Fanconi anemia (FA) 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 ... Fanconi anemia (FA) 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.
Levitus et al. (2004) reported on 8 unrelated Fanconi anemia patients who were excluded from the known subtypes on the basis of phenotypic correction (complementation) or genetic data. Four of these cell lines failed to complement each other ... Levitus et al. (2004) reported on 8 unrelated Fanconi anemia patients who were excluded from the known subtypes on the basis of phenotypic correction (complementation) or genetic data. Four of these cell lines failed to complement each other in somatic cell hybrids and therefore represented a new group, termed complementation group I (FANCI; 609053). The remaining cell lines complemented group FANCI but did not complement each other, thus representing a second new group, FANCJ. Both the FANCI and FANCJ cell lines were capable of forming a Fanconi anemia multiprotein core complex. This complex is required for activation of the FANCD2 protein (227646) by monoubiquitination, a key downstream event in the Fanconi anemia pathway. In FANCI cells, FANCD2 was not monoubiquitinated, indicating a defect upstream in the Fanconi anemia pathway, whereas in FANCJ cells FANCD2 was monoubiquitinated, indicating a downstream defect. The results suggested that the Fanconi anemia pathway of genome stabilization may be controlled by at least 11 different genes, including the FANCI gene (611360) and the FANCJ gene. Levitus et al. (2004) provided a tabulation of 11 genetically distinct Fanconi anemia subtypes.
Using genetic mapping, mutation identification, and Western blot data, Levran et al. (2005) identified the defective protein in FA-J cells as BRIP1. They found a nonsense mutation (R798X; 605882.0003) in homozygosity or compound heterozygosity in 10 unrelated individuals. ... Using genetic mapping, mutation identification, and Western blot data, Levran et al. (2005) identified the defective protein in FA-J cells as BRIP1. They found a nonsense mutation (R798X; 605882.0003) in homozygosity or compound heterozygosity in 10 unrelated individuals. After numerous unsuccessful attempts to identify the gene mutated in FA-J (FANCJ), using a complementation cloning strategy, Levitus et al. (2005) attempted positional cloning. They studied 8 individuals with FA-J, 4 of whom were from genetically informative families and 2 of whom were from a multiplex consanguineous family. They used DNA from 1 of these individuals in a genomewide scan using polymorphic markers positioned approximately 5 Mb apart. Chromosome 17 had the largest region of homozygosity, and they studied this region in more detail using the additional informative families. They also tested chromosome 17 for complementation of the Fanconi anemia defect by microcell-mediated chromosome transfer. By mapping the chromosome 17 fragment boundaries in clones that showed complementation of the sensitivity of FA-J fibroblasts to mitomycin C, together with the information obtained from the genomewide screen and the 3 remaining genetically informative families, they narrowed the FANCJ candidate region to 2 subregions. Of the predicted genes present in these regions, BRIP1 (605882) was considered a good candidate because chicken DT40 cells lacking BRIP1 expression had a Fanconi anemia-like phenotype. Levitus et al. (2005) sequenced this gene in families with FA-J and identified mutations in all affected individuals. One mutation, R798X in exon 17 (605882.0003), was found in 5 alleles from 4 individuals of diverse geographic origin, suggesting that it might be a hotspot or an ancient mutation. All the other mutations were private.