Since a New York City dermatologist in private practice described thefirst case of Bloom's syndrome in 1954, fewer than 170 peopleworldwide have been identified with this ultra-rare genetic disorder.Though small in number, their significance looms large today. Theyconstitute a unique human model for exploring how the genome staysstable, and why cancers happen.Babies born with Bloom's syndrome (BS) are extremely small, butperfectly proportioned. In childhood, their skin reacts violently tosunshine, with disfiguring rashes that led dermatologist David Bloomto describe his first case four decades ago as "Congenital telangiectaticerythema resembling lupus erythematosus in dwarfs."Then, in their teens and twenties, BS individuals develop cancers _plural. Not specific inherited malignancies _ as of breast and colon,for which the genes have lately been identified _ but the wholespectrum of tumors that modern man is heir to. They range fromleukemias and lymphomas to carcinomas of every organ in the body."The cells are mutating like crazy," says human geneticist JamesGerman, who founded the Bloom's Syndrome Registry at the NewYork Blood Center in 1960. "These mutations accumulate," he toldBioWorld Today, "but throughout the genome, not in any one locus.Sooner or later," he added, "in one of the tumor-suppressing genes,such as p53 or the ras protooncogene, BS is going to mutate in thewrong cell _ and that's what cancer is."So German sees BS as "a model for studying the origin of thegenerality of human malignancies, of neoplastic transformation."He and his associate at the Blood Center, molecular geneticist NathanEllis, have a paper in the current Proceedings of the National Academyof Sciences (PNAS) reporting their latest efforts to unravel and pindown this loose-cannon behavior of the bizarre BS gene. Its title:"Bloom's syndrome: An analysis of consanguineous families assignsthe locus mutated to chromosome band 15q26.1."Some four years ago, after they had already started their pedigreelinkage analysis of BS patients whose parents were cousins, Germanrecalls, "we learned of a research report _ which our PNAS paperactually confirms now _ suggesting that when you microinject anumber-15 chromosome into a BS cell, it will correct the mutation."So they fine-tuned their hunt from the entire human karyotype down tochromosome 15, "looking for DNA markers that were homozygous(contributed by both closely related parents) more often than theyshould be."In BS cells, portions of arms on pairs of same-number chromosomesmay trade places. Gaps, breakage or cross-overs may arise on the twosister arms of one of the pair. All in all, BS chromosomes act as if theywere too fragile to keep it all together.The Cancer ConnectionSuch excessive breakage and rearrangement brought on by geneticallydetermined chromosome instability led German to suspect arelationship to cancer, when one of his BS patients contracted leukemiain 1963. The most important reason for this "striking predisposition ofBS patients to develop a large variety of tumors in a large variety oftissues at an early age," he explained, "is that the somatic cells, not thegermline ones, accumulate an unusually large number of spontaneousmutations of multiple types." A contributing factor is that "immunedeficiency is a major clinical feature of the syndrome."What makes this syndrome so interesting to German and Ellis is itsprimary biochemical defect, which probably has to do with DNAreplication itself. "This must be a key gene in the whole mechanismthat maintains the stability of the genome, from generation togeneration and cell division to cell division," German marvels. "Themaintenance of DNA stability is really one of the most awesomeaspects of genetics."To accomplish the first step of locating that rare recessive gene, theBlood Center's human genetics laboratory, which German directs,resorted to homozygosity mapping. "When you have a patient with arare condition, and whose parents are cousins," he explained, "youknow that one of the grandparents carried that rare gene. So the twoparents of this child passed on the identical mutation _ truehomozygosity."Fantastic MarkersHe and his team worked with 21 pairs of consanguineous parents, whohad 26 BS offspring. Using restriction fragment length polymorphismsinitially, then microsatellite simple repeats, they tracked dinucleotidejunk DNA, such as C-A-C-A-C-A. . ., then trinucleotide and eventuallytetranucleotide stuttering DNA stretches. These last "fantasticmarkers," German observed, "are currently most valuable because oftheir enormous variability. We're all probably heterozygous for everyone of these. And they're also spread throughout the genome _ ingenes, between genes, all around."One day it suddenly struck the lab that a four-base repeating nucleotideon their suspect chromsome's long arm was homozygous in all but oneof their 26 BS patients, "and only a third of them should have been!"Cornering the still-unknown BS gene on a small stretch of chromosome15's long arm, German said, "was the first step. The second step, whichwe now have on the front burner, is to clone and isolate the gene itself.It's a hard nut to crack," he added, "but we're in the last stages, and Ithink _ I hope _ we'll have that within half a year." n
-- David N. Leff Science Editor
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