PubMed · 8348441
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E G Jung. The red face: photogenodermatoses.. https://doi.org/10.1016/0738-081x(93)90063-i
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Bloom's syndrome (BS) is an autosomal recessive disorder with a high cancer incidence. BS cells exhibit increased chromosomal instability and sister-chromatid exchange. The rate of spontaneous mutation at the locus encoding hypoxanthine phosphoribosyltransferase (HPRT) in a lymphoblastoid cell line derived from a BS patient, GM3403, was 1.39 x 10(-6) mutations/cell/generation, whereas that in TK6, a lymphoblastoid cell line derived from an individual who is not suffering from BS, was 1.75 x 10(-8) mutations/cell/generation. Molecular analysis of the HPRT gene in mutant clones by multiplex polymerase chain reaction revealed that 83.3% of the spontaneous mutants from GM3403 cells contained deletions at the HPRT locus, whereas 30.8% of mutants from TK6 cells had deletions. Approximately half of the BS mutants had lost the entire gene. Some mutant clones of GM3403 had also lost markers near the HPRT locus, although no mutant clones from TK6 cells had lost these markers. These results indicate that the mutator phenotype of BS cells is mainly due to an increase in large DNA alterations, reflecting the remarkable genomic instability that could be responsible for cancer proneness in this disease.
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Cells with abnormally high rates of sister-chromatid exchange (SCE) are uniquely characteristic of Bloom's syndrome (BS). However, in one in five persons a minor population of cells with a low-SCE phenotype circulates in the blood. The origin and significance of the low-SCE cells in BS have never been understood, although they are assumed to arise by somatic mutation. In the present investigation, the enigmatic high-SCE/low-SCE mosaicism was investigated by comparing the incidence in several subpopulations of persons in the Bloom's Syndrome Registry who exhibit the two types of cells, and a striking negative correlation emerged: in persons with BS whose parents share a common ancestor, the case in approximately half of registered persons, low-SCE cells are found only rarely; conversely, the mosaicism occurs almost exclusively in persons with BS whose parents are not known to share a common ancestor. Because those who share a common ancestor are predominantly homozygous-by-descent at the mutated BS locus, the negative correlation is interpreted to mean that the emergence of low-SCE cells in BS in some way depends on the pre-existence of compound heterozygosity. A corollary to this is that BS is genetically heterogeneous.