Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrome.

Bloom's syndrome (BS), a human recessive disorder associated with an increased risk of malignancy, arises through mutations in both alleles of the BLM gene, which was recently identified as a member of the RecQ helicase family. BS cells are characterized by an increased rate of sister chromatid exchange (SCE). However, a subpopulation of lymphocytes exhibiting a normal level of SCE is observed in some patients. It has been proposed that reversion to a low-SCE phenotype involves an intragenic crossing over between the paternal and maternal BLM alleles, generating a wild-type allele. In this study we characterize a new BLM mutation in a BS patient leading to the replacement, in the C-terminal region of Blm, of a highly conserved cysteine by a phenylalanine in codon 1036. Moreover, our data show that this patient also inherited a BLM allele carrying a mutation affecting its expression and that a somatic intragenic crossing over was involved in reversion to the low-SCE phenotype. Further, we show that both topoisomerase II alpha mRNA and protein levels are decreased in the high-SCE cells derived from this patient, whereas they are normal in the corresponding low-SCE cells. Altogether, our data led us to propose that besides its putative helicase activity, Blm could be involved in transcription regulation.