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ABSTRACT

  • Fanconi anemia (FA) is an autosomal recessive disorder that is characterized clinically by diverse congenital abnormalities and a predisposition to bone marrow failure and malignancy, particularly acute myelogenous leukemia (AML). FA patients exhibit extreme clinical heterogeneity and may have abnormalities in any major organ system. It is recognized that the FA phenotype is so variable, with considerable overlap with the phenotypes of a variety of genetic and nongenetic diseases, that diagnosis on the basis of clinical manifestations alone is difficult.

  • FA is found in all races and ethnic groups and has been widely reported to have a carrier frequency of 1 in 300. This estimate was based on the incidence of affected individuals before the full spectrum of the FA phenotype was recognized. The true gene frequency is likely to be considerably higher than this; a low estimate would result from an incomplete ascertainment of cases before the widespread application of chromosomal breakage tests for FA diagnosis. Up to 0.5 percent of the general population may be heterozygous at an FA locus.

  • Hypersensitivity of FA cells to the clastogenic (chromosome-breaking) effect of crosslinking agents provides a unique cellular marker for the disorder. This is used as a diagnostic criterion because of the difficulty of diagnosing FA on the basis of clinical manifestations alone. Comparative studies have led to the choice of diepoxybutane (DEB) as the agent most widely used for FA diagnosis. The crosslinking test can be used to identify preanemic patients as well as patients with aplastic anemia or leukemia who may or may not have the physical stigmata associated with FA.

  • The hypersensitivity of FA cells to crosslinking agents has been used to assess complementation in somatic cell hybrids. Complementation groups usually are considered to represent distinct disease genes, and for FA, at least four groups (A, C, D, and G) represent distinct genes. The first FA gene isolated by expression cloning methodology (FANCC, alias FAC) mapped to chromosome 9q22.3 by in situ hybridization. FANCA (alias FAA) was mapped by linkage of the disease in FA-A families to microsatellite markers positioned close to the telomere of chromosome 16 (16q24.3). FANCD (alias FAD) was mapped to 3p22-26 by microcell-mediated chromosome transfer. FANCG (alias FAG) is identical with the previously isolated human gene XRCC9, which was mapped to 9p13. Considerable variability in the prevalence of the different complementation groups has been observed among various ethnic groups. Overall, FA-A is the most prevalent group, accounting for 60 to 65 percent of all FA cases.

  • A cDNA expression cloning procedure was adapted and used successfully to clone the gene defective in FA-C cells (FANCC). The FANCC coding region contains 14 exons and leads to a predicted protein of 558 amino acids. The predicted structure of FANCC does not resemble that of any known protein and has no obvious functional domains. The protein is found primarily in the cytoplasm, although approximately 10 percent is in the ...

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