Human Molecular Genetics, Vol 5, 1457-1463, Copyright © 1996 by Oxford University Press
NA Ellis and J German
Mutation of the Bloom's syndrome (BS) gene, BLM, results in genomic
instability. As the first step toward positional cloning of the gene, tight
linkage of BLM and FES at 15q26.1 was detected by genotyping affected in
families in which the parents are cousins, so-called homozygosity mapping.
Linkage disequilibrium between BLM and FES was detected in Ashkenazi Jews
with BS, confirming the linkage results and supporting the hypothesis that
the increased frequency of the BS mutation in the Ashkenazim is due to
founder effect. The mutated BLM gene is inherited identical by descent in
BS persons whose parents are cousins or Ashkenazi Jewish; in persons whose
parents do not share a common ancestor, BLM can be mutant at different
positions within the gene. In such persons, crossing-over within BLM can
occur to form a functionally wild-type gene capable of correcting the
mutant phenotype of BS cells. In half the cases in which such somatic
intragenic recombination had occurred, reduction to homozygosity was
detectable distal to BLM but not proximal to it. We localized the
cross-over points in corrected cells to a 250 kb genomic segment and
isolated therefrom a 4437 bp cDNA that encodes a 1417 amino acid protein
homologous to the RecQ subfamily of DExH box-containing DNA and RNA
helicases. The identification of BLM as a putative DNA helicase provides a
new and powerful tool to investigate the primary defect in BS and the
function of the BLM gene product in maintaining the integrity of the
genome.
REVIEWS
Molecular genetics of Bloom's syndrome
Laboratory of Human Genetics, New York Blood Center, NY 10021, USA.
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