Bloom's Syndrome: Genetics

Bloom’s Syndrome (BS) was suspected to be a genetic disorder as early as 1963. In 1969 it was proven to be inherited and autosomal recessive, and in 1994 the BLM gene was mapped to a locus on the 15th chromosome. The mapping procedure used a process called homozygosity mapping, which takes advantage of the fact that so many BS patients come from very closely related parents. The gene was cloned in 1995, providing further evidence of a locus on the 15th chromosome (Ellis et al., 1995). A mutation in this area of the genome causes the cell to produce a truncated version of the BLM protein, which in turn causes BS. The shortened version of the protein lacks the nuclear localizer normally coded into the end (C-terminal) of the protein, and without this localizer the protein fails to migrate to the nucleus, where it could do its job.

A number of mutations to the BLM gene can cause BS. Most common of these are nonsense and frameshift mutations, or deletions. All of these mutations lead to a shortened and useless version of BLM protein being produced. Missense mutations are also known to cause BS, and these are an interesting case because they apparently do not cause a truncated protein, but rather a version of BLM protein that will migrate to the nucleus but remain useless because of impaired interactions with other DNA helicases and with ATPase enzymes. In either case, mutations cause a functional loss of the BLM protein to the cell.

The role of the BLM protein in the cell is still being explored. The protein is known to be 1417 amino acids long, and a member of the RecQ family of DNA helicases. Interestingly, mutations to other members of this family are believed to be the cause of a number of other progeroid diseases, including Werner’s Syndrome. BLM protein in particular is a powerful helicase that is vital for the repair of double strand breaks. It also unwinds DNA bubbles, forks, triple helixes, and g4 tetraplex formations.

Mutations in the BLM gene eliminate a key part of the cell’s DNA repair mechanisms, resulting in a far higher rate of mutations in BS patients than in the general population. A cellular inability to correct DNA problems, particularly double strand breaks, results in chromosomal instability, frequent mutations, and a rate of sister chromatid exchange that has been measured at up to 10 times that of a control group. This abnormally high exchange rate has been experimentally corrected by replacing the defective chromosome 15 with a normal chromosome from a non-Bloom cell. Experiments have also successfully replaced smaller segments of the chromosome with similar results, including a replacement of the 15p1476 site alone. This replacement, while not entirely eliminating the hyper-recombination which characterizes the disease, reduced the effect of the normal BS mutation by a factor of 3. Further research on this line is expected to be forthcoming.

On a more holistic level, BS cells are characterized by hyper-recombination, inability to repair damaged DNA, and extremely high levels of sister chromatid exchange during cell replication. This, in turn, leads to the observed hyper-sensitivity to the sun and other mutagens. The already mutation-prone cells respond quickly to these stressors, causing the high rate of cancers observed in BS patients.