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International Journal of Dermatology Jul 2014Bloom Syndrome (BS, MIM #210900) is an autosomal recessive genetic disorder caused by a mutation in the BLM gene, which codes for the DNA repair enzyme RecQL3 helicase.... (Review)
Review
Bloom Syndrome (BS, MIM #210900) is an autosomal recessive genetic disorder caused by a mutation in the BLM gene, which codes for the DNA repair enzyme RecQL3 helicase. Without proper DNA repair mechanisms, abnormal DNA exchange takes place between sister chromatids and results in genetic instability that may lead to cancer, especially lymphoma and acute myelogenous leukemia, lower and upper gastrointestinal tract neoplasias, cutaneous tumors, and neoplasias in the genitalia and urinary tract. BS patients are usually of Ashkenazi Jewish descent and exhibit narrow facial features, elongated limbs, and several dermatologic complications including photosensitivity, poikiloderma, and telangiectatic erythema. The most concerning manifestation of BS is multiple malignancies, which require frequent screenings and strict vigilance by the physician. Therefore, distinguishing between BS and other dermatologic syndromes of similar presentation such as Rothmund-Thomson Syndrome, Erythropoietic Protoporphyria, and Cockayne Syndrome is paramount to disease management and to prolonging life. BS can be diagnosed through a variety of DNA sequencing methods, and genetic testing is available for high-risk populations. This review consolidates several sources on BS sequelae and aims to suggest the importance of differentiating BS from other dermatologic conditions. This paper also elucidates the recently discovered BRAFT and FANCM protein complexes that link BS and Fanconi anemia.
Topics: Bloom Syndrome; Diagnosis, Differential; Humans; Prognosis
PubMed: 24602044
DOI: 10.1111/ijd.12408 -
Dermatologic Clinics Jan 1995Bloom's syndrome is a rare autosomal recessively transmitted disorder, the main clinical feature of which is small body size. A sun-sensitive, erythematous facial skin... (Review)
Review
Bloom's syndrome is a rare autosomal recessively transmitted disorder, the main clinical feature of which is small body size. A sun-sensitive, erythematous facial skin lesion, an excess of well-demarcated hyper- and hypopigmented skin lesions located anywhere on the body, and increased numbers of bacterial infections due to immunodeficiency are accompanying features of diagnostic value. In Bloom's syndrome, the complications are formidable: cancer, chronic lung disease, and diabetes. Cancers of the types and sites seen in the general population arise frequently and unusually early. Bloom's syndrome cells are hypermutable, and excessive numbers of somatic mutations are responsible for many of the clinical features. The clinical diagnosis is confirmed cytogenetically by demonstrating a characteristic chromosome instability.
Topics: Adult; Bloom Syndrome; Body Constitution; Chronic Disease; Diabetes Mellitus; Female; Genes; Humans; Lung Diseases; Male; Mutation; Precancerous Conditions; Skin Diseases
PubMed: 7712653
DOI: No ID Found -
Molecular Genetics and Metabolism May 2021Autosomal hereditary recessive diseases characterized by genetic instability are often associated with cancer predisposition. Bloom syndrome (BS), a rare genetic... (Review)
Review
Autosomal hereditary recessive diseases characterized by genetic instability are often associated with cancer predisposition. Bloom syndrome (BS), a rare genetic disorder, with <300 cases reported worldwide, combines both. Indeed, patients with Bloom's syndrome are 150 to 300 times more likely to develop cancers than normal individuals. The wide spectrum of cancers developed by BS patients suggests that early initial events occur in BS cells which may also be involved in the initiation of carcinogenesis in the general population and these may be common to several cancers. BS is caused by mutations of both copies of the BLM gene, encoding the RecQ BLM helicase. This review discusses the different aspects of BS and the different cellular functions of BLM in genome surveillance and maintenance through its major roles during DNA replication, repair, and transcription. BLM's activities are essential for the stabilization of centromeric, telomeric and ribosomal DNA sequences, and the regulation of innate immunity. One of the key objectives of this work is to establish a link between BLM functions and the main clinical phenotypes observed in BS patients, as well as to shed new light on the correlation between the genetic instability and diseases such as immunodeficiency and cancer. The different potential implications of the BLM helicase in the tumorigenic process and the use of BLM as new potential target in the field of cancer treatment are also debated.
Topics: Bloom Syndrome; DNA Replication; Genomic Instability; Humans; Mutation; Neoplasms; Protein Binding; RecQ Helicases
PubMed: 33736941
DOI: 10.1016/j.ymgme.2021.03.003 -
Structure (London, England : 1993) Feb 2021The Bloom syndrome complex is a DNA damage repair machine. It consists of several protein components which are functional in isolation, but interdependent in cells for... (Review)
Review
The Bloom syndrome complex is a DNA damage repair machine. It consists of several protein components which are functional in isolation, but interdependent in cells for the maintenance of accurate homologous recombination. Mutations to any of the genes encoding these proteins cause numerous physical and developmental markers as well as phenotypes of genome instability, infertility, and cancer predisposition. Here we review the published structural and biochemical data on each of the components of the complex: the helicase BLM, the type IA topoisomerase TOP3A, and the OB-fold-containing RMI and RPA subunits. We describe how each component contributes to function, interacts with each other, and the DNA that it manipulates/repairs.
Topics: Bloom Syndrome; DNA Topoisomerases, Type I; DNA-Binding Proteins; Homologous Recombination; Humans; RecQ Helicases
PubMed: 33357470
DOI: 10.1016/j.str.2020.11.020 -
BioEssays : News and Reviews in... Sep 2017The functions of the Bloom syndrome helicase (BLM) and its orthologs are well characterized in mitotic DNA damage repair, but their roles within the context of meiotic... (Review)
Review
The functions of the Bloom syndrome helicase (BLM) and its orthologs are well characterized in mitotic DNA damage repair, but their roles within the context of meiotic recombination are less clear. In meiotic recombination, multiple repair pathways are used to repair meiotic DSBs, and current studies suggest that BLM may regulate the use of these pathways. Based on literature from Saccharomyces cerevisiae, Arabidopsis thaliana, Mus musculus, Drosophila melanogaster, and Caenorhabditis elegans, we present a unified model for a critical meiotic role of BLM and its orthologs. In this model, BLM and its orthologs utilize helicase activity to regulate the use of various pathways in meiotic recombination by continuously disassembling recombination intermediates. This unwinding activity provides the meiotic program with a steady pool of early recombination substrates, increasing the probability for a DSB to be processed by the appropriate pathway. As a result of BLM activity, crossovers are properly placed throughout the genome, promoting proper chromosomal disjunction at the end of meiosis. This unified model can be used to further refine the complex role of BLM and its orthologs in meiotic recombination.
Topics: Animals; Bloom Syndrome; Chromosomes; DNA Helicases; DNA Repair; Humans; Meiosis; RecQ Helicases; Recombination, Genetic
PubMed: 28792069
DOI: 10.1002/bies.201700073 -
Ageing Research Reviews Jan 2017Genomic instability is a hallmark of cancer and aging. Premature aging (progeroid) syndromes are often caused by mutations in genes whose function is to ensure genomic... (Review)
Review
Genomic instability is a hallmark of cancer and aging. Premature aging (progeroid) syndromes are often caused by mutations in genes whose function is to ensure genomic integrity. The RecQ family of DNA helicases is highly conserved and plays crucial roles as genome caretakers. In humans, mutations in three RecQ genes - BLM, WRN, and RECQL4 - give rise to Bloom's syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS), respectively. WS is a prototypic premature aging disorder; however, the clinical features present in BS and RTS do not indicate accelerated aging. The BLM helicase has pivotal functions at the crossroads of DNA replication, recombination, and repair. BS cells exhibit a characteristic form of genomic instability that includes excessive homologous recombination. The excessive homologous recombination drives the development in BS of the many types of cancers that affect persons in the normal population. Replication delay and slower cell turnover rates have been proposed to explain many features of BS, such as short stature. More recently, aberrant transcriptional regulation of growth and survival genes has been proposed as a hypothesis to explain features of BS.
Topics: Aging; Aging, Premature; Bloom Syndrome; DNA Helicases; DNA Replication; Genomic Instability; Humans; Mutation; RecQ Helicases; Werner Syndrome; Werner Syndrome Helicase
PubMed: 27238185
DOI: 10.1016/j.arr.2016.05.010 -
Aging Cell Oct 2023Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor...
Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Interestingly, patients with BSyn do not have other signs of premature aging such as early, progressive hair loss and cataracts. We set out to determine epigenetic age in BSyn, which can be a better predictor of health and disease over chronological age. Our results show for the first time that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Additionally, homozygous Blm mice exhibit accelerated methylation age in multiple tissues, including brain, blood, kidney, heart, and skin, according to the brain methylation clock. Overall, we find that Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and more generally a strong effect on CpG methylation levels.
Topics: Humans; Animals; Mice; Bloom Syndrome; Epigenesis, Genetic; Aging; Aging, Premature; Methylation; DNA Methylation
PubMed: 37594403
DOI: 10.1111/acel.13964 -
Cold Spring Harbor Molecular Case... Apr 2018Bloom syndrome (BS) is a rare, autosomal recessive genetic disorder characterized by short stature, a skin rash associated with sun exposure, and an elevated likelihood... (Review)
Review
Bloom syndrome (BS) is a rare, autosomal recessive genetic disorder characterized by short stature, a skin rash associated with sun exposure, and an elevated likelihood of developing cancers of essentially all types, beginning at an early age. Cancer is the leading cause of death for persons with BS, and its early onset results in a reported median lifespan of <30 years. With fewer than 300 documented cases since BS was first described in 1954, its rarity has challenged progress in advancing both the care of and the cure for persons with BS. Presently, there are no known clinically actionable targets specific to persons with this cancer predisposition syndrome, despite the fact that standard cancer treatments are often contraindicated or must be substantially modified for persons with BS. Herein, Zachary Rogers recounts his experience as a cancer patient with BS contemplating a substantially customized chemotherapy regimen that highlights the need for development of individualized treatments in the BS community. We also outline a patient-centered research and community action road map with the goal of improving and prolonging the lives of persons with Bloom syndrome, including the facilitation of precision medicine development specific to this condition.
Topics: Bloom Syndrome; Family; Health Priorities; History, 20th Century; History, 21st Century; Humans; Precision Medicine; Research
PubMed: 29610394
DOI: 10.1101/mcs.a002816 -
Angewandte Chemie (International Ed. in... Sep 2022Bloom syndrome protein (BLM) is a conserved RecQ family helicase involved in the maintenance of genome stability. BLM has been widely recognized as a genome "caretaker"...
Bloom syndrome protein (BLM) is a conserved RecQ family helicase involved in the maintenance of genome stability. BLM has been widely recognized as a genome "caretaker" that processes structured DNA. In contrast, our knowledge of how BLM behaves on single-stranded (ss) DNA is still limited. Here, we demonstrate that BLM possesses the intrinsic ability for phase separation and can co-phase separate with ssDNA to form dynamically arrested protein/ssDNA co-condensates. The introduction of ATP potentiates the capability of BLM to condense on ssDNA, which further promotes the compression of ssDNA against a resistive force of up to 60 piconewtons. Moreover, BLM is also capable of condensing replication protein A (RPA)- or RAD51-coated ssDNA, before which it generates naked ssDNA by dismantling these ssDNA-binding proteins. Overall, our findings identify an unexpected characteristic of a DNA helicase and provide a new angle of protein/ssDNA co-condensation for understanding the genomic instability caused by BLM overexpression under diseased conditions.
Topics: Adenosine Triphosphate; Bloom Syndrome; DNA; DNA Repair; DNA, Single-Stranded; Genomic Instability; Humans; RecQ Helicases; Replication Protein A
PubMed: 35922882
DOI: 10.1002/anie.202209463 -
Clinical Genetics Jan 1989Bloom's syndrome has been known as a clinical entity for 34 years. Careful records of cases diagnosed throughout the world have been maintained since its recognition as... (Review)
Review
Bloom's syndrome has been known as a clinical entity for 34 years. Careful records of cases diagnosed throughout the world have been maintained since its recognition as an entity, and most instances of cytologically verified Bloom's syndrome have been accessioned to what has been referred to as the Bloom's Syndrome Registry since the mid-1960s. Presented here is the fourth in a series of progress reports from the Registry of information accumulated during this long-term surveillance of affected families, along with mention of selected recent advances that have been made in the understanding of the syndrome. 130 persons had been accessioned to the Registry by the end of 1987; 96 of these were alive, their mean age being 18.9 years. Although a number of clinical complications occur in Bloom's syndrome, the most important is malignant neoplasia. In the 130 persons in the Registry, 57 malignant neoplasms had been detected, the mean age at diagnosis being 24.8 years. Neoplasia in Bloom's syndrome is noteworthy not only because of its frequency and exceptionally early age of emergence but for its variety of histological types and sites of origin.
Topics: Adolescent; Adult; Bloom Syndrome; Child; Child, Preschool; Genetic Markers; Humans; Infant; Middle Aged; Mutation; Neoplasms; Registries
PubMed: 2647324
DOI: 10.1111/j.1399-0004.1989.tb02905.x