Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1.

Abstract

By the principle of identity by descent, parental consanguinity in individuals with rare recessively transmitted disorders dictates homozygosity not just at the mutated disease-assoiated locus but also at sequences that flank that locus closely. In 25 of 26 individuals with Bloom syndrome examined whose parents were related, a polymorphic tetranucleotide repeat in an intron of the protooncogene FES was homozygous, far more often than expected (P < 0.0001 by x2). Therefore, BLM, the gene that when mutated gives rise to Bloom syndrome, is tightly linked to FES, a gene whose chromosome position Is known to be l5q26.1. This successful approach to the aignment ofthe Bloom syndrome locus to one short segment of the human genome simultaneously (i) demonstrates the power of homozygosity mapping and (it) becomes the first step in a "reverse" genetics defmition of the primary defect in Bloom syndrome.Bloom syndrome (BS) (1, 2) is a rare autosomal recessive disorder the predominating clinical feature of which is a well-proportioned smallness of the body. The locus mutated, here named BLM, has long been recognized to be of central importance in the maintenance of genomic stability because persons with BS, blm/blm, feature a remarkable degree of genomic instability. In somatic cells having such a mutator genotype, increased numbers of different types of spontaneous mutations arise at various sites, mutations that qualitatively are similar to those that arise spontaneously in normal individuals. In addition to locus-specific mutations, increased numbers of microscopically visible chromosome mutations at randomly distributed sites are present in metaphase chromosomes-gaps, breaks, and rearrangements. In particular, a striking excess ofchromatid exchanges occurs in BS, including homologous chromatid interchange which is cytogenetic evidence of somatic crossing-over (3); therefore, a mutation that does arise at any particular site in a BS somatic cell also is at an increased risk of becoming homozygous. Other than the generalized growth deficiency ofclinical BS, which itself may be the consequence of an excessive number oflethal mutations, the most important manifestation of the genomic instability of the somatic cells is neoplasia; cancers of a wide variety of sites and types emerge unusually early and frequently in persons with BS.The primary defect in BS is unknown, and this has limited its usefulness as a model for studying neoplastic transformation and progression. Results of many studies do point to a disturbance of DNA replication. (i) The cytogenetic abnormalities (4) are best explained on the basis of excessive exchange of chromatids via an error-prone mechanism activated during S-phase replication. (ii) Replication-fork progression is retarded (5), and an unusual size distribution of DNA replication intermediates is found (6). (iii) Some cultured BS cell lines exhibit hypersensitivity to certain DNAdamaging agents-e.g., mitomycin C, N-nitroso-N-ethylurea, and ethyl methanesulfonate (7)(8)(9). (iv) Altered activ...

Syndrome-causing mutations of theBLMgene in persons in the Bloom's Syndrome Registry

“…A decade ago the gene that when mutated is responsible for the trait BS, referred to as BLM (MIM] 604610), was mapped to chromosome band 15q26.1 [German et al, 1994] and isolated [Ellis et al, 1995a]. BLM encodes the protein BLM, a DNA helicase of the highly conserved RecQ subfamily of helicases, a group of nuclear proteins important in the maintenance of genomic stability [Bennett and Keck, 2004].…”

Melanocytes and Their Diseases

“…McCune-Albright syndrome results from somatic mutations of the GNAS gene (G-protein a-subunit) especially mutations in Gsa (stimulatory G protein) (Dumitrescu and Collins 2008). The causative gene for Bloom syndrome, with photosensitivity and increased risk of malignancy, is BLM (Bloom syndrome, RecQ helicase-like), localized at chromosome 15q26.1 (German et al 1994). …”

Nuclear structure in normal and Bloom syndrome cells

“…Genomic DNA (19) was digested with AluI and HinfI, and Southern analysis and quantitation was performed as described (20).…”