title: Sequence variation in the Fanconi anemia gene FAA.
abstract: Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy. The gene for FA complementation group A (FAA) recently has been cloned. The cDNA is predicted to encode a polypeptide of 1,455 amino acids, with no homologies to any known protein that might suggest a function for FAA. We have used single-strand conformational polymorphism analysis to screen genomic DNA from a panel of 97 racially and ethnically diverse FA patients from the International Fanconi Anemia Registry for mutations in the FAA gene. A total of 85 variant bands were detected. Forty-five of the variants are probably benign polymorphisms, of which nine are common and can be used for various applications, including mapping studies for other genes in this region of chromosome 16q. Amplification refractory mutation system assays were developed to simplify their detection. Forty variants are likely to be pathogenic mutations. Seventeen of these are microdeletions/microinsertions associated with short direct repeats or homonucleotide tracts, a type of mutation thought to be generated by a mechanism of slipped-strand mispairing during DNA replication. A screening of 350 FA probands from the International Fanconi Anemia Registry for two of these deletions (1115-1118del and 3788-3790del) revealed that they are carried on about 2% and 5% of the FA alleles, respectively. 3788-3790del appears in a variety of ethnic groups and is found on at least two different haplotypes. We suggest that FAA is hypermutable, and that slipped-strand mispairing, a mutational mechanism recognized as important for the generation of germ-line and somatic mutations in a variety of cancer-related genes, including p53, APC, RB1, WT1, and BRCA1, may be a major mechanism for FAA mutagenesis.
authors.affiliation: Laboratory of Human Genetics and Hematology, The Rockefeller University, New York, NY 10021-6399, USA.
authors.forename: O
authors.initials: O
authors.lastname: Levran
authors.forename: T
authors.initials: T
authors.lastname: Erlich
authors.forename: N
authors.initials: N
authors.lastname: Magdalena
authors.forename: J J
authors.initials: JJ
authors.lastname: Gregory
authors.forename: S D
authors.initials: SD
authors.lastname: Batish
authors.forename: P C
authors.initials: PC
authors.lastname: Verlander
authors.forename: A D
authors.initials: AD
authors.lastname: Auerbach
mesh_terms: D018797:Cell Cycle Proteins; D016384:Consensus Sequence; D004268:DNA-Binding Proteins; D005199:Fanconi Anemia / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins