Chapter 30

## Abstract

1. Clinically, Bloom syndrome (BS) features (a) proportional dwarfism, usually accompanied by (b) a sun-sensitive erythematous skin lesion limited to the face and dorsa of the hands and forearms, (c) a characteristic facies and head configuration, and (d) immunodeficiency, often associated with otitis media and pneumonia. (e) Affected males fail to produce spermatozoa, and females although sometimes fertile experience an unusually early cessation of menstrual cycles. (f) Excessive numbers of well-circumscribed areas of dermal hypo- and hyperpigmentation are present. (g) The three major complications are chronic lung disease, diabetes mellitus, and—by far the most important and most frequent—cancer.

2. BS is a genetically determined trait that is transmitted in a straightforward autosomal recessive fashion, with mutations at a single locus, BLM, being responsible. Various mutations at BLM are segregating in human populations, but the same phenotype (BS) is produced by either homozygosity or compound heterozygosity of those so far identified. The mutations are predominantly null alleles, but missense mutations also have been detected. BS is rare in all populations, but in the Ashkenazi Jewish population, one particular mutant allele, a 6-bp deletion and 7-bp insertion that results in premature translation termination, has, through founder effect, reached a relatively high carrier frequency of approximately 1 percent; in 31 percent of all persons with BS, one or both parents are Ashkenazi Jews.

3. The genome is abnormally unstable in the somatic cells of persons with BS. Mutations arise spontaneously and accumulate in numbers manyfold greater than normal, including both microscopically visible chromatid gaps, breaks, and rearrangements and mutations at specific loci. Exchanges take place excessively between chromatids, usually at what appear to be homologous sites. One consequence of this hyperrecombinability is the reduction to homozygosity of constitutionally heterozygous loci distal to the points of crossing-over. The hyperrecombinability in persons with BS who are genetic compounds can lead to reversion at BLM itself: Crossing-over between two different mutated sites within BLM can result in the generation of a functionally normal gene, and thereby correction of the cellular phenotype of the somatic cells that comprise the progeny of the cell in which the recombinational event had occurred.

4. Many of the clinical characteristics of BS may be viewed as direct or indirect consequences of the hypermutability. It is postulated to be a major causative factor in BS's small size by way of the induction of factors which either inhibit further cell division or promote cell death. Another major consequence of the hypermutability is proneness to neoplasia; BS more than any other known human state predisposes to the development of cancer of the types and sites that affect the general population, and at unusually early ages. BS thus is the prototype of a class of disease that may be called the somatic mutational disorders.

5. Diagnosis of BS is based on clinical observation; the phenotype is striking. Laboratory confirmation ordinarily is by cytogenetic demonstration of the characteristically increased tendency of chromatid exchange to take place. BS is the only condition known that features a greatly increased rate of sister-chromatid exchange (SCE). Blood lymphocytes in short-term culture are suitable for demonstrating this. Under certain circumstances, diagnosis can be confirmed by demonstrating mutation(s) in BLM.

6. With respect to the clinical management of BS, measures to increase the size have not been found. Protection from the sun, especially during infancy and childhood, is valuable in reducing the severity of the facial skin lesion. Greater than normal surveillance for carcinoma is indicated in persons who reach adulthood; however, because many are the sites and types of neoplasm that may arise, devising a surveillance program in BS is a particularly challenging matter, for both the affected person and the physician.

7. The mapping of BLM to chromosome band 15q26.1 and its subsequent molecular isolation identified a nuclear protein that contains a 350-amino acid domain consisting of 7 motifs characteristic of DNA and RNA helicases. The helicase domain of the BLM protein is 40 to 45 percent identical to the helicase domain present in the RecQ subfamily of DNA helicases. Although DNA-dependent ATPase and DNA duplex unwinding activities have been demonstrated for several RecQ helicases, including BLM, the nucleic acid substrates these proteins act on in the cell are unknown. Whatever these substrates are, the molecular and genetic evidence implicates the RecQ helicases in the cellular mechanisms that maintain genomic stability. Therefore, the biochemical, molecular, and functional characterization of BLM, a protein not known earlier in mammalian cells, promises to provide fundamental understanding of how stability of the genome is maintained as the zygote expands via the cell-division cycle into the greater than 1017 cells that will constitute the normal size adult body.

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