-
Expert Review of Molecular Diagnostics May 2004Bloom syndrome is a rare autosomal recessive genetic disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency... (Review)
Review
Bloom syndrome is a rare autosomal recessive genetic disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency and predisposition to cancer. The causative gene for Bloom syndrome is BLM, which encodes the BLM RecQ helicase homolog protein. The first part of this review describes a long-term follow-up study of two Bloom syndrome siblings. Subsequently, the focus is placed on the functional domains of BLM. Laboratory diagnosis of Bloom syndrome by detecting mutations in BLM is laborious and impractical, unless there are common mutations in a population. Immunoblot and immunohistochemical analyses for the detection of the BLM protein using a polyclonal BLM antibody, which are useful approaches for clinical diagnosis of Bloom syndrome, are also described. In addition, a useful adjunct for the diagnosis of Bloom syndrome in terms of the BLM function is investigated, since disease cells must have the defective BLM helicase function. This review also discusses the nuclear localization signal of BLM, the proteins that interact with BLM and tumors originating from Bloom syndrome.
Topics: Adenosine Triphosphatases; Animals; Ataxia Telangiectasia Mutated Proteins; B-Lymphocytes; Bloom Syndrome; Cell Cycle Proteins; DNA Helicases; DNA-Binding Proteins; Follow-Up Studies; Gene Rearrangement; Genes, Immunoglobulin; Hematopoietic Stem Cells; Humans; Longitudinal Studies; Lymphoma; Nuclear Localization Signals; Protein Serine-Threonine Kinases; RecQ Helicases; Recombinant Fusion Proteins; Tumor Suppressor Proteins
PubMed: 15137905
DOI: 10.1586/14737159.4.3.393 -
Journal of the American Academy of... Sep 1987Bloom's syndrome is a rare autosomal recessive disorder that characteristically shows a telangiectatic, sun-sensitive facial rash in conjunction with stunted growth....
Bloom's syndrome is a rare autosomal recessive disorder that characteristically shows a telangiectatic, sun-sensitive facial rash in conjunction with stunted growth. These patients are prone to respiratory and gastrointestinal infections along with immunologic abnormalities. Chromosomal aberrations include an elevated frequency of sister chromatid exchange in cultured lymphocytes, a phenomenon pathognomonic for this disorder. These patients exhibit a great tendency for neoplasia, particularly acute leukemia and lymphoma. Three cases are reported, including a follow-up of a patient diagnosed 16 years ago.
Topics: Adult; Bloom Syndrome; Child, Preschool; Diagnosis, Differential; Female; Follow-Up Studies; Genes, Recessive; Humans; Infant; Male; Neoplasms; Risk Factors; Sister Chromatid Exchange
PubMed: 3655026
DOI: 10.1016/s0190-9622(87)70233-3 -
Human Molecular Genetics 1996Mutation of the Bloom's syndrome (BS) gene, BLM, results in genomic instability. As the first step toward positional cloning of the gene, tight linkage of BLM and FES at... (Review)
Review
Mutation of the Bloom's syndrome (BS) gene, BLM, results in genomic instability. As the first step toward positional cloning of the gene, tight linkage of BLM and FES at 15q26.1 was detected by genotyping affected in families in which the parents are cousins, so-called homozygosity mapping. Linkage disequilibrium between BLM and FES was detected in Ashkenazi Jews with BS, confirming the linkage results and supporting the hypothesis that the increased frequency of the BS mutation in the Ashkenazim is due to founder effect. The mutated BLM gene is inherited identical by descent in BS persons whose parents are cousins or Ashkenazi Jewish; in persons whose parents do not share a common ancestor, BLM can be mutant at different positions within the gene. In such persons, crossing-over within BLM can occur to form a functionally wild-type gene capable of correcting the mutant phenotype of BS cells. In half the cases in which such somatic intragenic recombination had occurred, reduction to homozygosity was detectable distal to BLM but not proximal to it. We localized the cross-over points in corrected cells to a 250 kb genomic segment and isolated therefrom a 4437 bp cDNA that encodes a 1417 amino acid protein homologous to the RecQ subfamily of DExH box-containing DNA and RNA helicases. The identification of BLM as a putative DNA helicase provides a new and powerful tool to investigate the primary defect in BS and the function of the BLM gene product in maintaining the integrity of the genome.
Topics: Alleles; Amino Acid Sequence; Bloom Syndrome; Chromosome Mapping; Chromosomes, Human, Pair 15; Genetic Heterogeneity; Humans; Jews; Molecular Biology; Molecular Sequence Data; Recombination, Genetic; Sequence Homology, Amino Acid
PubMed: 8875252
DOI: 10.1093/hmg/5.supplement_1.1457 -
Genetics in Medicine : Official Journal... Jul 2022This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these...
PURPOSE
This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these are not well-defined.
METHODS
Data from the Bloom Syndrome Registry (BSR) was used for this study. Cancer history, ages of first cancer diagnosis, and ages of death were compiled from the BSR and analyzed.
RESULTS
Among the 290 individuals in the BSR, 155 (53%) participants developed 251 malignant neoplasms; 100 (65%) were diagnosed with 1 malignancy, whereas the remaining 55 (35%) developed multiple malignancies. Of the 251 neoplasms, 83 (33%) were hematologic and 168 (67%) were solid tumors. Hematologic malignancies (leukemia and lymphoma) were more common than any of the solid tumors. The most commonly observed solid tumors were colorectal, breast, and oropharyngeal. The cumulative incidence of any malignancy by age 40 was 83%. The median survival for all participants in the BSR was 36.2 years. There were no significant differences in time to first cancer diagnosis or survival by genotype among the study participants.
CONCLUSION
We describe the spectrum of cancers observed in Bloom syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome. We also highlight the significant differences in survival and age of diagnosis seen among different tumor types and genotypes.
Topics: Adult; Bloom Syndrome; Hematologic Neoplasms; Humans; Incidence; Neoplasms; Registries
PubMed: 35420546
DOI: 10.1016/j.gim.2022.03.008 -
Biochemical Society Transactions May 2001The RecQ family of DNA helicases has members in all organisms analysed. In humans, defects in three family members are associated with disease conditions: BLM is... (Review)
Review
The RecQ family of DNA helicases has members in all organisms analysed. In humans, defects in three family members are associated with disease conditions: BLM is defective in Bloom's syndrome, WRN in Werner's syndrome and RTS in Rothmund-Thomson syndrome. In each case, cells from affected individuals show inherent genomic instability. The focus of our work is the Bloom's syndrome gene and its product, BLM. Here, we review the latest information concerning the roles of BLM in the maintenance of genome integrity.
Topics: Adenosine Triphosphatases; Bloom Syndrome; Chromosome Aberrations; DNA Helicases; Genome, Human; Humans; Phenotype; Protein Binding; Protein Structure, Tertiary; Protein Transport; RecQ Helicases; Recombination, Genetic
PubMed: 11356154
DOI: 10.1042/0300-5127:0290201 -
Clinical Genetics May 2022Bloom syndrome (BS) is an autosomal recessive disorder with characteristic clinical features of primary microcephaly, growth deficiency, cancer predisposition, and...
Bloom syndrome (BS) is an autosomal recessive disorder with characteristic clinical features of primary microcephaly, growth deficiency, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative pathogenic variants in all families including three different variants in BLM and one variant in RMI1. The homozygous c.581_582delTT;p.Phe194* and c.3164G>C;p.Cys1055Ser variants in BLM have already been reported in BS patients, while the c.572_573delGA;p.Arg191Lysfs*4 variant is novel. Additionally, we present the detailed clinical characteristics of two cases with BS in which we previously identified the biallelic loss-of-function variant c.1255_1259delAAGAA;p.Lys419Leufs*5 in RMI1. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, skin lesions and upper airway infections were observed only in some of the patients. Overall, patients with pathogenic BLM variants had a more severe BS phenotype compared to patients carrying the pathogenic variants in RMI1, especially in terms of immunodeficiency, which should be considered as one of the most important phenotypic characteristics of BS.
Topics: Bloom Syndrome; DNA-Binding Proteins; Genotype; Humans; Microcephaly; Phenotype; RecQ Helicases
PubMed: 35218564
DOI: 10.1111/cge.14125 -
European Journal of Medical Genetics Feb 2018Bloom syndrome is an autosomal recessive condition characterized by severe pre- and postnatal growth deficiency, immunodeficiency, an increased risk for malignancies,...
Bloom syndrome is an autosomal recessive condition characterized by severe pre- and postnatal growth deficiency, immunodeficiency, an increased risk for malignancies, craniofacial dysmorphisms, and "typical" erythematous sun-sensitive skin lesions of the face. This facial rash has a butterfly-shaped distribution around the nose and is usually observed for the first time during the early years of life. Though reported as being a main feature of Bloom syndrome, there seems to be phenotypic variability regarding this facial skin rash among patients. It has been previously reported that in some individuals with Bloom syndrome these sun-sensitive lesions are less prominent or even absent. In this report we describe a 36 year old woman with short stature, microcephaly, several dysmorphisms, congenital hypothyroidism and premature ovarian failure. She was diagnosed with nasopharyngeal carcinoma at 36 years of age, only a few months after her consultation at the department of Clinical Genetics. Whole Exome Sequencing demonstrated that she had Bloom syndrome caused by a compound heterozygous mutation in BLM (c.2207_2212delinsTAGATTC; p.(Tyr736Leufs*5) and c.3681del; p.(Lys1227Asnfs*52)). She did not have facial sun-sensitive erythematous rash during childhood nor adulthood. We conclude that Bloom syndrome does not always present with erythematous sun-sensitive skin lesions of the face. We would like to underline that phenotypic variation regarding this "hallmark" feature of Bloom syndrome exists. Being aware of this might prevent a delay in diagnosing this rare short-stature syndrome and, subsequently, its potential clinical implications.
Topics: Adult; Bloom Syndrome; Diagnosis, Differential; Erythema; Female; Humans; Phenotype; RecQ Helicases; Sunlight
PubMed: 29056561
DOI: 10.1016/j.ejmg.2017.10.010 -
Indian Journal of Experimental Biology Apr 1996Bloom syndrome (BS), an autosomal recessive genetic disorder, is an instructive model to explore variety of questions in "deregulation of normal cell functioning". Most... (Review)
Review
Bloom syndrome (BS), an autosomal recessive genetic disorder, is an instructive model to explore variety of questions in "deregulation of normal cell functioning". Most of the BS patients are homozygous for mutant BLM gene and depict high sister chromatid exchanges (SCEs) in almost all the cells. However, a few possess cells with dimorphic SCE phenotype. A majority of patients with dimorphic SCE phenotype have been suggested to be compound heterozygotes, inheriting two different mutations in the BLM locus from each parent. An intragenic somatic recombination event in a precursor stem cell in such patients is envisaged to give rise to a population of cells with functionally wild-type (BLM) gene and normal SCE phenotype. Adopting unique dual approaches of positional mapping through "homozygosity by descent" and "somatic crossover point mapping", a candidate for BLM has been identified and localized to a 250 Kb interval between polymorphic loci, DI5S1108 and D15127. The sequence has been found to encode a 1417 amino acid peptide with homology to the RecQ helicases, a sub-family of DExH box-containing DNA and RNA helicases. The presence of chain terminating mutations in the 'candidate' gene in BS patients has suggested it to be the BLM gene. Apparantly the proposed gene product does not seem to provide answer for a variety of clinical, biochemical and experimental observations made in BS or BS cells till date. Our recent observation of a significant decrease in the activity of pyruvate kinase in three BS B-lymphoblastoid cell lines when compared to a similar cell line established from a normal healthy subject presents with another possible candidate to elucidate the defects in BS. Experiments using okadaic acid, a phosphatase-2a/1 inhibitor, have depicted in our study that many of the clinical features characteristic of BS, not easily explanable by the recently proposed BLM gene, can be explained by the deficiency in the PK alone and/or PP2a/PP1 activity.
Topics: Bloom Syndrome; Chromosome Mapping; Genes, Recessive; Humans
PubMed: 8698416
DOI: No ID Found -
Nihon Rinsho. Japanese Journal of... Jul 2000Bloom syndrome (BS) is a rare genetic disorder characterized by small body size, sunsensitivity, immunodeficiency and a high predisposition to various types of cancer.... (Review)
Review
Bloom syndrome (BS) is a rare genetic disorder characterized by small body size, sunsensitivity, immunodeficiency and a high predisposition to various types of cancer. BLM was identified as the causative gene for BS, and BLM protein is homologous to DNA helicase. In 1995 the causative gene for BS was identified using somatic crossover point mapping and termed BLM. BLM is a 4437 bp cDNA that encodes a 1417 amino acid peptide which is homologous to ATP-dependent DNA helicases. DNA helicases are the enzymes which catalyze the unwinding of double-stranded DNA to provide single- stranded templates for the processes of replication, repair, recombination and transcription. BLM is a member of the RecQ helicase family, consisting of human WRN, RECQL and yeast Sgs1. The BLM protein translocates into the nucleus and the distal arm of the bipartite basic residues in the C-terminus of the BLM protein is essential for targeting the nucleus. Here, we also describe relationship between the BLM gene and the cancer.
Topics: Adenosine Triphosphatases; Amino Acid Sequence; Bloom Syndrome; DNA Helicases; DNA Repair; Humans; Molecular Sequence Data; Mutation; RecQ Helicases
PubMed: 10921324
DOI: No ID Found -
Annals of Surgical Oncology Jun 2022
Editorial Comment to "High Expression of Bloom Syndrome Helicase is a Key Factor for Poor Prognosis and Advanced Malignancy in Patients with Pancreatic Cancer: A Retrospective Study".
Topics: Bloom Syndrome; Humans; Pancreatic Neoplasms; Prognosis; Retrospective Studies
PubMed: 35312901
DOI: 10.1245/s10434-022-11587-0