Bone marrow failure can result from genetic defects which arise from congenital or acquired etiologies. The paradigm for constitutional bone marrow failure is Fanconi anemia (FA). Fa is a heterogeneous genetic disorder characterized clinically by progressive bone marrow failure, congenital physical abnormalities, and a predisposition to malignancy. At the cellular level, the hallmark of the FA phenotype is hypersensitivity to DNA cross-linking agents resulting in chromosomal instability and cell death. Complementation of this cellular hypersensitivity was achieved by somatic cell fusion, studies which established that FA cell lines could be divided into four groups, termed A, B, C, and D. Transfection of cDNAs from an expression library into a cell line from complementation group C led to the identification of the gene defect in group C cells. This novel gene, termed FACC for Fanconi anemia C complementing, has a coding region of 1,677 basepairs. The 558 amino acid FACC protein has a molecular mass of 63kD and contains abundant hydrophobic amino acids. Sequence analysis has revealed no consensus motifs that would be informative to the protein's function. FACC maps to chromosome 9q and encodes a set of RNAs that share the same coding region but differ at both 5' and 3' untranslated regions. Current mutational analysis of FACC in over 170 families has identified 6 different disease-associated mutations constituting 10-15% of the patients and families tested.
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