Bloom syndrome
Encyclopedia
Bloom's syndrome 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 chromosome
s. The condition was discovered and first described by dermatologist Dr. David Bloom in 1954.
, and prominent nose and ears; pigment
ation changes of the skin including hypo- and hyper-pigmented areas and cafe-au-lait spots; telangiectasias (dilated blood vessel
s) 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; hypogonadism 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.
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.
, 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.
protein can justify other features of Bloom's syndrome.
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
chromosomal disorder characterized by a high frequency of breaks and rearrangements in an affected person's chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s. 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, micrognathismMicrognathism
Micrognathism is a condition where the jaw is undersized. It is also sometimes called "Mandibular hypoplasia". It is common in infants, but is usually self-corrected during growth, due to the jaws increasing in size. It may be a cause of abnormal tooth alignment and in severe cases can hamper...
, and prominent nose and ears; pigment
Pigment
A pigment is a material that changes the color of reflected or transmitted light as the result of wavelength-selective absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which a material emits light.Many materials selectively absorb...
ation changes of the skin including hypo- and hyper-pigmented areas and cafe-au-lait spots; telangiectasias (dilated blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s) 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
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
and ear infections; hypogonadism characterized by a failure to produce sperm, hence infertility in males, and premature cessation of menses (premature menopause
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
), 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
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
. 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 cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
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 geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, 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
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
, 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.
Inheritance
Inheritance is the practice of passing on property, titles, debts, rights and obligations upon the death of an individual. It has long played an important role in human societies...
in an autosomal recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
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
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
and genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
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 PKM2PKM2
Pyruvate kinase isozymes M1/M2 also known as pyruvate kinase muscle isozyme , pyruvate kinase type K, cytosolic thyroid hormone-binding protein , thyroid hormone-binding protein 1 , or opa-interacting protein 3 is an enzyme that in humans is encoded by the PKM2 gene.PKM2 is an isoenzyme of the...
protein can justify other features of Bloom's syndrome.
See also
- Accelerated aging diseaseAccelerated aging diseaseA DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.DNA repair defects are seen in nearly all of the diseases described as accelerated aging disease, in which various tissues, organs or systems of the human body age prematurely...
- Bloom syndrome (gene)
- DNA repairDNA repairDNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
- ProgeriaProgeriaProgeria is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word progeria comes from the Greek words "pro" , meaning "before", and "géras" , meaning "old age"...
- Tumor M2-PKTumor M2-PKTumor M2-PK is a synonym for the dimeric form of the pyruvate kinase isoenzyme type M2 , a key enzyme within tumor metabolism. Tumor M2-PK can be elevated in many tumor types, rather than being an organ-specific tumor marker such as PSA...
External links
- Bloom's Syndrome on GONUTS
- GeneReviews/NCBI/NIH/UW entry on Bloom Syndrome
- Blooms Connect - a forum by and for people with Bloom's Syndrome and their loved ones
- Bloom's Syndrome Registry - research and information about Bloom's Syndrome
- Bloom's Syndrome Foundation - devoted to medical & scientific research to discover a treatment or cure for Bloom's Syndrome
- DNA Repair
- Segmental Progeria
- Article on Bloom's Syndrome