao, Yuanming Mao, May Sanyoura, Giacomo Glotzer, et al. "Prevalence of RFC1-mediated spinocerebellar ataxia in a North American ataxia cohort." Neurology Genetics 6, no. 3 (May 20, 2020): e440. http://dx.doi.org/10.1212/nxg.0000000000000440.
Abstract:
ObjectiveWe evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 (RFC1) and disabled adaptor protein 1 (DAB1) in an undiagnosed ataxia cohort from North America.MethodsA cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in RFC1 (AAGGG) and DAB1 (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for RFC1, resulting in a combined 911 subjects tested.ResultsIn the initial cohort, 41 samples were identified with 1 expanded allele in the RFC1 gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in RFC1 (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the DAB1 gene (spinocerebellar ataxia type 37).ConclusionsIn a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in RFC1 was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.
19
Tanaka, Hiroyuki, Koichi Tanaka, Hiroshi Murakami, and Hiroto Okayama. "Fission Yeast Cdc24 Is a Replication Factor C- and Proliferating Cell Nuclear Antigen-Interacting Factor Essential for S-Phase Completion." Molecular and Cellular Biology 19, no. 2 (February 1, 1999): 1038–48. http://dx.doi.org/10.1128/mcb.19.2.1038.
Abstract:
ABSTRACT At the nonpermissive temperature the fission yeastcdc24-M38 mutant arrests in the cell cycle with incomplete DNA replication as indicated by pulsed-field gel electrophoresis. Thecdc24 + gene encodes a 501-amino-acid protein with no significant homology to any known proteins. The temperature-sensitive cdc24 mutant is effectively rescued by pcn1 +, rfc1 + (a fission yeast homologue of RFC1), andhhp1 +, which encode the proliferating cell nuclear antigen (PCNA), the large subunit of replication factor C (RFC), and a casein kinase I involved in DNA damage repair, respectively. The Cdc24 protein binds PCNA and RFC1 in vivo, and the domains essential for Cdc24 function and for RFC1 and PCNA binding colocalize in the N-terminal two-thirds of the molecule. In addition,cdc24 + genetically interacts with the gene encoding the catalytic subunit of DNA polymerase ɛ, which is stimulated by PCNA and RFC, and with those encoding the fission yeast counterparts of Mcm2, Mcm4, and Mcm10. These results indicate that Cdc24 is an RFC- and PCNA-interacting factor required for DNA replication and might serve as a target for regulation.
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Naiki, Takahiro, Toshiyasu Shimomura, Tae Kondo, Kunihiro Matsumoto, and Katsunori Sugimoto. "Rfc5, in Cooperation with Rad24, Controls DNA Damage Checkpoints throughout the Cell Cycle inSaccharomyces cerevisiae." Molecular and Cellular Biology 20, no. 16 (August 15, 2000): 5888–96. http://dx.doi.org/10.1128/mcb.20.16.5888-5896.2000.
Abstract:
ABSTRACT RAD24 and RFC5 are required for DNA damage checkpoint control in the budding yeast Saccharomyces cerevisiae. Rad24 is structurally related to replication factor C (RFC) subunits and associates with RFC subunits Rfc2, Rfc3, Rfc4, and Rfc5. rad24Δ mutants are defective in all the G1-, S-, and G2/M-phase DNA damage checkpoints, whereas the rfc5-1 mutant is impaired only in the S-phase DNA damage checkpoint. Both the RFC subunits and Rad24 contain a consensus sequence for nucleoside triphosphate (NTP) binding. To determine whether the NTP-binding motif is important for Rad24 function, we mutated the conserved lysine115 residue in this motif. The rad24-K115E mutation, which changes lysine to glutamate, confers a complete loss-of-function phenotype, while the rad24-K115R mutation, which changes lysine to arginine, shows no apparent phenotype. Although neitherrfc5-1 nor rad24-K115R single mutants are defective in the G1- and G2/M-phase DNA damage checkpoints, rfc5-1 rad24-K115R double mutants become defective in these checkpoints. Coimmunoprecipitation experiments revealed that Rad24K115R fails to interact with the RFC proteins in rfc5-1 mutants. Together, these results indicate that RFC5, like RAD24, functions in all the G1-, S- and G2/M-phase DNA damage checkpoints and suggest that the interaction of Rad24 with the RFC proteins is essential for DNA damage checkpoint control.
21
Reilly, Mary M. "RFC1 CANVAS: the expanding phenotype." Journal of Neurology, Neurosurgery & Psychiatry 92, no. 4 (February 9, 2021): 345. http://dx.doi.org/10.1136/jnnp-2020-325504.
22
Scriba, Carolin K., Sarah J. Beecroft, Joshua S. Clayton, Andrea Cortese, Roisin Sullivan, Wai Yan Yau, Natalia Dominik, et al. "A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families." Brain 143, no. 10 (October 1, 2020): 2904–10. http://dx.doi.org/10.1093/brain/awaa263.
Abstract:
Abstract Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected individuals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in individuals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from >26 000 genetically diverse individuals in gnomAD to show enrichment of (ACAGG) in non-European populations.
23
Biselli, Joice Matos, Daniela Brumati, Vivian Fernanda Frigeri, Bruna Lancia Zampieri, Eny Maria Goloni-Bertollo, and Érika Cristina Pavarino-Bertelli. "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 126, no. 6 (November 2008): 329–32. http://dx.doi.org/10.1590/s1516-31802008000600007.
Abstract:
CONTEXT AND OBJECTIVE: There is evidence that polymorphisms of genes involved in folate metabolism may be associated with higher risk that mothers may bear a Down's syndrome (DS) child. This study therefore had the objective of investigating the A80G polymorphism of the reduced folate carrier 1 (RFC1) gene and the C776G polymorphism of the transcobalamin 2 (TC2) gene as maternal risk factors for DS among Brazilian women. DESIGN AND SETTING: Analytical cross-sectional study with control group, at Faculdade de Medicina de São José do Rio Preto (Famerp). METHODS: Sixty-seven mothers of DS individuals with free trisomy 21, and 113 control mothers, were studied. Molecular analysis of the polymorphisms was performed by means of the polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP), followed by electrophoresis on 2% agarose gel. RESULTS: The frequencies of the polymorphic alleles were 0.51 and 0.52 for RFC1 80G, and 0.34 and 0.34 for TC2 776G, in the case and control groups, respectively. Thus, there were no differences between the groups in relation to either the allele or the genotype frequency, for both polymorphisms (P = 0.696 for RFC1 A80G; P = 0.166 for TC2 C776G; P = 0.268 for combined genotypes). CONCLUSION: There was no evidence of any association between the RFC1 A80G and TC2 C776G polymorphisms and the maternal risk of DS in the sample evaluated.
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Malaquias, Maria João, Luis Braz, Cláudia Santos Silva, Joana Damásio, André Jorge, João M. Lemos, Catarina F. Campos, et al. "MultisystemicRFC1-Related Disorder." Neurology: Clinical Practice 13, no. 5 (September 5, 2023): e200190. http://dx.doi.org/10.1212/cpj.0000000000200190.
Abstract:
Background and ObjectivesTheRFC1spectrum has become considerably expanded as multisystemic features beyond the triad of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) have started to be unveiled, although many still require clinical replication. Here, we aimed to clinically characterize a cohort ofRFC1-positive patients by addressing both classic and multisystemic features. In a second part of this study, we prospectively assessed small nerve fibers (SNF) and autonomic function in a subset of theseRFC1-related patients.MethodsWe retrospectively enrolled 67 RFC1-positive patients from multiple neurologic centers in Portugal. All patients underwent full neurologic and vestibular evaluation, as well as neuroimaging and neurophysiologic studies. For SNF and autonomic testing (n = 15), we performed skin biopsies, quantitative sensory testing, sudoscan, sympathetic skin response, heart rate deep breathing, and tilt test.ResultsMultisystemic features beyond CANVAS were present in 82% of the patients, mainly chronic cough (66%) and dysautonomia (43%). Other features included motor neuron (MN) affection and motor neuropathy (18%), hyperkinetic movement disorders (16%), sleep apnea (6%), REM and non-REM sleep disorders (5%), and cranial neuropathy (5%). Ten patients reported an inverse association between cough and ataxia severity. A very severe epidermal denervation was found in skin biopsies of all patients. Autonomic dysfunction comprised cardiovascular (67%), cardiovagal (54%), and/or sudomotor (50%) systems.DiscussionThe presence of MN involvement, motor neuropathy, small fiber neuropathy, or extrapyramidal signs should not precludeRFC1testing in cases of sensory neuronopathy. Indeed, theRFC1spectrum can overlap not only with multiple system atrophy but also with hereditary motor and sensory neuropathy, hereditary sensory and autonomic neuropathy, and feeding dystonia phenotypes. Some clinical-paraclinical dissociations can pose diagnostic challenges, namely large and small fiber neuropathy and sudomotor dysfunction which are usually subclinical.
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Gisatulin, Maria, Valerija Dobricic, Christine Zühlke, Yorck Hellenbroich, Vera Tadic, Alexander Münchau, Klaus Isenhardt, et al. "Clinical spectrum of the pentanucleotide repeat expansion in the RFC1 gene in ataxia syndromes." Neurology 95, no. 21 (September 1, 2020): e2912-e2923. http://dx.doi.org/10.1212/wnl.0000000000010744.
Abstract:
ObjectiveTo determine the clinical significance of an intronic biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 (RFC1) in patients with late-onset cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), in patients with other ataxias, and in healthy controls by comprehensive genetic analyses.MethodsIn this case-control study, we included 457 individuals comprising 26 patients with complete or incomplete CANVAS, 70 patients with late-onset cerebellar ataxia, 208 healthy controls, and 153 individuals from 39 multigenerational families without ataxia to determine repeat stability. All 96 patients were screened for the repeat expansion by duplex PCR. To further characterize the repeat type and lengths, we used fragment length analysis, repeat-primed PCR, Sanger sequencing, and Southern blotting. Expression of RFC1 and the neighboring gene WDR19 were determined by quantitative PCR.ResultsMassive biallelic pentanucleotide expansions were found in 15/17 patients with complete CANVAS (88%), in 2/9 patients with incomplete CANVAS (22%), in 4/70 patients with unspecified, late-onset cerebellar ataxia (6%), but not in controls. In patients, the expansion comprised 800–1,000 mostly AAGGG repeats. Nonmassively expanded repeat numbers were in the range of 7–137 repeats and relatively stable during transmission. Expression of RFC1 and WDR19 were unchanged and RFC1 intron retention was not found.ConclusionsA biallelic pentanucleotide repeat expansion is a frequent cause of CANVAS and found in a considerable number of patients with an incomplete clinical presentation or other forms of cerebellar ataxia. The mechanism by which the repeat expansions are causing disease remains unclear and warrants further investigations.
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Rajgopal, Arun, Esteban E. Sierra, Rongbao Zhao, and I. David Goldman. "Expression of the reduced folate carrier SLC19A1 in IEC-6 cells results in two distinct transport activities." American Journal of Physiology-Cell Physiology 281, no. 5 (November 1, 2001): C1579—C1586. http://dx.doi.org/10.1152/ajpcell.2001.281.5.c1579.
Abstract:
Intestinal absorption of folates has been characterized as a facilitative process with a low pH optimum. Studies with intestinal epithelial cells have suggested that this activity is mediated by the reduced folate carrier (RFC1). In this paper, we report on folate transport characteristics in an immortalized rat IEC-6 cell line that was found to exhibit the predominant influx activity for methotrexate (MTX) at pH 5.5 with a low level of activity at pH 7.4. Transfection of this cell line with an RFC1 construct resulted in clones exhibiting increased MTX uptake at both the pHs and high folic acid uptake only at the low pH. For the two clones with the highest level of transport activity, relative MTX influx at the two pHs was reversed. Moreover, the low pH MTX influx activity ([MTX]e = 0.5 μM) was markedly inhibited by 20 μM folic acid while influx at neutral pH was not. Furthermore, in the presence and absence of glucose at low pH, MTX and folic acid influx activity was inhibited by azide, while MTX influx at pH 7.4 was stimulated by azide in the absence of glucose but was unchanged in the presence of glucose and azide. This was contrasted with the results of transfection of the same RFC1 construct into an L1210 murine leukemia cell line bearing a nonfunctional endogenous carrier. In this case, the activity expressed was only at pH 7.4. These data indicate that RFC1 can exhibit two distinct types of folate transport activities in intestinal cells that must depend on tissue-specific modulators.
27
Roberts, Rhys C. "Removing the idiopathic from the chronic sensory neuropathies." Brain 144, no. 5 (May 1, 2021): 1291–92. http://dx.doi.org/10.1093/brain/awab150.
28
Paisán-Ruiz, Coro, and Joanna C. Jen. "CANVAS with cerebellar/sensory/vestibular dysfunction from RFC1 intronic pentanucleotide expansion." Brain 143, no. 2 (February 1, 2020): 386–90. http://dx.doi.org/10.1093/brain/awaa015.
29
Stewart, D. J., M. I. Nunez, J. Jelinek, Z. Guo, D. Hong, S. Gupta, Y. Oki, J. Issa, R. Kurzrock, and I. I. Wistuba. "Decitabine effect on human tumor expression of various transporters." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2540. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2540.
Abstract:
2540 Background: We reported that immunohistochemistry (IHC) expression of the platinum/copper transporter CTR1 in human tumors correlated inversely with DNA methylation and was increased by the DNA demethylating agent decitabine (D. Stewart et al, Proc ASCO 2008). Decitabine also increased expression of folate transporters in platinum-resistant cell lines that have decreased expression of folate transporters and of small GTPases such as RHOA that regulate endocytosis (D Shen et al. Br J Cancer 2004). Methods: Tumors were biopsied pre decitabine and on cycle 1 day 12 in 31 patients with refractory malignancies in a phase I study of decitabine given days 1–5 ± 8–12 each cycle. We used IHC to assess the folate carriers FOLR1 and RFC1, the glucose transporter GLUT4 and the endocytosis regulating small GTPase RHOA. Scores of 0–300 were calculated by multiplying staining intensity (0–3) by % cells staining. LINE assays were used to assess % global DNA methylation. Results: DNA methylation did not correlate with FOLR1, RFC1 and GLUT4 scores but did correlate inversely with RHOA (r= -0.58, p=0.006). Median tumor IHC scores post vs pre decitabine were 80 vs 80 (range, 0–270 vs 0–210, p=0.89) for FOLR1, 90 vs 90 (range, 15–300 vs 0–300, p=0.17) for RFC1, 0 vs 0 (range 0- 140 vs 0–70, p=0.61) for GLUT4, and 77.5 vs 50 (range, 0–210 vs 0–210, p=0.03) for RHOA. If only tumors with pre decitabine scores <150 were included, post vs pre RFC1 differences were significant (95 vs 80, p=0.004). Outcomes were similar whether or not 4 melanoma patients (in whom melanin pigment decreased the reliability of IHC scoring) were included. Conclusions: As previously noted with the copper/platinum transporter CTR1, treatment with the DNA demethylating agent decitabine was associated with a significant increase in tumor expression of the endocytosis regulator RHOA in resistant human tumors. Expression of the folate transporter RFC1 was also increased if only patients with levels that were initially low were included. This suggests that decitabine should be tested for its ability to increase uptake of chemotherapy in resistant tumors. Promoter methylation for these transporters has not yet been assessed. Supported in part by NIH grant UO1 CA062461–10 & R21 CA112895–01A1. No significant financial relationships to disclose.
30
Noskov, Vladimir N., Hiroyuki Araki, and Akio Sugino. "The RFC2 Gene, Encoding the Third-Largest Subunit of the Replication Factor C Complex, Is Required for an S-Phase Checkpoint in Saccharomyces cerevisiae." Molecular and Cellular Biology 18, no. 8 (August 1, 1998): 4914–23. http://dx.doi.org/10.1128/mcb.18.8.4914.
Abstract:
ABSTRACT Replication factor C (RF-C), an auxiliary factor for DNA polymerases δ and ɛ, is a multiprotein complex consisting of five different polypeptides. It recognizes a primer on a template DNA, binds to a primer terminus, and helps load proliferating cell nuclear antigen onto the DNA template. The RFC2 gene encodes the third-largest subunit of the RF-C complex. To elucidate the role of this subunit in DNA metabolism, we isolated a thermosensitive mutation (rfc2-1) in the RFC2 gene. It was shown that mutant cells having the rfc2-1 mutation exhibit (i) temperature-sensitive cell growth; (ii) defects in the integrity of chromosomal DNA at restrictive temperatures; (iii) progression through cell cycle without definitive terminal morphology and rapid loss of cell viability at restrictive temperatures; (iv) sensitivity to hydroxyurea, methyl methanesulfonate, and UV light; and (v) increased rate of spontaneous mitotic recombination and chromosome loss. These phenotypes of the mutant suggest that the RFC2 gene product is required not only for chromosomal DNA replication but also for a cell cycle checkpoint. It was also shown that the rfc2-1mutation is synthetically lethal with either the cdc44-1 orrfc5-1 mutation and that the restrictive temperature ofrfc2-1 mutant cells can be lowered by combining either with the cdc2-2 or pol2-11 mutation. Finally, it was shown that the temperature-sensitive cell growth phenotype and checkpoint defect of the rfc2-1mutation can be suppressed by a multicopy plasmid containing theRFC5 gene. These results suggest that the RFC2gene product interacts with the CDC44/RFC1 andRFC5 gene products in the RF-C complex and with both DNA polymerases δ and ɛ during chromosomal DNA replication.
31
Deng, Jianxiong, Fangyan Zhong, Weiguo Gu, and Feng Qiu. "Exploration of Prognostic Biomarkers among Replication Factor C Family in the Hepatocellular Carcinoma." Evolutionary Bioinformatics 17 (January 2021): 117693432199410. http://dx.doi.org/10.1177/1176934321994109.
Abstract:
Hepatocellular carcinoma (HCC) is one of the common cancers with a high incidence and mortality. The human replication factor C (RFC) family contains 5 subunits that play an important role in DNA replication and DNA damage repair. RFCs are abnormally expressed in a variety of cancers; some of them are differentially expressed in HCC tissues and related to tumor growth. However, the expression, prognostic value, and effect targets of the whole RFC family in HCC are still unclear. To address these issues, we performed a multidimensional analysis of RFCs in HCC patients by Oncomine, UALCAN, GEPIA, Human protein atlas, Kaplan-Meier plotter, cBioPortal, GeneMANIA, String, and LinkedOmics. mRNA expression of RFCs was significantly increased in HCC tissues. There was a significant correlation between the expression of RFC2/3/4/5 and tumor stage of HCC patients. Besides, high mRNA expression of RFC2/4 was associated with worse overall survival (OS). Moreover, genetic alterations of RFCs were associated with worse OS in HCC patients. We found that genes co-expressed with RFC2/4 were mainly involved in biological processes, such as chromosome segregation, mitotic cell cycle phase transition, and telomere organization and they activated the cell cycle and spliceosome pathways. The gene set is mainly enriched in cancer-related kinases AURKA, ATR, CDK1, PLK1, and CHEK1. E2F family members were the key transcription factors for RFCs. Our results suggest that differentially expressed RFC2 and RFC4 are potential prognostic biomarkers in HCC and may act on E2F transcription factors and some kinase targets to dysregulate the cell cycle pathway. These efforts may provide new research directions for prognostic biomarkers and therapeutic targets in HCC.
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Нужный, Е. П., Н. Ю. Абрамычева, Е. Г. Воробьева, Е. О. Иванова, Ю. А. Шпилюкова, А. И. Белякова-Бодина, Д. В. И, et al. "CANVAS is a common form of late-onset hereditary ataxia." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 4(213) (April 30, 2020): 51–52. http://dx.doi.org/10.25557/2073-7998.2020.04.51-52.
Abstract:
Синдром CANVAS (мозжечковая атаксия, невропатия и вестибулярная арефлексия) - аутосомно-рецессивная атаксия с поздним дебютом, обусловленная носительством биаллельной экспансии (AAGGG)n во 2-м интроне гена RFC1. До настоящего момента отсутствуют сведения о распространенности данного заболевания в российских семьях. Нами был проведен поиск биаллельной экспансии AAGGG-повторов у 35 российских пациентов с поздней мозжечковой атаксией. Верифицированы 5 пациентов (14,3%) с синдромом CANVAS и характерной клинической картиной. CANVAS (cerebellar ataxia, neuropathy and vestibular areflexia) is a late-onset autosomal recessive ataxia due to biallelic (AAGGG)n repeat expansion in the 2nd intron of the RFC1 gene. There is no information on the CANVAS prevalence in Russian families. We searched for biallelic expansion of AAGGG repeats in 35 Russian patients with late-onset cerebellar ataxia. Five patients (14.3%) with CANVAS syndrome and a characteristic clinical picture were verified.
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Cortese, Andrea, Stefano Tozza, Wai Yan Yau, Salvatore Rossi, Sarah J. Beecroft, Zane Jaunmuktane, Zoe Dyer, et al. "Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion." Brain 143, no. 2 (February 1, 2020): 480–90. http://dx.doi.org/10.1093/brain/awz418.
Abstract:
Abstract Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.
34
Abramzon, Yevgenya, Ramita Dewan, Andrea Cortese, Susan Resnick, Luigi Ferrucci, Henry Houlden, and Bryan J. Traynor. "Investigating RFC1 expansions in sporadic amyotrophic lateral sclerosis." Journal of the Neurological Sciences 430 (November 2021): 118061. http://dx.doi.org/10.1016/j.jns.2021.118061.
35
Devald, I. V., E. A. Hodus, D. Yu Nokhrin, E. B. Khromova, G. L. Ignatova, D. S. Stashkevich, A. M. Lila, and A. L. Burmistrova. "Evaluation of the influence of polymorphisms of the transporter genes (<i>RFC1</i>, <i>MDR1</i>) and <i>GGH</i> on the efficacy of methotrexate in rheumatoid arthritis." Modern Rheumatology Journal 17, no. 4 (August 20, 2023): 28–34. http://dx.doi.org/10.14412/1996-7012-2023-4-28-34.
Abstract:
The efficacy of methotrexate (MT) in patients with rheumatoid arthritis (RA) may be determined by genetic factors.Objective: to evaluate the isolated and combined effects of single nucleotide polymorphisms (SNPs) of membrane transporter proteins (RFC1 80G>A and MDR1 3435C>T) and the GGH -401C>T gamma-glutamyl hydrolase enzyme genes on the efficacy of MT in patients with RA.Material and methods. The study group consisted of 85 patients with a confirmed diagnosis of RA, who received therapy with MT starting at 10 mg/week and increasing in dose to a maximum of 25 mg/week. Efficacy was assessed after six months of treatment using the dynamics of the DAS28 index, identifying patients who responded and those who did not respond to MT therapy.Genotyping of RFC1, MDR1 and GGH gene polymorphisms was performed by real-time polymerase chain reaction. Three different approaches were used to analyze the results: 1) analysis for each of the genes; 2) logistic regression; and 3) multifactor dimensionality reduction (MDR).Results and discussion. Single gene analysis was used to determine the most likely predictors of non-response to therapy: 1) for GGH-401C>T, TT genotype (odds ratio, OR 5.09; 95% confidence interval, C11.11—23.3); 2) forMDR13435C>T, the TT genotype (OR 2.38; 95% CI0.89-6.37); 3) for RFC180G>A, not - AA genotype (OR 1.87; 95% CI 0.93-3.76).The logistic regression model showed a significant effect of homozygous genotype GGH -401TT on the efficacy of MT with low sensitivity of the method. The multifactorial dimensionality reduction results show a significant synergistic effect of the MT transport genes (MDR1, RFC1) and the GGH enzyme encoding the conversion of MT to the elimination form.Conclusion. Using various statistical methods, the following results were obtained: Single gene analysis revealed the most likely predictors of nonresponse to MT therapy: GGH -401C>T - TT genotype, MDR1 3435C>T - TT genotype, RFC1 80G>A - not-AA genotype; the method of multiple logistic regression allowed to determine the significant effect of GGH -401ТТ genotype on the effect of the drug with a low sensitivity of the method; the isolated effect of polymorphisms is probably less pronounced than their combined effect on the effectiveness of MT. SNP synergism is a major contributor to the development of treatment resistance. MDR is a promising method that can be used in the future to assess the impact of SNPs.
36
Herrmann, Laura, Mathias Gelderblom, Maxim Bester, Natalie Deininger, Thorsten Schütze, Ute Hidding, Caspar Gross, et al. "Multisystemic neurodegeneration caused by biallelic pentanucleotide expansions in RFC1." Parkinsonism & Related Disorders 95 (February 2022): 54–56. http://dx.doi.org/10.1016/j.parkreldis.2022.01.001.
37
Terryn, Joke, Amélie Van Eesbeeck, Sascha Vermeer, and Wim Vandenberghe. "The Characteristic Eye Movement Disorder of RFC1 ‐Linked CANVAS." Movement Disorders Clinical Practice 7, no. 2 (January 24, 2020): 230–31. http://dx.doi.org/10.1002/mdc3.12896.
38
Zheng, Fengwei, Roxana E. Georgescu, Nina Y. Yao, Michael E. O’Donnell, and Huilin Li. "DNA is loaded through the 9-1-1 DNA checkpoint clamp in the opposite direction of the PCNA clamp." Nature Structural & Molecular Biology 29, no. 4 (March 21, 2022): 376–85. http://dx.doi.org/10.1038/s41594-022-00742-6.
Abstract:
AbstractThe 9-1-1 DNA checkpoint clamp is loaded onto 5′-recessed DNA to activate the DNA damage checkpoint that arrests the cell cycle. The 9-1-1 clamp is a heterotrimeric ring that is loaded in Saccharomyces cerevisiae by Rad24-RFC (hRAD17-RFC), an alternate clamp loader in which Rad24 replaces Rfc1 in the RFC1-5 clamp loader of proliferating cell nuclear antigen (PCNA). The 9-1-1 clamp loading mechanism has been a mystery, because, unlike RFC, which loads PCNA onto a 3′-recessed junction, Rad24-RFC loads the 9-1-1 ring onto a 5′-recessed DNA junction. Here we report two cryo-EM structures of Rad24-RFC–DNA with a closed or 27-Å open 9-1-1 clamp. The structures reveal a completely unexpected mechanism by which a clamp can be loaded onto DNA. Unlike RFC, which encircles DNA, Rad24 binds 5′-DNA on its surface, not inside the loader, and threads the 3′ ssDNA overhang into the 9-1-1 clamp from above the ring.
39
Facchini, Stefano, Natalia Dominik, Arianna Manini, Stephanie Efthymiou, Riccardo Currò, Bianca Rugginini, Elisa Vegezzi, et al. "Optical Genome Mapping Enables Detection and Accurate Sizing of RFC1 Repeat Expansions." Biomolecules 13, no. 10 (October 19, 2023): 1546. http://dx.doi.org/10.3390/biom13101546.
Abstract:
A recessive Short Tandem Repeat expansion in RFC1 has been found to be associated with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), and to be a frequent cause of late onset ataxia and sensory neuropathy. The usual procedure for sizing these expansions is based on Southern Blotting (SB), a time-consuming and a relatively imprecise technique. In this paper, we compare SB with Optical Genome Mapping (OGM), a method for detecting Structural Variants (SVs) based on the measurement of distances between fluorescently labelled probes, for the diagnosis of RFC1 CANVAS and disease spectrum. The two methods are applied to 17 CANVAS patients’ blood samples and resulting sizes compared, showing a good agreement. Further, long-read sequencing is used for two patients to investigate the agreement of sizes with either SB or OGM. Our study concludes that OGM represents a viable alternative to SB, allowing for a simpler technique, a more precise sizing of the expansion and ability to expand analysis of SV in the entire genome as opposed to SB which is a locus specific method.
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Merrill, Bradley J., and Connie Holm. "The RAD52 Recombinational Repair Pathway is Essential in pol30 (PCNA) Mutants That Accumulate Small Single-Stranded DNA Fragments During DNA Synthesis." Genetics 148, no. 2 (February 1, 1998): 611–24. http://dx.doi.org/10.1093/genetics/148.2.611.
Abstract:
Abstract To identify in vivo pathways that compensate for impaired proliferating cell nuclear antigen (PCNA or Pol30p in yeast) activity, we performed a synthetic lethal screen with the yeast pol30-104 mutation. We identified nine mutations that display synthetic lethality with pol30-104; three mutations affected the structural gene for the large subunit of replication factor C (rfc1), which loads PCNA onto DNA, and six mutations affected three members of the RAD52 epistasis group for DNA recombinational repair (rad50, rad52, and rad57). We also found that pol30-104 displayed synthetic lethality with mutations in other members of the RAD52 epistasis group (rad51 and rad54), but not with mutations in members of the RAD3 nor the RAD6 epistasis group. Analysis of nine different pol30 mutations shows that the requirement for the RAD52 pathway is correlated with a DNA replication defect but not with the relative DNA repair defect caused by pol30 mutations. In addition, mutants that require RAD52 for viability (pol30-100, pol30-104, rfc1-1 and rth1Δ) accumulate small single-stranded DNA fragments during DNA replication in vivo. Taken together, these data suggest that the RAD52 pathway is required when there are defects in the maturation of Okazaki fragments.
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Watanabe, Kazuki, Mitsuko Nakashima, Rie Wakatsuki, Tomoyasu Bunai, Yasuomi Ouchi, Tomohiko Nakamura, Hiroaki Miyajima, and Hirotomo Saitsu. "Cognitive Impairment in a Complex Family With AAGGG and ACAGG Repeat Expansions in RFC1 Detected by ExpansionHunter Denovo." Neurology Genetics 8, no. 3 (May 16, 2022): e682. http://dx.doi.org/10.1212/nxg.0000000000000682.
Abstract:
Background and ObjectivesWe investigated the genetic basis and brain metabolism and blood flow of a Japanese family with spinocerebellar degeneration (SCD), with multiple affected members for 3 generations.MethodsAfter excluding DNA repeat expansion (RE) of common SCD genes by fragment analysis, we performed whole-exome sequencing (WES) and whole-genome sequencing (WGS). Homozygosity mapping was performed using these data. REs were investigated with WGS data using ExpansionHunter Denovo and Expansion Hunter.ResultsWES and WGS were unable to identify likely pathogenic variants, and homozygosity mapping failed to narrow down the locus. However, ExpansionHunter Denovo detected REs in intron 2 of the RFC1 gene and led us to the diagnosis of RFC1-related disorders. Subsequent repeat-primed PCR and Southern blot hybridization analyses revealed that 3 of 6 patients and 1 suspected individual had expansions of AAGGG ((AAGGG)exp) and (ACAGG)exp repeats in a compound heterozygous state and 3 had a homozygous (ACAGG)exp. The patients showed a variety of clinical features, including adult-onset ataxia, sensorimotor neuropathy, head tremor, parkinsonism, dystonia, and cognitive impairment. A comparison of previous reports with those of the family in study suggested that motor neuropathy could be a feature of compound heterozygous patients and biallelic (ACAGG)exp patients. Cognitive function tests showed cognitive impairment with a predominance of frontal lobe dysfunction. Examination of MRI, SPECT, and 18F-fluorodeoxyglucose-PET showed clear cortical damage with frontal lobe predominance in 1 case, but no cerebral damage was evident in the other 2 cases.DiscussionOur report shows the usefulness of WGS and RE detection tools for SCD of unknown cause. The studied family with RFC1-related disorders included patients with (ACAGG)exp and (AAGGG)exp in a compound heterozygous state and was characterized by motor neuropathy. Based on the results of cognitive function tests and imaging studies, 1 patient presented with cognitive impairment due to frontal lobe metabolic changes, but there were also patients who presented with cognitive impairment without apparent cerebral metabolic or blood flow, suggesting that other factors are also associated with cognitive impairment.
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Park, Jeong A., Hyoung Jin Kang, Ho Joon Im, Hee Young Shin, and Hyo Seop Ahn. "Association of genetic polymorphisms in the folate pathway with efficacy and toxicity of methotrexate in pediatric osteosarcoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 10051. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10051.
Abstract:
10051 Background: Osteosarcoma is the most common childhood malignant bone tumor. Methotrexate (MTX), one of the main drugs used for osteosarcoma, is a representative folic acid antagonist. Genetic polymorphisms in folate pathway genes are expected to influence the response and toxicity of high-dose MTX therapy. However, there are scarce data available regarding associations between genetic polymorphisms and pediatric osteosarcoma. This study evaluated the effect of common genetic polymorphisms in the folate metabolic pathway on overall survival, event-free survival and histological response to neoadjuvant chemotherapy including high-dose MTX. In addition, whether these genetic polymorphisms affect the concentrations of MTX and toxicity after high-dose MTX therapy for osteosarcoma was investigated. Methods: Blood and tissue samples from 48 osteosarcoma patients who had completed chemotherapy were obtained, and the following polymorphisms were analyzed; RFC1 80G>A, DHFR 829C>T, MTHFR 677C>T, MTHFR 1298A>C, AMPD1 34C>T, ATIC 347C>G, and ITPA 94C>A. Associations between candidate polymorphisms and survival, histological response (tumor necrosis rate) and MTX level and toxicity after high-dose MTX therapy were analyzed. Results: Event-free survival significantly decreased in DHFR 829 CC homozygote (P=0.045). Variant carriers of MTHFR 677C>T had tendency towards poor histological response (P=0.078). MTX concentration was significantly associated with RFC1 80G>A polymorphism (P=0.027). Liver toxicity after high-dose MTX was associated with ATIC 347C>G (P=0.043) and tended to increase in carriers of MTHFR 677C>T (P=0.069). Severe stomatitis was associated with RFC1 80G>A (P=0.012). Conclusions: This study has demonstrated that several genetic polymorphisms in folate pathway can significantly influence therapeutic response, clinical outcome and MTX level and toxicity after high-dose MTX therapy in osteosarcoma patients. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of patients with osteosarcoma, aiding the development of tailored therapeutic approaches.
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Halmágyi, Gábor M., and David J. Szmulewicz. "Correction to: Vestibular function testing in patients with RFC1 mutations." Journal of Neurology 269, no. 4 (March 10, 2022): 2264. http://dx.doi.org/10.1007/s00415-022-10975-6.
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Silva Schmitt, Gabriel, Alberto R. M. Martinez, Felipe F. Graça, Fabrício Diniz Lima, Luciana C. Bonadia, Bárbara Juarez Amorim, Anamarli Nucci, and Marcondes Cavalcante França. "Dopa‐Responsive Parkinsonism in a Patient With Homozygous RFC1 Expansions." Movement Disorders 35, no. 10 (October 2020): 1889–90. http://dx.doi.org/10.1002/mds.28286.
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Guerra-Shinohara, Elvira Maria, Kelma Cordeiro da Silva Giusti, Nathalia Sierra Monteiro, Robson José Lazaro, Fernanda Midori Seino, Carolina Tosin Bueno, Mário Henrique Burlacchini Carvalho, Antônio Amorim Filho, Carlos Chiattone, and Marcelo Zugaib. "Effect of Genetic Polymorphisms Related to Folate and Homocysteine Metabolism In the Etiology of Recurrent Miscarriages." Blood 116, no. 21 (November 19, 2010): 5136. http://dx.doi.org/10.1182/blood.v116.21.5136.5136.
Abstract:
Abstract Abstract 5136 Introduction: Folic acid deficiency has been associated with obstetric complications such as preeclampsia, placental abruption and recurrent miscarriages (RM). Folic acid is a methyl group donating in various reactions. Low concentrations of 5,10-methylenetetrahydrofolate, the cofactor of enzyme thymidylate synthase, decrease the synthesis of thymidylate, which results in increased ratio deoxyuridylate monophosphate/deoxytimidylate monophosphate (dUMP/dTMP) and increased incorporation of deoxyuridylate triphosphate (dUTP) to DNA. The removal of dUTP by DNA-glycosylase can cause permanent damage to DNA, which may lead to apoptosis or increase the risk of developing cancer. Polymorphisms in genes of enzymes (MTHFR - methylene tetrahydrofolate reductase, MTR - methionine synthase and MTRR - methionine synthase reductase) and also in the gene of the reduced folate carrier (RFC1) were related to reduced folate and increased total homocysteine concentrations and have been associated as risk factors for RM. Material and Methods: 171 women with a history of three or more recurrent miscarriages and 95 healthy women with no history of abortion and having two or more normal babies were included. Weight and height of women were obtained and the body mass index (BMI) was calculated. The presence of antibodies (ANA and anti-DNA) was evaluated using immunofluorescence kits. The genotypes of the polymorphisms MTHFR c. 677C>T, MTR c. 2756A>G and RFC1 c.80G>A were obtained by PCR-RFLP, while genotyping for polymorphisms MTRR c. 66A>G and MTHFR c. 1298A>C was made by real time PCR. Multivariate logistic regression model (forward conditional) was used to obtain the odds ratio and its 95% confidence intervals of having MR (dependent variable). The independent variables were: quartiles of BMI, age range, positive ANA (titer of 1/40), positive anti-DNA (titre 1/10), genotypes for the MTHFR c. 677C>T, MTHFR c.1298A>C, MTR c. 2756A>G, MTRR c. 66A>G and RFC1 c. 80G>A. Results: No differences between the groups were observed for serum total homocysteine or allele frequencies for MTHFR c. 677C>T, MTHFR c. 1298A>C, MTR c. 2756A>G and RFC1 c.80G>A polymorphisms. In a conditional logistic regression analysis the risk of RM was significantly associated with BMI OR [95% CI] = 1.40 [1.02, 1.93] per quartile increase in BMI), positive anti-DNA OR [95% CI] = 7.24 [0.92, 57.25], positive ANA OR [95% CI] = 2.48 [1.21, 5.08], and AA genotype for MTRR c. 66A>G polymorphism (OR [95% CI] = 2.19 [1.16, 4.12]. Conclusion: The etiology of RM is multifactorial and it is associated with increasing of BMI, presence of autoantibodies and AA genotype for MTRR c. 66A>G polymorphism. Disclosures: No relevant conflicts of interest to declare.
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Ando, Masahiro, Yujiro Higuchi, Junhui Yuan, Akiko Yoshimura, Takaki Taniguchi, Fumikazu Kojima, Yutaka Noguchi, et al. "Comprehensive Genetic Analyses of Inherited Peripheral Neuropathies in Japan: Making Early Diagnosis Possible." Biomedicines 10, no. 7 (June 29, 2022): 1546. http://dx.doi.org/10.3390/biomedicines10071546.
Abstract:
Various genomic variants were linked to inherited peripheral neuropathies (IPNs), including large duplication/deletion and repeat expansion, making genetic diagnosis challenging. This large case series aimed to identify the genetic characteristics of Japanese patients with IPNs. We collected data on 2695 IPN cases throughout Japan, in which PMP22 copy number variation (CNV) was pre-excluded. Genetic analyses were performed using DNA microarrays, next-generation sequencing-based gene panel sequencing, whole-exome sequencing, CNV analysis, and RFC1 repeat expansion analysis. The overall diagnostic rate and the genetic spectrum of patients were summarized. We identified 909 cases with suspected IPNs, pathogenic or likely pathogenic variants. The most common causative genes were MFN2, GJB1, MPZ, and MME. MFN2 was the most common cause for early-onset patients, whereas GJB1 and MPZ were the leading causes of middle-onset and late-onset patients, respectively. Meanwhile, GJB1 and MFN2 were leading causes for demyelinating and axonal subtypes, respectively. Additionally, we identified CNVs in MPZ and GJB1 genes and RFC1 repeat expansions. Comprehensive genetic analyses explicitly demonstrated the genetic basis of our IPN case series. A further understanding of the clinical characteristics of IPN and genetic spectrum would assist in developing efficient genetic testing strategies and facilitate early diagnosis.
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Giovannini, Sara, Marie-Christine Weller, Hana Hanzlíková, Tetsuya Shiota, Shunichi Takeda, and Josef Jiricny. "ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition." Nucleic Acids Research 48, no. 9 (April 16, 2020): 4928–39. http://dx.doi.org/10.1093/nar/gkaa255.
Abstract:
Abstract Replication factor C (RFC), a heteropentamer of RFC1-5, loads PCNA onto DNA during replication and repair. Once DNA synthesis has ceased, PCNA must be unloaded. Recent findings assign the uloader role primarily to an RFC-like (RLC) complex, in which the largest RFC subunit, RFC1, has been replaced with ATAD5 (ELG1 in Saccharomyces cerevisiae). ATAD5-RLC appears to be indispensable, given that Atad5 knock-out leads to embryonic lethality. In order to learn how the retention of PCNA on DNA might interfere with normal DNA metabolism, we studied the response of ATAD5-depleted cells to several genotoxic agents. We show that ATAD5 deficiency leads to hypersensitivity to methyl methanesulphonate (MMS), camptothecin (CPT) and mitomycin C (MMC), agents that hinder the progression of replication forks. We further show that ATAD5-depleted cells are sensitive to poly(ADP)ribose polymerase (PARP) inhibitors and that the processing of spontaneous oxidative DNA damage contributes towards this sensitivity. We posit that PCNA molecules trapped on DNA interfere with the correct metabolism of arrested replication forks, phenotype reminiscent of defective homologous recombination (HR). As Atad5 heterozygous mice are cancer-prone and as ATAD5 mutations have been identified in breast and endometrial cancers, our finding may open a path towards the therapy of these tumours.
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Turner, Richard D., Barnaby Hirons, Andrea Cortese, and Surinder S. Birring. "Chronic Cough as a Genetic Neurological Disorder? Insights from Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS)." Lung 201, no. 6 (November 18, 2023): 511–19. http://dx.doi.org/10.1007/s00408-023-00660-4.
Abstract:
AbstractChronic cough is common, and in many cases unexplained or refractory to otherwise effective treatment of associated medical conditions. Cough hypersensitivity has developed as a paradigm that helps to explain clinical and research observations that frequently point towards chronic cough as a neuropathic disorder. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recently described neurological condition whose clinical features include gait ataxia, unsteadiness, peripheral neuropathy, and autonomic dysfunction. Chronic cough is also a common feature of the syndrome, with features of hypersensitivity, often preceding core neurological symptoms by up to 30 years or more. The genetic basis in a majority of cases of CANVAS appears to be biallelic variable repeat intron expansion sequences within RFC1, a gene normally involved in the regulation of DNA replication and repair. The same polymorphism has now been identified at an increased frequency in patients with unexplained or refractory chronic cough in the absence of defining clinical features of CANVAS. This review expands on these points, aiming to increase the awareness of CANVAS amongst clinicians and researchers working with chronic cough. We discuss the implications of a link between RFC1 disease and cough. Improved understanding of CANVAS may lead to an enhanced grasp of the pathophysiology of chronic cough, and new approaches to antitussive treatments.
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Sullivan, Roisin, Wai Yan Yau, Viorica Chelban, Salvatore Rossi, Natalia Dominik, Emer O'Connor, John Hardy, Nicholas Wood, Andrea Cortese, and Henry Houlden. "RFC1-related ataxia is a mimic of early multiple system atrophy." Journal of Neurology, Neurosurgery & Psychiatry 92, no. 4 (February 9, 2021): 444–46. http://dx.doi.org/10.1136/jnnp-2020-325092.
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Misbah, Md, Manoj Kumar, Abul Kalam Najmi, and Mymoona Akhtar. "Identification of expression profiles and prognostic value of RFCs in colorectal cancer." Scientific Reports 14, no. 1 (March 19, 2024). http://dx.doi.org/10.1038/s41598-024-56361-2.
Abstract:
AbstractColorectal cancer (CRC) ranks among the most prevalent cancers globally, with its incidence closely tied to DNA damage. The Replication Factor C (RFC) complexes comprises five protein subunits: RFC1, RFC2, RFC3, RFC4, and RFC5. These RFC complexes play crucial roles in DNA replication, repair pathways, activities post DNA damage, and ATP-dependent processes during DNA synthesis. However, the impact of RFC complexes proteins on CRC prognosis remains unclear. To explore this, we employed a computational analysis approach, utilizing platforms such as the DepMap portal, GEPIA, DAVID Bioinformatics for KEGG pathway analysis, Human Protein Atlas (HPA), STRING, and TIMER. Our results indicate that the mRNA levels of RFC1 and RFC5 were the least expressed among CRC cell lines compared to other RFC complex subunits. Notably, low RFC1 and RFC5 expression was correlated with poor prognosis in terms of CRC patients' overall survival (OS). Immunohistochemical results from the Human Protein Atlas demonstrated medium staining for RFC1, RFC2, and RFC5 in CRC tissues. Furthermore, the low expression of RFC1 and RFC5 showed a significant correlation with high expression levels of miR-26a-5p and miR-636, impacting cell proliferation through mismatch repair, DNA replication, and the nucleotide excision repair pathway. Although the precise functions of RFC1 in cancer are still unknown, our findings suggest that the small-molecule single target, CHEMBL430483, and multiple target molecules could be potential treatments for CRC. In conclusion, the elevated expression of miR-26a-5p and miR-636 targeting RFC1 and RFC5 expression holds promise as a potential biomarker for early-stage CRC detection. These insights provide novel directions and strategies for CRC therapies.