Bloom syndrome

Bloom's syndrome (BLM), also known as Bloom–Torre–Machacek syndrome, is a rare autosomal recessive chromosomal disorder characterized by a high frequency of breaks and rearrangements in an affected person's chromosomes. The condition was discovered and first described by dermatologist Dr. David Bloom in 1954.

Presentation
Bloom's syndrome is characterized by short stature and a facial rash that develops shortly after first exposure to sun. This rash can make a butterfly-shaped patch of reddened skin on the cheeks. The rash can develop on other sun-exposed areas such as the backs of the hands. Other clinical features include a high-pitched voice; distinct facial features, such as a long, narrow face, micrognathism of the mandible, and prominent nose and ears; pigmentation changes of the skin including hypo- and hyper-pigmented areas and cafe-au-lait spots; telangiectasias (dilated blood vessels) which can appear on the skin but also in the eyes; moderate immune deficiency, characterized by deficiency in certain immunoglobulin classes, that apparently leads to recurrent pneumonia and ear infections; hypo-gonadism characterized by a failure to produce sperm, hence infertility in males, and premature cessation of menses (premature menopause), hence sub-fertility in females. However, several women with Bloom's syndrome have had children.

Complications of the disorder may include chronic lung problems, diabetes, and learning disabilities. In a small number of persons, there is mental retardation. The most striking complication of the disorder is susceptibility to cancer, as described in more detail in the next section.

Relationship to cancer
A greatly elevated rate of mutation in Bloom's syndrome results in a high risk of cancer in affected individuals. The cancer predisposition is characterized by 1) broad spectrum, including leukemias, lymphomas, and carcinomas, 2) early age of onset relative to the same cancer in the general population, and 3) multiplicity. Persons with Bloom's syndrome may develop cancer at any age. The average age of cancer diagnoses in the cohort is approximately 25 years old.

Pathophysiology
Mutations in the BLM gene, which is a member of the DNA helicase family, are associated with Bloom's syndrome. DNA helicases are enzymes that unwind the two strands of a duplex DNA molecule. DNA unwinding is required for most processes that involve the DNA, including synthesis of DNA copies, RNA transcription, DNA repair, etc.

When a cell prepares to divide to form two cells, the chromosomes are duplicated so that each new cell will get a complete set of chromosomes. The duplication process is called DNA replication. Errors made during DNA replication can lead to mutations. The BLM protein is important in maintaining the stability of the DNA during the replication process. The mutations in the BLM gene associated with Bloom's syndrome inactivate the BLM protein's DNA helicase activity or nullify protein expression (the protein is not made). Lack of BLM protein or protein activity leads to an increase mutations; however, the molecular mechanism(s) by which BLM maintains stability of the chromosomes is still a very active area of research.

Persons with Bloom's syndrome have an enormous increase in exchange events between homologous chromosomes or sister chromatids (the two DNA molecules that are produced by the DNA replication process); and there are increases in chromosome breakage and rearrangements compared to persons who do not have Bloom's syndrome. Direct connections between the molecular processes in which BLM operates and the chromosomes themselves are under investigation. The relationships between molecular defects in Bloom's syndrome cells, the chromosome mutations that accumulate in somatic cells (the cells of the body), and the many clinical features seen in Bloom's syndrome are also areas of intense research.



Bloom's syndrome is inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. The carrier frequency in individuals of Eastern European Jewish (Ashkenazi Jewish) ancestry is about 1/100. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of Bloom's syndrome. For families in which carrier status is known, prenatal testing is available using cytogenetic or molecular methods. Molecular DNA testing for the mutation that is common in the Ashkenazi Jewish population is also available.

Other mutations in Bloom's Syndrome
For the first time pyruvate kinase M2 enzyme was reported with two missense mutations, H391Y and K422R, found in cells from Bloom's syndrome patients, prone to develop cancer. Results show that despite the presence of mutations in the inter-subunit contact domain, the K422R and H391Y mutant proteins maintained their homotetrameric structure, similar to the wild-type protein, but showed a loss of activity of 75 and 20%, respectively. Interestingly, H391Y showed a 6-fold increase in affinity for its substrate phosphoenolpyruvate and behaved like a non-allosteric protein with compromised cooperative binding. However, the affinity for phosphoenolpyruvate was lost significantly in K422R. Unlike K422R, H391Y showed enhanced thermal stability, stability over a range of pH values, a lesser effect of the allosteric inhibitor Phe, and resistance toward structural alteration upon binding of the activator (fructose 1,6-bisphosphate) and inhibitor (Phe). Both mutants showed a slight shift in the pH optimum from 7.4 to 7.0. The co-expression of homotetrameric wild type and mutant PKM2 in the cellular milieu resulting in the interaction between the two at the monomer level was substantiated further by in vitro experiments. The cross-monomer interaction significantly altered the oligomeric state of PKM2 by favoring dimerisation and heterotetramerization. In silico study provided an added support in showing that hetero-oligomerization was energetically favorable. The hetero-oligomeric populations of PKM2 showed altered activity and affinity, and their expression resulted in an increased growth rate of Escherichia coli as well as mammalian cells, along with an increased rate of polyploidy. These features are known to be essential to tumor progression.

PKM2(M2-PK); A potential multi-functional protein
It is hypothesized that an aberrant PKM2 protein can justify other features of Bloom's syndrome.