Bloom syndrome: is the gene mapped to the point?

ABSTRACT

Bloom syndrome (BS), an autosomal recessive genetic disorder, is an instructive model to explore variety of questions in "deregulation of normal cell functioning". Most of the BS patients are homozygous for mutant BLM gene and depict high sister chromatid exchanges (SCEs) in almost all the cells. However, a few possess cells with dimorphic SCE phenotype. A majority of patients with dimorphic SCE phenotype have been suggested to be compound heterozygotes, inheriting two different mutations in the BLM locus from each parent. An intragenic somatic recombination event in a precursor stem cell in such patients is envisaged to give rise to a population of cells with functionally wild-type (BLM) gene and normal SCE phenotype. Adopting unique dual approaches of positional mapping through "homozygosity by descent" and "somatic crossover point mapping", a candidate for BLM has been identified and localized to a 250 Kb interval between polymorphic loci, DI5S1108 and D15127. The sequence has been found to encode a 1417 amino acid peptide with homology to the RecQ helicases, a sub-family of DExH box-containing DNA and RNA helicases. The presence of chain terminating mutations in the 'candidate' gene in BS patients has suggested it to be the BLM gene. Apparantly the proposed gene product does not seem to provide answer for a variety of clinical, biochemical and experimental observations made in BS or BS cells till date. Our recent observation of a significant decrease in the activity of pyruvate kinase in three BS B-lymphoblastoid cell lines when compared to a similar cell line established from a normal healthy subject presents with another possible candidate to elucidate the defects in BS. Experiments using okadaic acid, a phosphatase-2a/1 inhibitor, have depicted in our study that many of the clinical features characteristic of BS, not easily explanable by the recently proposed BLM gene, can be explained by the deficiency in the PK alone and/or PP2a/PP1 activity.