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Hum Genet. 1981;58(2):149-55.

Fanconi's anemia: anomaly of enzyme passage through the nuclear membrane? Anomalous intracellular distribution of topoisomerase activity in placental extracts in a case of Fanconi's anemia.


In cells of Fanconi's anemia (FA) spontaneous breakage of chromosomes was first recognized by Schroeder et al. (1964). Sensitivity to bivalent alkylants has been found to be a constant feature, whereas low levels of several repair-related enzymes have been described in different FA cell lines. In a family with known FA, during a further pregnancy the prenatal diagnosis of the disease was made by cytogenetic analysis of amniotic cells. After birth the fresh placenta was extracted for further enzymologic analysis. An unusual distribution of DNA topoisomerase activity was noted: high in the cytoplasm and only a little activity in the nuclear sap. This contrasts with findings in normal placentae. Since amniotic cells, lymphocytes, and fibroblasts of this child exhibited both high spontaneous breakage of chromosomes and sensitivity to the bivalent alkylant, diepoxybutane, a correlation between the findings on cytogenetic and enzymologic levels is assumed. Whereas in other published cases, a true reduction of activities of enzymes involved in DNA replication and repair has been found, the present results suggest the interpretation that in our patient the genetic anomaly does not affect the level of synthesis of the enzyme itself, but the passage of the enzyme from the place of synthesis (the cytoplasm) to the substrate (inside the nucleus). A genetic anomaly of the nuclear membrane might be a possible explanation, or alternatively, a structural mutation of the enzyme at a site not affecting the catalytic activity, but affecting the membrane passage or intranuclear accumulation. Meanwhile, placentae of two other cases gave similar results, thus supporting our findings.

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