Heterogeneous spectrum of mutations in the Fanconi anemia group A gene

Department of Human Genetics, Free University of Amsterdam, The Netherlands.
European Journal of HumanGenetics (Impact Factor: 4.35). 02/1999; 7(1):52-9. DOI: 10.1038/sj.ejhg.5200248
Source: PubMed


Fanconi anaemia (FA) is a genetically heterogeneous autosomal recessive disorder associated with chromosomal fragility, bone-marrow failure, congenital abnormalities and cancer. The gene for complementation group A (FAA), which accounts for 60-65% of all cases, has been cloned, and is composed of an open reading frame of 4.3 kb, which is distributed among 43 exons. We have investigated the molecular pathology of FA by screening the FAA gene for mutations in a panel of 90 patients identified by the European FA research group, EUFAR. A highly heterogeneous spectrum of mutations was identified, with 31 different mutations being detected in 34 patients. The mutations were scattered throughout the gene, and most are likely to result in the absence of the FAA protein. A surprisingly high frequency of intragenic deletions was detected, which removed between 1 and 30 exons from the gene. Most microdeletions and insertions occurred at homopolymeric tracts or direct repeats within the coding sequence. These features have not been observed in the other FA gene which has been cloned to date (FAC) and may be indicative of a higher mutation rate in FAA. This would explain why FA group A is much more common than the other complementation groups. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. A scan of the entire coding sequence of the FAA gene may be required to detect the causative mutations, and scanning protocols will have to include methods which will detect the deletions in compound heterozygotes.

Download full-text


Available from: Gerard Pals, Oct 27, 2015
  • Source
    • "Whole-exome sequencing (WES) of DNA derived from proband LCLs and parental peripheral blood samples was performed. Analysis of WES data revealed a single FANCA mutation, c.2574C > G/p.Ser858Arg, previously described in FA (Wijker et al., 1999). Normal levels of FANCA were detected by western blot in RA2627 cells (Figure 2A), and overexpression of wild-type FANCA in RA2627 failed to rescue the monoubiquitination defect of FANCD2 and FANCI, excluding FANCA as a causative gene in this cell line (Figures 2B and 2C). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 06/2015; 12(1). DOI:10.1016/j.celrep.2015.06.014 · 8.36 Impact Factor
  • Source
    • "Table 1 Cell line Gender Mutated Gene Mutation 1 Predicted protein change Mutation 2 Predicted protein change Ref. HSC93 ? Wild type na na – MAN-EBV M Wild type na na – RUFA-EBV M Wild type na na – VU012-L M Wild type na na – EUFA689-L F FANCA c.3788 3790del c.3788 3790del [32] p.Phe1263del p.Phe1263del HSC72OT ? FANCA Deletion exon 18–28 Deletion exon 18–28 [33] p.? p.? HSC230 M FANCB a c.1856 1857insT – [34] "
    [Show abstract] [Hide abstract]
    ABSTRACT: The encouraging response rates of BRCA1- and BRCA2-mutated cancers toward PARP inhibitors make it worthwhile to identify other potential determinants of PARP inhibitor responsiveness. Since the Fanconi anemia (FA) pathway coordinates several DNA repair pathways, including homologous recombination in which BRCA1 and BRCA2 play important roles, we investigated whether this pathway harbors other predictors of PARP inhibitor sensitivity. Lymphoblastoid cell lines derived from individuals with FA or clinically related syndromes, such as Warsaw breakage syndrome, were tested for PARP inhibitor sensitivity. Remarkably, we found a strong variability in PARP inhibitor sensitivity among different FANCD1/BRCA2-deficient lymphoblasts, suggesting that PARP inhibitor response depends on the type of FANCD1/BRCA2 mutation. We identified the DNA helicases FANCM and DDX11 as determinants of PARP inhibitor response. These results may extend the utility of PARP inhibition as effective anticancer treatment. Copyright © 2014 Elsevier B.V. All rights reserved.
    DNA Repair 12/2014; 26. DOI:10.1016/j.dnarep.2014.12.003 · 3.11 Impact Factor
  • Source
    • "Abnormalities of FA genes are inherited in an autosomal recessive manner, except for FANCB mutations, which are inherited in an X-linked manner. Molecular diagnosis of FA is quite complicated, not only because at least 15 genes are associated with its development, but also the mutation spectra of most FA-associated genes are very diverse and some of these genes frequently contain large deletions or duplications [7-9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fanconi anemia (FA) is a rare genetic disorder affecting multiple body systems. Genetic testing, including prenatal testing, is a prerequisite for the diagnosis of many clinical conditions. However, genetic testing is complicated for FA because there are often many genes that are associated with its development, and large deletions, duplications, or sequence variations are frequently found in some of these genes. This study describes successful genetic testing for molecular diagnosis, and subsequent prenatal diagnosis, of FA in a patient and his family in Korea. We analyzed all exons and flanking regions of the FANCA, FANCC, and FANCG genes for mutation identification and subsequent prenatal diagnosis. Multiplex ligation-dependent probe amplification analysis was performed to detect large deletions or duplications in the FANCA gene. Molecular analysis revealed two mutations in the FANCA gene: a frameshift mutation c.2546delC and a novel splice-site mutation c.3627-1G>A. The FANCA mutations were separately inherited from each parent, c.2546delC was derived from the father, whereas c.3627-1G>A originated from the mother. The amniotic fluid cells were c.3627-1G>A heterozygotes, suggesting that the fetus was unaffected. This is the first report of genetic testing that was successfully applied to molecular diagnosis of a patient and subsequent prenatal diagnosis of FA in a family in Korea.
    Annals of Laboratory Medicine 09/2012; 32(5):380-4. DOI:10.3343/alm.2012.32.5.380 · 1.48 Impact Factor
Show more