Alternative titles; symbols
SNOMEDCT: 1285021005; ORPHA: 84; DO: 0111087;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q22.32 | Fanconi anemia, complementation group C | 227645 | Autosomal recessive | 3 | FANCC | 613899 |
A number sign (#) is used with this entry because Fanconi anemia of complementation group C (FANCC) is caused by homozygous or compound heterozygous mutation in the FANCC gene (613899) on chromosome 9q22.
Fanconi anemia is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011).
For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.
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.
Strathdee et al. (1992) and Gavish et al. (1992) identified a missense mutation in the FANCC gene in the Fanconi anemia complementation group C cell line HSC536N (613899.0001).
Approximately 25% of patients with Fanconi anemia have evidence of spontaneously occurring mosaicism as manifested by the presence of 2 subpopulations of lymphocytes, one of which is hypersensitive to crosslinking agents (e.g., mitomycin C) while the other behaves normally in response to these agents. In 3 patients who were compound heterozygotes for pathogenic FAC gene mutations, Lo Ten Foe et al. (1997) investigated the molecular mechanism of mosaicism by haplotype analysis. The results indicated that an intragenic mitotic recombination must have occurred leading to a segregation of a wildtype allele in the revertant cells and suggested 2 patterns of recombination. In 1 patient, a single intragenic crossover between the maternally and paternally inherited mutations occurred associated with markers located distal to the FAC gene; in the other 2 patients (sibs), the mechanism appeared to have been gene conversion resulting in segregants that had lost 1 pathogenic mutation. In 6 of 8 patients with mosaicism, the hematologic symptoms were relatively mild despite an age range of 9 to 30 years.
Waisfisz et al. (1999) demonstrated the functional correction of a pathogenic microdeletion, microinsertion, and missense mutation in homozygous Fanconi anemia patients resulting from compensatory secondary sequence alterations in cis. A mutation in the FANCC gene, 1749T to G, which resulted in a substitution of arginine for leucine-496, was altered by 1748C-to-T creating a cysteine codon (613899.0008). Although the predicted proteins were different from wildtype, their cDNAs complemented the characteristic hypersensitivity of FA cells to crosslinking agents, thus establishing a functional correction to wildtype.
Krasnoshtein and Buchwald (1996) used RNA in situ hybridization to study the distribution of Fac transcripts during mouse development. Fac was initially expressed (8-10 days p.c.) in the mesenchyme and its derivatives with osteogenic potential. The transcript was also apparent at later stages of bone development (13-19.5 days p.c.), localized to cells of the inner perichondrium, periosteum, and zone of endochondral ossification. In the third site, Fac transcripts were seen in cells from both osteogenic and hematopoietic lineages. Fac mRNA was also seen in intramembranous cranial and facial bones. In addition, Fac signal was detected in nonskeletal tissues: brain, whisker follicles, lung, kidney, gut, and stomach. The pattern of expression was consistent with the skeletal and non-skeletal congenital abnormalities in FA patients. The authors commented that expression in rapidly dividing progenitors is consistent with hypotheses regarding the nature of the basic defect in FA: a role of the protein in DNA repair or protection from oxygen toxicity.
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.
Chen, M., Tomkins, D. J., Auerbach, W., McKerlie, C., Youssoufian, H., Liu, L., Gan, O., Carreau, M., Auerbach, A., Groves, T., Guidos, C. J., Freedman, M. H., Cross, J., Percy, D. H., Dick, J. E., Joyner, A. L., Buchwald, M. Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia. Nature Genet. 12: 448-451, 1996. [PubMed: 8630504] [Full Text: https://doi.org/10.1038/ng0496-448]
Deakyne, J. S., Mazin, A. V. Fanconi anemia: at the crossroads of DNA repair. Biochemistry 76: 36-48, 2011. [PubMed: 21568838] [Full Text: https://doi.org/10.1134/s0006297911010068]
Gavish, H., dos Santos, C. C., Buchwald, M. Generation of a non-functional Fanconi anemia group C protein (FACC) by site-directed in vitro mutagenesis. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A128 only, 1992.
Krasnoshtein, F., Buchwald, M. Developmental expression of the Fac gene correlates with congenital defects in Fanconi anemia patients. Hum. Molec. Genet. 5: 85-93, 1996. [PubMed: 8789444] [Full Text: https://doi.org/10.1093/hmg/5.1.85]
Lehmann, A. R., Bootsma, D., Clarkson, S. G., Cleaver, J. E., McAlpine, P. J., Tanaka, K., Thompson, L. H., Wood, R. D. Nomenclature of human DNA repair genes. Mutat. Res. 315: 41-42, 1994. [PubMed: 7517009] [Full Text: https://doi.org/10.1016/0921-8777(94)90026-4]
Lo Ten Foe, J. R., Kwee, M. L., Rooimans, M. A., Oostra, A. B., Veermans, A. J. P., van Weel, M., Pauli, R. M., Shahidi, N. T., Dokal, I., Roberts, I., Altay, C., Gluckman, E., Gibson, R. A., Mathew, C. G., Arwert, F., Joenje, H. Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance. Europ. J. Hum. Genet. 5: 137-148, 1997. [PubMed: 9272737]
Segal, G. M., Magenis, R. E., Brown, M., Keeble, W., Smith, T. D., Heinrich, M. C., Bagby, G. C., Jr. Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor cells. J. Clin. Invest. 94: 846-852, 1994. [PubMed: 7518843] [Full Text: https://doi.org/10.1172/JCI117405]
Strathdee, C. A., Gavish, H., Shannon, W. R., Buchwald, M. Cloning of cDNAs for Fanconi's anaemia by functional complementation. Nature 356: 763-767, 1992. Note: Erratum: Nature 356, 763 only, 1992. [PubMed: 1574115] [Full Text: https://doi.org/10.1038/356763a0]
Waisfisz, Q., Morgan, N. V., Savino, M., de Winter, J. P., van Berkel, C. G. M., Hoatlin, M. E., Ianzano, L., Gibson, R. A., Arwert, F., Savoia, A., Mathew, C. G., Pronk, J. C., Joenje, H. Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nature Genet. 22: 379-383, 1999. [PubMed: 10431244] [Full Text: https://doi.org/10.1038/11956]
Whitney, M. A., Royle, G., Low, M. J., Kelly, M. A., Axthelm, M. K., Reifsteck, C., Olson, S., Braun, R. E., Heinrich, M. C., Rathbun, R. K., Bagby, G. C., Grompe, M. Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the Fanconi anemia C gene. Blood 88: 49-58, 1996. [PubMed: 8704201]