Alternative titles; symbols
HGNC Approved Gene Symbol: FANCC
SNOMEDCT: 1285021005;
Cytogenetic location: 9q22.32 Genomic coordinates (GRCh38): 9:95,099,054-95,317,709 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q22.32 | Fanconi anemia, complementation group C | 227645 | Autosomal recessive | 3 |
The FANCC gene is one of a group of classical Fanconi anemia genes whose protein products physically interact in a multiprotein core complex. The main function of this core complex with E3 ubiquitin ligase activity appears to be the posttranslational activations of FANCD2 (613984) and FANCI (611360) by monoubiquitination of specific lysine residues (summary by Hartmann et al., 2010).
Using a functional complementation method, Strathdee et al. (1992) cloned cDNAs that corrected the defect of Fanconi anemia group C cells. The cDNAs encoded alternatively processed transcripts of a new gene, designated FACC, mutated in patients with Fanconi anemia complementation group C. FACC transcripts were detected in a wide variety of tissues and cell lines by use of PCR with reverse-transcribed RNA.
Gavish et al. (1993) corrected the previously published FACC cDNA sequence which omitted 3 nucleotides. The corrected sequence predicts a 1,677-bp ORF and a protein of 558 amino acids.
Wevrick et al. (1992) cloned cDNAs corresponding to the mouse Facc gene. The sequence of the human and mouse proteins are 81% identical. The mouse gene encodes a protein of 558 amino acids, compared to 557 amino acids in the human protein.
Gibson et al. (1993) isolated a YAC clone containing the FACC gene and used vectorette PCR to determine that the gene contains 14 exons. (Vectorette PCR was illustrated by their Figure 1. It was performed according to the method of Riley et al. (1990), described in detail by Roberts et al. (1992).)
Several different forms of FACC mRNA that share the same coding region have been isolated. At least 2 species result from the use of alternative exons at the 5-prime end, and 3 result from the use of distinct polyadenylation signals. Savoia et al. (1995) isolated genomic clones corresponding to the 5-prime region, including a putative promoter and 2 alternate 5-prime exons. These exons, which they referred to as exons -1 and -1a, were found to be separated by a small intron, with exon -1 located 5-prime to the exon -1a. Further, these exons were flanked by consensus sequences of donor sites at the 5-prime ends of introns. An acceptor splice site was not evident 5-prime of exon -1a, suggesting that exon -1 is not spliced onto exon -1a. The sequences upstream of exon -1 and -1a had no obvious TATA or CAAT boxes but included CG-rich sequences. Savoia et al. (1995) suggested that mutations affecting the 5-prime UTR and the promoter region may underlie some cases of Fanconi anemia.
Strathdee et al. (1992) mapped the FACC gene to chromosome 9q22.3 by in situ hybridization.
Gibson et al. (1994) used a polymorphism within the FACC gene to localize it within a 5-cM interval on 9q, bounded by D9S196/D9S197 and D9S176. Linkage analysis with 3 highly informative microsatellite polymorphisms flanking the FACC locus in 36 Fanconi anemia families showed that only 8% of them were linked to 9q22.3. The markers also allowed rapid exclusion of 56% of the families in the panel from complementation group C, thus substantially reducing the number of patients who need to be screened for FACC mutations.
By interspecific backcross analysis, Wevrick et al. (1993) showed that the cloned mouse homolog of Facc is located on mouse chromosome 13; the rat homolog is located on chromosome 17. A previously described anemic mouse mutant, 'flexed-tail,' had been mapped to the same region of chromosome 13. However, the authors found no evidence that Facc is mutated in flexed-tail mice.
Using a polyclonal antiserum against FACC and by immunofluorescence and subcellular fractionation studies of human cell lines, Youssoufian (1994) showed that the FACC protein was localized primarily to the cytoplasm under steady-state conditions, transient through the cell cycle, and exposure to crosslinking or cytotoxic agents. These observations suggested an indirect role for FACC in regulating DNA repair in group C Fanconi anemia. Yamashita et al. (1994) found that the wildtype FACC was a 60-kD protein, consistent with its predicted molecular mass. Different Fanconi anemia group C cell lines expressed full-length FACC, truncated FACC, or no detectable FACC polypeptide. In addition, the antiserum specifically immunoprecipitated a 50-kD and a 150-kD FACC-related protein (FRP-50 and FRP-150, respectively). Cell fractionation and immunofluorescence studies demonstrated that the FACC polypeptide localizes to the cytoplasm.
The pathogenesis of the bone marrow failure that is a consistent feature of Fanconi anemia was investigated by Segal et al. (1994), who pointed out that it is not known whether the pancytopenia is a direct and specific result of the inherited mutation or a consequence of accumulated stem cell losses resulting from the nonspecific DNA damage that is characteristic of the disease. They tested the hypothesis that the FACC protein plays a regulatory role in hematopoiesis by exposing normal human lymphocytes, bone marrow cells, endothelial cells, and fibroblasts to an antisense oligodeoxynucleotide (ODN) complementary to bases -4 to +14 of FACC mRNA. The mitomycin C assay demonstrated that the antisense ODN, but not missense or sense ODNs, repressed FACC gene expression in lymphocytes. The antisense ODN substantially reduced cytoplasmic levels of FACC mRNA in bone marrow cells and lymphocytes. Escalating doses of antisense ODN increasingly inhibited clonal growth of erythroid and granulocyte-macrophage progenitor cells but did not inhibit growth of fibroblasts or endothelial cells. Segal et al. (1994) concluded that while the FACC gene product plays a role in defining cellular tolerance to crosslinking agents, it also functions to regulate growth, differentiation, and/or survival of normal hematopoietic progenitor cells.
Although abnormalities in DNA repair had been suspected in Fanconi anemia complementation group C, localization of the FAC gene product to the cytoplasm had cast doubt on such a mechanism. Youssoufian (1996) monitored interstrand DNA crosslinking and found that the predominant defect in group C cells is in the initial induction of crosslinks, not in repair synthesis. The author demonstrated that both the crosslinking defect and the enhanced cytotoxicity of crosslinkers on Fanconi anemia group C cells were corrected completely by cytoplasmic isoforms of the FAC protein, but not by an isoform targeted to the nucleus. Furthermore, the major molecular defect in these cells preceded crosslink repair. Youssoufian (1996) also showed that the ability of FAC to impart resistance to FA-C cells reached a threshold despite overexpression of the gene product. Youssoufian (1996) proposed a cellular defense pathway for genotoxic agents in which FAC acts through a cytoplasmic compartment and at a proximal step within this pathway.
The tumor suppressor protein p53 (191170) can bind to specific target sequences and activate transcription of genes adjacent to these DNA elements. Liebetrau et al. (1997) noted that there are 2 p53 binding sites in the FACC gene, 1 in the promoter region and 1 in the coding region. Gel shift experiments showed that wildtype p53 protein binds to the p53 target sequence in the promoter region of the FACC gene. Transfection experiments showed that overexpression of wildtype p53 in human diploid fibroblasts and lymphoblasts augmented transcription of the FACC gene up to 3-fold. The transfection efficiency was approximately 15% for both cell types. The FACC expression activity for transformed cells was stimulated to an estimated level of 18- to 21-fold upon p53 overexpression. The tumor-derived p53 mutants, his175 and his273, that failed to bind DNA showed only a reduced stimulatory activity on FACC transcription. Liebetrau et al. (1997) concluded that the FACC gene can be added to the list of genes that interact with p53.
Cells derived from FA patients are sensitive to crosslinking agents and have a prolonged G2 phase, suggesting a cell cycle abnormality. Transfection of type-C FA cells with the FAC cDNA corrects these cellular abnormalities. Kupfer et al. (1997) found that in synchronized HeLa cells, FAC protein expression increased during S phase, was maximal at the G2/M transition, and declined during M phase. In addition, the FAC protein coimmunoprecipitated with the cyclin-dependent kinase, cdc2. A patient-derived mutant FAC polypeptide, containing a point mutation at L554P (613899.0001), failed to bind to cdc2. The FAC/cdc2 binding interaction therefore correlated with the functional activity of the FAC protein. Binding of FAC to cdc2 was mediated by the C-terminal 50 amino acids of FAC in a region of the protein required for FAC function. Taken together, these results suggested to Kupfer et al. (1997) that the binding of FAC and cdc2 is required for normal G2/M progression in mammalian cells. Absence of a functional interaction between FAC and cdc2 in FA cells may underlie the cell cycle abnormality and clinical abnormalities of FA.
Kupfer et al. (1997) demonstrated that FAA (607139) and FAC bind each other and form a complex. Protein binding correlated with the functional activity of FAA and FAC, as patient-derived mutant FAC, L554P (613899.0001), failed to bind FAA. Although unbound FAA and FAC localized predominantly to the cytoplasm, the FAA-FAC complex was found in similar abundance in both cytoplasm and nucleus. The results confirmed the interrelatedness of the FA genes in a pathway and suggested the cooperation of FAA and FAC in a nuclear function.
Garcia-Higuera et al. (1999) determined that FANCG (602956) is required for binding between FANCA and FANCC and that all 3 proteins are components of a nuclear protein complex. Analysis of the protein interactions formed by lymphoblasts from each of the complementation groups suggested that the interaction between FANCA and FANCG is constitutive and is not regulated by FANCC or by the products of other FA genes. In contrast, the binding of FANCC required FANCA/FANCG binding and the products of other FA genes.
Hoatlin et al. (1998) reproducibly detected approximately 10% of FAC protein in nuclear fractions. They concluded also that while the cytoplasmic localization of the FAC protein appears to be functionally important, the protein may also exert some essential nuclear function.
Activation of STAT1 (600555) in response to gamma-interferon (IFNG; 147570) is suppressed in hematopoietic cells from children with FA-C. However, interferon regulatory factor-1 (IRF1; 147575) is expressed at high levels in mutant FA-C cells (Parganas et al., 1998), suggesting that a non-STAT1 pathway is involved in constitutive activation of IRF1 in FA cells. In addition, hematopoietic cells from FA-C patients are hypersensitive to the apoptotic effects of IFNG.
Pang et al. (2000) reported that in IFNG-stimulated FA-C cells, phosphorylation of JAK1 (147795), JAK2 (147796), and IFNG receptor-alpha (IFNGR1; 107470) occurs normally, but STAT1 does not dock at the IFNGR1 chain, does not form nuclear DNA complexes, and does not induce the expression of IRF1. Expression of normal FANCC cDNA in mutant cells restored all of these normal functions of STAT1. Various cytokines stimulated the association of STAT1 with normal but not mutant (L554P) FANCC. Pang et al. (2000) proposed that hematopoietic defects in FA derive, at least in part, from an imbalance between mitogenic cues (due to reduced transduction of signals through growth factor receptors that activate STAT1) and mitogenic inhibitory cues (due to FANCC-dependent, STAT1-independent constitutive activation of mitotic inhibitory factors, such as IRF1).
Pang et al. (2001) presented evidence that a central, highly conserved domain of FANCC is required for functional interaction with STAT1 and that structural elements required for STAT1-related functions differ from those required for genotoxic responses to crosslinking agents. They commented that preservation of signaling capacity of cells bearing the 322delG mutation (613899.0007) may account for the reduced severity and later onset of bone marrow failure associated with this mutation.
Donahue and Campbell (2002) found that fibroblasts from FA patients from complementation groups A, C, D2 (613984), and G were hypersensitive to restriction enzyme-induced cell death following electroporation of restriction enzymes. These fibroblasts also showed reduced efficiency in plasmid end-joining activity. Normal sensitivity and activity were restored following retrovirus mediated expression of the respective FA cDNAs. Donahue and Campbell (2002) also found that the L554P FANCC allele has dominant-negative activity. A fibrosarcoma cell line overexpressing this mutation showed significantly diminished efficiency in rejoining cohesive-ended and blunt-ended linearized plasmids and were hypersensitive to restriction enzyme-induced cell death.
The Fanconi anemia nuclear complex (composed of the FA proteins A, C, G and F) is essential for protection against chromosome breakage. It activates the downstream protein FANCD2 by monoubiquitylation; this then forges an association with the BRCA1 (113705) protein at sites of DNA damage. Pace et al. (2002) showed that the FANCE (613976) protein is part of this nuclear complex, binding both FANCC and FANCD2. Indeed, FANCE is required for the nuclear accumulation of FANCC and provides a critical bridge between the FA complex and FANCD2. Disease-associated FANCC mutants do not bind to FANCE, cannot accumulate in the nucleus and are unable to prevent chromosome breakage.
Pichierri et al. (2002) studied the assembly and activation of the RMN (RAD50, 604040/MRE11, 600814/NBS1, 602667) complex by exposing cultured cells to the chemical interstrand crosslink inducers mitomycin C and photoactivated 8-methoxypsoralen. The authors determined that FA cells were unable to form subnuclear RMN foci in response to either interstrand crosslink inducer. In particular, mitomycin C-treated FANCC cells formed double-strand breaks and unhooked mitomycin C-induced interstrand crosslink similarly to FANCC wildtype cells. Additionally, the authors showed that the formation of foci, including BRCA1 (113705) and/or RAD51 (179617) proteins, was significantly delayed in FA cells. The authors concluded that FANCC may play a direct role in RMN focus assembly in response to interstrand crosslink inducers.
By coimmunoprecipitation of HeLa cell nuclear extracts, Meetei et al. (2003) identified 3 distinct multiprotein complexes associated with BLM (RECQL3; 604610). One of the complexes, designated BRAFT, contained the Fanconi anemia core complementation group proteins FANCA, FANCG, FANCC, FANCE, and FANCF (613897), as well as topoisomerase III-alpha (TOP3A; 601243) and replication protein A (RPA; see 179835). BLM complexes isolated from an FA cell line had a lower molecular mass, likely due to loss of FANCA and other FA components. BLM- and FANCA-associated complexes had DNA unwinding activity, and BLM was required for this activity.
Zhang et al. (2004) used immunoprecipitation and reconstituted kinase assays to show that the FANCC, FANCA, and FANCG proteins functionally interacted with and inhibited the proapoptotic kinase PKR (176871), a kinase that represses translation when activated. PKR showed strongest binding to the FANCC protein. PKR activity was increased in bone marrow cells of patients with Fanconi anemia with mutations in the FANCC, FANCA, and FANCG genes. All 3 of these cell lines showed significant increases in PKR bound to the FANCC protein, which correlated with increased PKR activation. The cells also showed hypersensitivity to growth repression mediated by IFN-gamma and TNF-alpha (191160). Forced expression of a patient-derived FANCC mutation increased PKR activation and cell death. Zhang et al. (2004) concluded that FA mutations cause increased binding of PKR to FANCC and increased PKR activation, leading to growth inhibition of hematopoietic progenitors and bone marrow failure in Fanconi anemia.
Pace et al. (2010) found a genetic interaction between the FANCC gene and the nonhomologous end joining (NHEJ) factor Ku70 (152690). Disruption of both FANCC and Ku70 suppressed sensitivity to crosslinking agents, diminished chromosome breaks, and reversed defective homologous recombination. Ku70 binds directly to free DNA ends, committing them to NHEJ repair. Pace et al. (2010) showed that purified FANCD2, a downstream effector of the Fanconi anemia pathway, might antagonize Ku70 activity by modifying such DNA substrates. Pace et al. (2010) concluded that these results reveal a function for the Fanconi anemia pathway in processing DNA ends, thereby diverting double-strand break repair from abortive NHEJ and toward homologous recombination.
Chen et al. (1996) found that mice homozygous for a disrupted Fac gene did not show developmental abnormalities or hematologic defects during observations up to 9 months of age. However, their spleen cells had dramatically increased numbers of chromosomal aberrations in response to mitomycin C (MMC) and diepoxybutane. Homozygous male and female mice also had compromised gametogenesis, leading to markedly impaired fertility, a characteristic of Fanconi anemia patients.
Whitney et al. (1996) generated mice homozygous for a targeted deletion of exon 9 of the murine FA complementation group C gene. They selected this exon for knockout since there was evidence from mutation analysis in patients with FAC that the carboxy terminus of the protein is essential for its function. Mutant mice had normal neonatal viability and gross morphology. Their cells demonstrated chromosome breakage and crosslinker sensitivity. Male and female mutant mice had reduced numbers of germ cells and females had markedly impaired fertility. No anemia was detectable during the first year of life. The colony-forming capacity of bone marrow progenitor cells was abnormal and these cells were hypersensitive to gamma-interferon (147570). Whitney et al. (1996) concluded that this abnormal sensitivity to gamma-interferon may form the basis for bone marrow failure in Fanconi anemia.
Pulliam-Leath et al. (2010) found that Fancc -/-;Fancg -/- (602956) double-mutant mice developed spontaneous hematologic sequelae, including bone marrow failure, acute myeloid leukemia, myelodysplasia, and complex random chromosomal abnormalities, that Fancc -/- mice or Fancg -/- mice did not develop. Studies on cells derived from single-mutant mice showed that loss of Fancg resulted in a more severe defect in multiple hematopoietic compartments than loss of Fancc, suggesting that the 2 genes have nonoverlapping roles in hematopoiesis. However, both single- and double-mutant cells showed similar sensitivity to a DNA crosslinking agent. The phenotype of the double-mutant mice was most consistent with that of human patients with Fanconi anemia.
Rhee et al. (2010) studied the role of Fancc in telomere length regulation in mice. Deletion of Fancc did not affect telomerase activity, telomere length, or telomeric end-capping in a mouse strain possessing intrinsically long telomeres. However, ablation of Fancc did exacerbate telomere attrition when murine bone marrow cells experienced high cell turnover after serial transplantation. When Fancc-null mice were crossed into a telomerase reverse transcriptase (TERT; 187270) heterozygous or null background (Tert +/- or Tert -/-) with short telomeres, Fancc deficiency led to an increase in the incidence of telomere sister chromatid exchange. In contrast, these phenotypes were not observed in Tert mutant mice with long telomeres. The authors concluded that Fancc deficiency accelerates telomere shortening during high turnover of hematopoietic cells and may promote telomere recombination initiated by short telomeres.
Strathdee et al. (1992) and Gavish et al. (1992) demonstrated that HSC536N cells, which represented the only confirmed Fanconi anemia cell line of complementation group C (FANCC; 227645), have a T-to-C transition at base 1913 that changes codon 553 from leucine to proline (L553P). Gavish et al. (1993) corrected the previously published FACC cDNA sequence which omitted 3 nucleotides. The corrected sequence predicts a 1,677-bp ORF and a protein of 558 amino acids. Therefore, the previously reported L553P mutation is, in fact, L554P. To avoid confusion, they chose to refer to the site of the mutation as base 1661, on the basis of the ORF, and amino acid 554 on the basis of its location in the protein. Using site-directed in vitro mutagenesis, Gavish et al. (1993) demonstrated that the leu554-to-pro mutation completely abolishes the activity of the FACC protein as analyzed by functional complementation assay.
The polypeptide encoded by the FAC gene binds to a group of cytoplasmic proteins in vitro and may form a multimeric complex. The leu554-to-pro mutant allele fails to correct the sensitivity of FA group C cells to mitomycin C. Youssoufian et al. (1996) reasoned that overexpression of the mutant protein in a wildtype cellular background might induce the FA phenotype by competing with endogenous FAC for binding to the accessory proteins. After stable transfection of human kidney 293 cells with wildtype and a mutant FAC allele containing the L554P substitution, 4 independent clones that expressed 4- to 15-fold higher levels of transcript from the mutant transgene relative to the endogenous FAC gene showed hypersensitivity to mitomycin C. By contrast, both parental and FAC-overexpressing cells maintained their relative resistance to mitomycin C. No differences in the biosynthesis, subcellular localization, and protein interactions of the normal and mutant proteins were detected. Youssoufian et al. (1996) stated that the induction of the FA phenotype in this system is compatible with the competition hypothesis and provides support for a functional role of the FAC-binding proteins in vivo.
Using the BbvI restriction site change as a screening method, Gibson et al. (1992) found no instance of the L554P FANCC mutation (613899.0001) in 38 unrelated patients with Fanconi anemia (FANCC; 227645). However, they identified a truncated transcript that was shown to be due to a nonsense mutation changing arginine-185 to a stop codon (R185X). The mutation was a C-to-T transition at nucleotide 808.
Using reverse transcription PCR and chemical mismatch cleavage (CMC), Whitney et al. (1993) demonstrated homozygosity for an identical splice mutation in the FANCC gene in 2 Ashkenazi Jewish patients with Fanconi anemia (FANCC; 227645). Three additional patients bearing this allele were found through screening 21 other families. A single base change in the fourth intronic base changed the sequence from a consensus A to T, resulting in deletion of the 111-bp exon 4. They referred to the allele as IVS4+4, A-to-T.
Whitney et al. (1994) used allele-specific oligonucleotide hybridization to determine the frequency of this mutation in Ashkenazi Jews with Fanconi anemia (FA). They studied 11 patients, each of whom had 2 Jewish parents, and 1 patient who had a Jewish mother and a non-Jewish father. The mutation was found in 19 of the 23 Jewish FA chromosomes (83%), but was not found in 2 other Jewish patients, in 39 non-Jewish patients, or in 130 non-Jewish persons without FA. Two of 315 Jewish individuals without FA were found to be carriers of the mutation. Verlander et al. (1995) developed amplification refractory mutation system (ARMS) assays for 5 known mutations in FAC and used these assays to determine the carrier frequency of the IVS4 +4 A-to-T mutation in an Ashkenazi Jewish population. Among 3,104 Jewish individuals, primarily of Ashkenazi descent, 35 IVS4 carriers were identified, for a carrier frequency of 1 in 89 (1.1%). Among 563 Iraqi Jews, no carriers of the IVS4 mutation were found. They suggested that a founder effect is responsible for the high frequency of the mutation in Ashkenazim and that the carrier frequency of more than 1% justified inclusion of this mutation in the battery of tests routinely provided to the Jewish population.
Verlinsky et al. (2001) presented a means for guaranteeing HLA-matching tissues for stem cell transplantation. The advent of single-cell PCR provided the opportunity for combined preimplantation genetic diagnosis (PGD) and HLA antigen testing. They identified a couple, both carriers of the IVS4+4A-T mutation in the FANCC gene, with an affected child requiring an HLA-compatible donor for cord blood transplantation. They used DNA analysis of single blastomeres to preselect unaffected embryos representing an HLA match for the affected sib. The transfer of mutation-negative, HLA-compatible embryos resulted in the pregnancy and birth of an unaffected child.
By mismatch analysis with chemical cleavage with osmium tetroxide and hydroxylamine, Murer-Orlando et al. (1993) demonstrated compound heterozygosity for a gln13-to-ter (Q13X) mutation in exon 1 of the FACC gene and an R548X mutation in exon 14 (613899.0005) in chorionic villus samples obtained for prenatal diagnosis of Fanconi anemia of complementation group C (FANCC; 227645). The 2 mutations were derived from the father and mother, respectively, and were also demonstrated in an affected sib. Chromosome breakage analysis on cultured chorionic cells had shown a higher response to diepoxybutane in the pregnancy at risk than in normal control samples.
For discussion of the arg548-to-ter (R548X) mutation in the FANCC gene that was found in compound heterozygous state in chorionic villus samples obtained for prenatal diagnosis of Fanconi anemia of complementation group C (FANCC; 227645) by Murer-Orlando et al. (1993), see 613899.0004.
Lo Ten Foe et al. (1996) described a frameshift mutation in the FANCC gene resulting from insertion of an adenine after nucleotide 1806 in exon 14. The insertion caused a frameshift that was expected to give rise to a truncated protein of 526 amino acids, which is shorter than the protein resulting from premature termination caused by the R548X mutation (613899.0005), and therefore presumed to be inactive. Mutations in exon 14 are the most C-terminal of 7 pathogenic mutations that the authors discussed. Three pathogenic mutations are located in exon 14, suggesting that the C-terminal part of FAC protein is essential for an as yet unknown function. The other 2 exon 14 mutations reported to that time were L554P (613899.0001) and R548X (613899.0005).
Mutations within the Fanconi anemia complementation group C (FAC) gene account for approximately 14% of diagnosed Fanconi anemia (FA; see 227645) cases. Two mutations, one in exon 1 (322delG) and the other in exon 4 (IVS4+4A-T; 613899.0003), account for 90% of known FAC mutations. The 322delG mutation results in a mild FA phenotype, while the IVS4 donor splice site mutation results in a severe FA phenotype. To determine the molecular basis for this clinical variability, Yamashita et al. (1996) analyzed patient-derived cell lines for the expression of characteristic mutant FAC polypeptides. All cell lines with the 322delG mutation expressed a 50-kD FAC polypeptide, shown to be an N-terminal truncated isoform of FAC reinitiated at methionine 55. All cell lines with the IVS4 donor splice site mutation lacked FRP-50 (FAC-related protein). Overexpression of a cDNA encoding FRP-50 in a FAC cell line resulted in partial correction of mitomycin C sensitivity. Thus, expression of an N-terminal truncated FAC protein accounted, at least in part, for the clinical heterogeneity.
Pang et al. (2001) observed that cells bearing the 322delG mutation, which preserves a conserved region of FANCC, showed normal STAT1 activation but remained hypersensitive to mitomycin C. Preservation of signaling capacity of cells bearing this mutation may account for the reduced severity and later onset of bone marrow failure associated with it.
In a patient with Fanconi anemia of complementation group C (FANCC; 227645) and his affected brother, Waisfisz et al. (1999) detected a homozygous 1749T-to-G missense mutation in the FANCC gene, predicting a change from leucine to arginine at codon 496 (L496R). Cytogenetic analysis revealed the patient and his brother to be mosaics with an additional de novo 1748C-to-T transition at 1 allele. The combination of the 2 mutations on 1 allele predicted a change from the mutant arginine to cysteine. Evaluation of the functional status of the proteins encoded by both alleles showed full correction by the cDNA with both mutations.
In affected members of 2 unrelated but consanguineous families of Arabian ancestry with Fanconi anemia of complementation group C (FANCC; 227645), Hartmann et al. (2010) identified a homozygous G-to-T transversion in intron 2 of the FANCC gene (165+1G-T), changing a highly conserved GT dinucleotide to TT at the 5-prime splice site. Two affected individuals from a family of mixed Arabian/British ancestry were compound heterozygous for the intron 2 mutation and a 250-bp deletion (613899.0010), resulting in the skipping of exons 2 and 3. The phenotype was relatively mild in the 2 Arabian families, but was severe in the 2 patients in the mixed Arabian/British family, who died at ages 13.5 and 16 years. RT-PCR analysis of the splice site mutation yielded 4 distinct products, including the wildtype product at 27% of the total transcripts. Functional analysis of the splice site mutation within splicing reporters showed that increasing complementarity to U1 snRNA could reconstitute splicing at the noncanonical TT dinucleotide, and that artificial TT-adapted U1 snRNA improved correct mRNA processing at the mutant TT splice site. These results were replicated in patient fibroblasts, with correctly spliced transcripts increasing from about 30% to 56-58%. Finally, Hartmann et al. (2010) demonstrated that use of lentiviral vectors as a delivery system to introduce expression cassettes for TT-adapted U1 snRNAs into primary FANCC patient fibroblasts allowed the continuous correction of the DNA damage-induced G2 cell-cycle arrest in these cells. These findings indicated an alternative transcript-targeting approach for genetic therapy of inherited splice site mutations.
For discussion of the 250-bp deletion in the FANCC gene that was found in compound heterozygous state in patients with Fanconi anemia of complementation group C (FANCC; 227645) by Hartmann et al. (2010), see 613899.0009.
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