By David N. Leff
In any contest for the title ¿mostest with the worstest,¿ Bloom¿s syndrome would probably take win, place and show. Consider these superlatives:
Rarity: Among the least-numerous cases of disease known in the world.
Smallness: Diagnosed by its diminutive birth size.
Mutations: Most highly hypermutable cells known.
Neoplasms: Greatest risk of multiple cancers.
Bloom¿s syndrome (BS) got its eponym nearly half a century ago from a well-known practicing New York dermatologist named David Bloom. A contemporary at the time, pediatrician James German, told BioWorld Today the story:
¿Bloom examined a case of what the referring doctor thought was lupus, but he was impressed with the smallness of the child. He followed the patient for more than 10 years, and then two others, one at Cornell Hospital, the other from Columbia Physicians and Surgeons. In 1953, a case from each of those two places was presented at one of the local dermatology meetings, and Bloom realized it was a syndrome. Then he wrote a paper in 1954 describing these three.¿
German, then at the Rockefeller Institute in New York, picked up the story:
¿Shortly after that presentation,¿ he recounted, ¿I found a tendency in that syndrome for genomic instability ¿ that the chromosomes break and rearrange much more often than in other people¿s cells. The patient I found it in was being followed at the Rockefeller Institute hospital. I studied her several times, and then asked Dr. Bloom about other cases of which he was aware, among the handful known in the world. So we looked at them all.
¿They all had this chromosome breakage,¿ German continued, ¿which is what got me interested. Then when we got more cases, and looked at their gene mutations, we found that the Bloom¿s cells are the most highly hypermutable known, and so of course carried the highest risk of cancers in the general population.¿
In 1995, German¿s lab cloned the gene for BS, then expressed its protein, BLM, to which it raised antibodies. A research pediatrician emeritus at Cornell University Medical College in New York, German now follows 178 BS cases of the estimated 200 worldwide.
¿Bloom¿s is a clinical syndrome,¿ he pointed out, ¿and its predominating feature is small size. This is present in every stage of life after conception. So the embryo, the fetus and the newborn are all very small, and stay small after birth. Their birth weight is considerably lower than normal, but these neonates are perfectly formed,¿ he went on. ¿They are very ready to pop out. And being so small, they are quite agile. They stand earlier and develop very well, but always stay small ¿ and that¿s the main clinical feature.¿
BS Spells Lifetime Of Serial Cancers
However, the main pathological feature is a BS child¿s proneness, from early in life, to develop malignancies. ¿In childhood,¿ German observed, ¿there can be leukemia. A little later lymphoma starts to appear, and carcinoma in the late teens. Then in the 20s and 30s they get cancer of the esophagus, colon, breast, uterus. It cuts short the life of many of them.¿
One other striking hallmark of the disease pointed to a link between malignancy and that genomic hypermutability. Dermatologist Bloom noticed it early in the 1950s: a lupus-like eruption on the face ¿ a sun-sensitive redness on both cheeks connected by the so-called ¿butterfly area¿ across the bridge of the nose.
Skin sensitivity to solar radiation is a feature of another rare genomically mutated disorder, ataxia-telangiectasia. Its gene shares with that of BS residence on human chromosome 11, and both, said molecular cytogeneticist Terry Ashley, ¿have been implicated in the replication and repair activities of somatic cells.¿
Ashley is senior author of a paper in the current Proceedings of the National Academy of Sciences, dated May 11, 1999. German is co-senior author. Their article bears the title: ¿Bloom¿s syndrome protein, BLM, colocalizes with replication protein A in meiotic prophase nuclei of mammalian spermatocytes.¿
Ashley¿s research focus, she told BioWorld Today, is ¿studying mammalian meiosis, the process of germ-line cell division that correctly pairs and recombines the chromosomes of each parent in each future sex cell ¿ sperm and egg.¿
This hyper-complex operation, which lasts about two weeks in a dividing single germ-line cell, Ashley said, ¿relies mainly on two mechanisms ¿ synapsis and DNA recombination.¿
¿Synapsis,¿ she explained, ¿is the process of holding homologous chromosomes in position, and checking that the DNA sequences for each parental chromosome are in register, so they can recombine. Among other dangers, synapsis prevents Down¿s syndrome.¿
Parental Heritage: Getting It Right In Progeny
¿Recombination,¿ she explained, ¿sort of ties the parental chromosomes together until it¿s time for them to divide and go their separate ways. This involves putting one chromosome one into an egg and one chromosome one into a sperm ¿ no more, no less. It takes place when chromosomal DNA crosses over during meiosis. Recombination is also nature¿s way of creating genetic novelty conducive to evolutionary change.¿
In the mutated genes of BS, both of these vital steps go awry. BS boys are born infertile, unable to make sperm. Girls can have children, but with a reduced reproductive life. The mutations lead to somatic (non-reproductive) cells throughout the body riddled by chromosomal gaps, breaks and rearrangements. These frustrate the mission of DNA repair enzymes, notably helicase in BS, to correct those errors during meiosis.
Ashley noted that for lack of a knockout mouse model of BS, her in vivo experiments ¿took reproductive tissue, specifically sperm cells, from normal mice, and visualized their meiotic pairing microscopically, with antibodies to the mutated BLM protein.¿
¿This gave us a better idea,¿ she observed, ¿of what those proteins are doing in the synaptic complex and during recombination. Now,¿ she concluded, ¿we are looking at how other proteins interact with BS, and hoping to find a transgenic BS mouse.¿ n