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Sample records for fanconi anemia gene

  1. Fanconi anemia

    MedlinePlus

    ... People with Fanconi anemia should avoid cancer-causing substances (carcinogens) and have regular check-ups to screen for cancer. Alternative Names Fanconi's anemia; Anemia - Fanconi's Images Formed elements of blood References Bagby GC. Aplastic anemia ...

  2. Fanconi Anemia Genes, of Menders and Sweepers.

    PubMed

    Campello, Silvia; Cecconi, Francesco

    2016-05-23

    Reporting recently in Cell, Sumpter et al. (2016) provide evidence that Fanconi anemia (FA) pathway genes, which are mutated in the homonymous disease and are tumor suppressors known as damaged nuclear DNA "menders," also act as intracellular sweepers in selective virophagy and mitophagy. PMID:27219059

  3. Fanconi anemia

    MedlinePlus

    ... blood cells may result in fatigue ( anemia ). A lower-than-normal amount of platelets may lead to excess bleeding. Most people with Fanconi's anemia have some of these symptoms: Abnormal heart, lungs, and digestive tract Bone problems (especially the hips, spine or ...

  4. Fanconi Anemia Research Fund

    MedlinePlus

    ... Support Publications Fundraising News What is the Fanconi Anemia Research Fund? Fanconi anemia is an inherited disease that can lead to ... population. Lynn and Dave Frohnmayer started the Fanconi Anemia Research Fund, in 1989 to find effective treatments ...

  5. Stem Cell Gene Therapy for Fanconi Anemia: Report from the 1st International Fanconi Anemia Gene Therapy Working Group Meeting

    PubMed Central

    Tolar, Jakub; Adair, Jennifer E; Antoniou, Michael; Bartholomae, Cynthia C; Becker, Pamela S; Blazar, Bruce R; Bueren, Juan; Carroll, Thomas; Cavazzana-Calvo, Marina; Clapp, D Wade; Dalgleish, Robert; Galy, Anne; Gaspar, H Bobby; Hanenberg, Helmut; Von Kalle, Christof; Kiem, Hans-Peter; Lindeman, Dirk; Naldini, Luigi; Navarro, Susana; Renella, Raffaele; Rio, Paula; Sevilla, Julián; Schmidt, Manfred; Verhoeyen, Els; Wagner, John E; Williams, David A; Thrasher, Adrian J

    2011-01-01

    Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA. PMID:21540837

  6. Mutation analysis of the Fanconi Anemia Gene FACC

    SciTech Connect

    Verlander, P.C.; Lin, J.D.; Udono, M.U.; Zhang, Q.; Auerbach, A.D. ); Gibson, R.A.; Mathew, C.G. )

    1994-04-01

    Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive disorder characterized by a unique hypersensitivity of cells to DNA cross-linking agents; a gene for complementation group C (FACC) has recently been cloned. The authors have amplified FACC exons with their flanking intron sequences from genomic DNA from 174 racially and ethnically diverse families in the International Fanconi Anemia Registry and have screened for mutations by using SSCP analysis. They have identified eight different variants in 32 families; three were detected in exon 1, one in exon 4, one in intron 4, two in exon 6, and one in exon 14. Two of the eight variants, in seven families, did not segregate with the disease allele in multiplex families, suggesting that these variants represented benign polymorphisms. Disease-associated mutations in FACC were detected in a total of 25 (14.4%) of 174 families screened. The most frequent mutations were IVS4 + 4 A [yields] T (intron 4; 12 families) and 322delG (exon 1; 9 families). Other, less common mutations include Q13X in exon 1, R185X and D195V in exon 6, and L554P in exon 14. The polymorphisms were S26F in exon 1 and G139E in exon 4. All patients in the study with 322delG, Q13X, R185X, and D195V are of northern or eastern European or southern Italian ancestry, and 18 of 19 have a mild form of the disease, while the 2 patients with L554P, both from the same family, have a severe phenotype. All 19 patients with IVS4 + 4 A [yields] T have Jewish ancestry and have a severe phenotype. 19 refs., 1 fig., 3 tabs.

  7. Targeted gene therapy and cell reprogramming in Fanconi anemia

    PubMed Central

    Rio, Paula; Baños, Rocio; Lombardo, Angelo; Quintana-Bustamante, Oscar; Alvarez, Lara; Garate, Zita; Genovese, Pietro; Almarza, Elena; Valeri, Antonio; Díez, Begoña; Navarro, Susana; Torres, Yaima; Trujillo, Juan P; Murillas, Rodolfo; Segovia, Jose C; Samper, Enrique; Surralles, Jordi; Gregory, Philip D; Holmes, Michael C; Naldini, Luigi; Bueren, Juan A

    2014-01-01

    Gene targeting is progressively becoming a realistic therapeutic alternative in clinics. It is unknown, however, whether this technology will be suitable for the treatment of DNA repair deficiency syndromes such as Fanconi anemia (FA), with defects in homology-directed DNA repair. In this study, we used zinc finger nucleases and integrase-defective lentiviral vectors to demonstrate for the first time that FANCA can be efficiently and specifically targeted into the AAVS1 safe harbor locus in fibroblasts from FA-A patients. Strikingly, up to 40% of FA fibroblasts showed gene targeting 42 days after gene editing. Given the low number of hematopoietic precursors in the bone marrow of FA patients, gene-edited FA fibroblasts were then reprogrammed and re-differentiated toward the hematopoietic lineage. Analyses of gene-edited FA-iPSCs confirmed the specific integration of FANCA in the AAVS1 locus in all tested clones. Moreover, the hematopoietic differentiation of these iPSCs efficiently generated disease-free hematopoietic progenitors. Taken together, our results demonstrate for the first time the feasibility of correcting the phenotype of a DNA repair deficiency syndrome using gene-targeting and cell reprogramming strategies. PMID:24859981

  8. How Is Fanconi Anemia Treated?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Fanconi Anemia Treated? Doctors decide how to treat Fanconi anemia (FA) based on a person's age and how ... Long-term treatments for FA can: Cure the anemia. Damaged bone marrow cells are replaced with healthy ...

  9. How Is Fanconi Anemia Diagnosed?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Fanconi Anemia Diagnosed? People who have Fanconi anemia (FA) are born with the disorder. They may ... questions about: Any personal or family history of anemia Any surgeries you’ve had related to the ...

  10. Homozygosity mapping of Fanconi anemia

    SciTech Connect

    Gschwend, M.; Botstein, D.; Kruglyak, L.

    1994-09-01

    Fanconi anemia (FA) is a rare, recessive, genetically heterogeneous disease characterized by progressive insufficiency of the bone marrow and increased cellular sensitivity to DNA crosslinking agents. Complementation tests among different FA cells have indicated the presence of at least 4 FA-causing genes. One of the genes, FACC, was identified by functional complementation but appears unlikely to account for many phenotypically indistinguishable FA caes. We have begun a linkage study of FA using {open_quotes}homozygosity mapping{close_quotes}, a method that involves genotyping with DNA markers on affected individuals whose parents are related. Because FA is a rare recessive disease, it is most likely that probands are homozygous by descent at the disease locus and, therefore, at nearby DNA markers. Although the probability that any given marker will be homozygous in an inbred individual is high, given markers with moderate heterozygosities, the chance that two unrelated inbred individuals will be homozygous at the same marker is considerably lower. By locating overlapping regions of homozygosity between different families we hope to identify genes that cause FA. Sixteen consanguineous non-FACC FA families from the International Fanconi Anemia Registry at Rockefeller University are under study. An efficient algorithm for data analysis was developed and incorporated into software that can quickly compute exact multipoint lod scores using all markers on an entire chromosome. At the time of this writing, 171 of 229 microsatellite markers spaced at 20 cM intervals across the genome have been analyzed.

  11. Fanconi Anemia Gene Editing by the CRISPR/Cas9 System

    PubMed Central

    Osborn, Mark J.; Gabriel, Richard; Webber, Beau R.; DeFeo, Anthony P.; McElroy, Amber N.; Jarjour, Jordan; Starker, Colby G.; Wagner, John E.; Joung, J. Keith; Voytas, Daniel F.; von Kalle, Christof; Schmidt, Manfred; Blazar, Bruce R.

    2015-01-01

    Abstract Genome engineering with designer nucleases is a rapidly progressing field, and the ability to correct human gene mutations in situ is highly desirable. We employed fibroblasts derived from a patient with Fanconi anemia as a model to test the ability of the clustered regularly interspaced short palindromic repeats/Cas9 nuclease system to mediate gene correction. We show that the Cas9 nuclease and nickase each resulted in gene correction, but the nickase, because of its ability to preferentially mediate homology-directed repair, resulted in a higher frequency of corrected clonal isolates. To assess the off-target effects, we used both a predictive software platform to identify intragenic sequences of homology as well as a genome-wide screen utilizing linear amplification-mediated PCR. We observed no off-target activity and show RNA-guided endonuclease candidate sites that do not possess low sequence complexity function in a highly specific manner. Collectively, we provide proof of principle for precision genome editing in Fanconi anemia, a DNA repair-deficient human disorder. PMID:25545896

  12. Linkage analysis of the Fanconi anemia gene FACC with chromosome 9q markers

    SciTech Connect

    Auerbach, A.D.; Shin, H.T.; Kaporis, A.G.

    1994-09-01

    Fanconi anemia (FA) is a genetically heterogeneous syndrome, with at least four different complementation groups as determined by cell fusion studies. The gene for complementation group C, FACC, has been cloned and mapped to chromosome 9q22.3 by in situ hybridization, while linkage analysis has supported the placement of another gene on chromosome 20q. We have analyzed five microsatellite markers and one RFLP on chromosome 9q in a panel of FA families from the International Fanconi Anemia Registry (IFAR) in order to place FACC on the genetic map. Polymorphisms were typed in 308 individuals from 51 families. FACC is tightly linked to both D9S151 [{Theta}{sub max}=0.025, Z{sub max}=7.75] and to D9S196 [{Theta}{sub max}=0.041, Z{sub max}=7.89]; multipoint analysis is in progress. We are currently screening a YAC clone that contains the entire FACC gene for additional microsatellite markers suitable for haplotype analysis of FA families.

  13. The genomic organization of the Fanconi anemia group A (FAA) gene

    SciTech Connect

    Ianzano, L.; Centra, M.; Savino, M.

    1997-05-01

    Fanconi anemia (FA) is a genetically heterogeneous disease involving at least five genes on the basis of complementation analysis (FAA to FAE). The FAA gene has been recently isolated by two independent approaches, positional and functional cloning. In the present study we describe the genomic structure of the FAA gene. The gene contains 43 exons spanning approximately 80 kb as determined by the alignment of four cosmids and the fine localization of the first and the last exons in restriction fragments of these clones. Exons range from 34 to 188 bp. All but three of the splice sites were consistent with the ag-gt rule. We also describe three alternative splicing events in cDNA clones that result in the loss of exon 37, a 23-bp deletion at the 5{prime} end of exon 41. Sequence analysis of the 5{prime} region upstream of the putative transcription start site showed no obvious TATA and CAAT boxes, but did show a GC-rich region, typical of housekeeping genes. Knowledge of the structure of the FAA gene will provide an invaluable resource for the discovery of mutations in the gene that accounts for about 60-66% of FA patients. 24 refs., 3 figs., 1 tab.

  14. Mutated Fanconi anemia pathway in non-Fanconi anemia cancers

    PubMed Central

    Shen, Yihang; Lee, Yuan-Hao; Panneerselvam, Jayabal; Zhang, Jun; Loo, Lenora W. M.; Fei, Peiwen

    2015-01-01

    An extremely high cancer incidence and the hypersensitivity to DNA crosslinking agents associated with Fanconi Anemia (FA) have marked it to be a unique genetic model system to study human cancer etiology and treatment, which has emerged an intense area of investigation in cancer research. However, there is limited information about the relationship between the mutated FA pathway and the cancer development or/and treatment in patients without FA. Here we analyzed the mutation rates of the seventeen FA genes in 68 DNA sequence datasets. We found that the FA pathway is frequently mutated across a variety of human cancers, with a rate mostly in the range of 15 to 35 % in human lung, brain, bladder, ovarian, breast cancers, or others. Furthermore, we found a statistically significant correlation (p < 0.05) between the mutated FA pathway and the development of human bladder cancer that we only further analyzed. Together, our study demonstrates a previously unknown fact that the mutated FA pathway frequently occurs during the development of non-FA human cancers, holding profound implications directly in advancing our understanding of human tumorigenesis as well as tumor sensitivity/resistance to crosslinking drug-relevant chemotherapy. PMID:26015400

  15. FANCA Gene Mutations with 8 Novel Molecular Changes in Indian Fanconi Anemia Patients

    PubMed Central

    Solanki, Avani; Mohanty, Purvi; Shukla, Pallavi; Rao, Anita; Ghosh, Kanjaksha; Vundinti, Babu Rao

    2016-01-01

    Fanconi anemia (FA), a rare heterogeneous genetic disorder, is known to be associated with 19 genes and a spectrum of clinical features. We studied FANCA molecular changes in 34 unrelated and 2 siblings of Indian patients with FA and have identified 26 different molecular changes of FANCA gene, of which 8 were novel mutations (a small deletion c.2500delC, 4 non-sense mutations c.2182C>T, c.2630C>G, c.3677C>G, c.3189G>A; and 3 missense mutations; c.1273G>C, c.3679 G>C, and c.3992 T>C). Among these only 16 patients could be assigned FA-A complementation group, because we could not confirm single exon deletions detected by MLPA or cDNA amplification by secondary confirmation method and due to presence of heterozygous non-pathogenic variations or heterozygous pathogenic mutations. An effective molecular screening strategy should be developed for confirmation of these mutations and determining the breakpoints for single exon deletions. PMID:26799702

  16. The Simple Chordate Ciona intestinalis Has a Reduced Complement of Genes Associated with Fanconi Anemia.

    PubMed

    Stanley, Edward C; Azzinaro, Paul A; Vierra, David A; Howlett, Niall G; Irvine, Steven Q

    2016-01-01

    Fanconi anemia (FA) is a human genetic disease characterized by congenital defects, bone marrow failure, and increased cancer risk. FA is associated with mutation in one of 24 genes. The protein products of these genes function cooperatively in the FA pathway to orchestrate the repair of DNA interstrand cross-links. Few model organisms exist for the study of FA. Seeking a model organism with a simpler version of the FA pathway, we searched the genome of the simple chordate Ciona intestinalis for homologs of the human FA-associated proteins. BLAST searches, sequence alignments, hydropathy comparisons, maximum likelihood phylogenetic analysis, and structural modeling were used to infer the likelihood of homology between C. intestinalis and human FA proteins. Our analysis indicates that C. intestinalis indeed has a simpler and potentially functional FA pathway. The C. intestinalis genome was searched for candidates for homology to 24 human FA and FA-associated proteins. Support was found for the existence of homologs for 13 of these 24 human genes in C. intestinalis. Members of each of the three commonly recognized FA gene functional groups were found. In group I, we identified homologs of FANCE, FANCL, FANCM, and UBE2T/FANCT. Both members of group II, FANCD2 and FANCI, have homologs in C. intestinalis. In group III, we found evidence for homologs of FANCJ, FANCO, FANCQ/ERCC4, FANCR/RAD51, and FANCS/BRCA1, as well as the FA-associated proteins ERCC1 and FAN1. Evidence was very weak for the existence of homologs in C. intestinalis for any other recognized FA genes. This work supports the notion that C. intestinalis, as a close relative of vertebrates, but having a much reduced complement of FA genes, offers a means of studying the function of certain FA proteins in a simpler pathway than that of vertebrate cells. PMID:27279728

  17. The Simple Chordate Ciona intestinalis Has a Reduced Complement of Genes Associated with Fanconi Anemia

    PubMed Central

    Stanley, Edward C.; Azzinaro, Paul A.; Vierra, David A.; Howlett, Niall G.; Irvine, Steven Q.

    2016-01-01

    Fanconi anemia (FA) is a human genetic disease characterized by congenital defects, bone marrow failure, and increased cancer risk. FA is associated with mutation in one of 24 genes. The protein products of these genes function cooperatively in the FA pathway to orchestrate the repair of DNA interstrand cross-links. Few model organisms exist for the study of FA. Seeking a model organism with a simpler version of the FA pathway, we searched the genome of the simple chordate Ciona intestinalis for homologs of the human FA-associated proteins. BLAST searches, sequence alignments, hydropathy comparisons, maximum likelihood phylogenetic analysis, and structural modeling were used to infer the likelihood of homology between C. intestinalis and human FA proteins. Our analysis indicates that C. intestinalis indeed has a simpler and potentially functional FA pathway. The C. intestinalis genome was searched for candidates for homology to 24 human FA and FA-associated proteins. Support was found for the existence of homologs for 13 of these 24 human genes in C. intestinalis. Members of each of the three commonly recognized FA gene functional groups were found. In group I, we identified homologs of FANCE, FANCL, FANCM, and UBE2T/FANCT. Both members of group II, FANCD2 and FANCI, have homologs in C. intestinalis. In group III, we found evidence for homologs of FANCJ, FANCO, FANCQ/ERCC4, FANCR/RAD51, and FANCS/BRCA1, as well as the FA-associated proteins ERCC1 and FAN1. Evidence was very weak for the existence of homologs in C. intestinalis for any other recognized FA genes. This work supports the notion that C. intestinalis, as a close relative of vertebrates, but having a much reduced complement of FA genes, offers a means of studying the function of certain FA proteins in a simpler pathway than that of vertebrate cells. PMID:27279728

  18. Mutations of the Fanconi anemia group A gene (FAA) in Italian patients.

    PubMed Central

    Savino, M; Ianzano, L; Strippoli, P; Ramenghi, U; Arslanian, A; Bagnara, G P; Joenje, H; Zelante, L; Savoia, A

    1997-01-01

    Fanconi anemia (FA) is an autosomal recessive disease characterized by progressive pancytopenia, congenital malformations, and predisposition to acute myeloid leukemia. At least five complementation groups (FA-A-FA-E) have been identified. The relative prevalence of FA-A has been estimated at an average of approximately 65% but may widely vary according to ethnic background. In Italy, 11 of 12 patients analyzed by cell-fusion studies were assigned to group FA-A, suggesting an unusually high relative prevalence of this FA subtype in patients of Italian ancestry. We have screened the 43 exons of the FAA gene and their flanking intronic sequences in 38 Italian FA patients, using RNA-SSCP. Ten different mutations were detected: three nonsense and one missense substitutions, four putative splice mutations, an insertion, and a duplication. Most of the mutations are expected to cause a premature termination of the FAA protein at various sites throughout the molecule. Four protein variants were also found, three of which were polymorphisms. The missense mutation D1359Y, not found in chromosomes from healthy unrelated individuals, was responsible for a local alteration of hydrophobicity in the FAA protein, and it was likely to be pathogenic. Thus, the mutations so far encountered in the FAA gene are essentially all different. Since screening based on the analysis of single exons by genomic DNA amplification apparently detects only a minority of the mutations, methods designed to detect alterations in the genomic structure of the gene or in the FAA polypeptide may be helpful in the identification of FAA mutations. Images Figure 1 Figure 2 Figure 3 PMID:9399890

  19. Diagnosis of Fanconi Anemia by Diepoxybutane Analysis

    PubMed Central

    Auerbach, Arleen D.

    2015-01-01

    Fanconi anemia (FA) is a genetically and phenotypically heterogeneous disorder characterized by congenital malformations, progressive bone marrow failure, and predisposition to cancer, particularly hematological malignancies and solid tumors of the head and neck. The main role of FA proteins is in the repair of DNA interstrand crosslinks (ICLs). FA results from pathogenic variants in at least 16 distinct genes, causing genomic instability. Although the highly variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, diagnosis based on a profound sensitivity to DNA crosslinking agents can be used to identify the pre-anemia patient as well as patients with aplastic anemia or leukemia who may or may not have the physical stigmata associated with the syndrome. Diepoxybutane (DEB) analysis is the preferred test for FA because other agents have higher rates of false-positive and false-negative results. PMID:25827349

  20. Lentiviral-Mediated Gene Therapy in Fanconi Anemia-A Mice Reveals Long-Term Engraftment and Continuous Turnover of Corrected HSCs.

    PubMed

    Molina-Estevez, F Javier; Nowrouzi, Ali; Lozano, M Luz; Galy, Anne; Charrier, Sabine; von Kalle, Christof; Guenechea, Guillermo; Bueren, Juan A; Schmidt, Manfred

    2015-01-01

    Fanconi anemia is a DNA repair-deficiency syndrome mainly characterized by cancer predisposition and bone marrow failure. Trying to restore the hematopoietic function in these patients, lentiviral vector-mediated gene therapy trials have recently been proposed. However, because no insertional oncogenesis studies have been conducted so far in DNA repair-deficiency syndromes such as Fanconi anemia, we have carried out a genome-wide screening of lentiviral insertion sites after the gene correction of Fanca(-/-) hematopoietic stem cells (HSCs), using LAM-PCR and 454-pyrosequencing. Our studies first demonstrated that transduction of Fanca(-/-) HSCs with a lentiviral vector designed for clinical application efficiently corrects the phenotype of Fanconi anemia repopulating cells without any sign of toxicity. The identification of more than 6,500 insertion sites in primary and secondary recipients showed a polyclonal pattern of reconstitution, as well as a continuous turnover of corrected Fanca(-/-) HSC clones, without evidences of selection towards specific common integration sites. Taken together our data show, for the first time in a DNA repair-deficiency syndrome, that lentiviral vector-mediated gene therapy efficiently corrects the phenotype of affected HSCs and promotes a healthy pattern of clonal turnover in vivo. These studies will have a particular impact in the development of new gene therapy trials in patients affected by DNA repair syndromes, particularly in Fanconi anemia. PMID:26415575

  1. Targeted disruption of the murine Facc gene: Towards the establishment of a mouse model for Fanconi anemia

    SciTech Connect

    Chen, M.; Auerbach, W.; Buchwald, M.

    1994-09-01

    Fanconi anemia (FA) is an autosomal recessive disease characterized by bone marrow failure, congenital malformations and predisposition to malignancies. The gene responsible for the defect in FA group C has been cloned and designated the Fanconi Anemia Complementation Group C gene (FACC). A murine cDNA for this gene (Facc) was also cloned. Here we report our progress in the establishment of a mouse model for FA. The mouse Facc cDNA was used as probe to screen a genomic library of mouse strain 129. More than twenty positive clones were isolated. Three of them were mapped and found to be overlapping clones, encompassing the genomic region from exon 8 to the end of the 3{prime} UTR of the mouse cDNA. A targeting vector was constructed using the most 5{prime} mouse genomic sequence available. The end result of the homologous recombination is that exon 8 is deleted and the neo gene is inserted. The last exon, exon 14, is essential for the complementing function of the FACC gene product; the disruption in the middle of the murine Facc gene should render this locus biologically inactive. This targeting vector was linearized and electroporated into R1 embryonic stem (ES) cells which were derived from the 129 mouse. Of 102 clones screened, 19 positive cell lines were identified. Four targeted cell lines have been used to produce chimeric mice. 129-derived ES cells were aggregated ex vivo into the morulas derived from CD1 mice and then implanted into foster mothers. 22 chimeras have been obtained. Moderately and strongly chimeric mice have been bred to test for germline transmission. Progeny with the expected coat color derived from 2 chimeras are currently being examined to confirm transmission of the targeted allele.

  2. Fanconi anemia-D1 due to homozygosity for the BRCA2 gene Cypriot founder mutation: A case report

    PubMed Central

    LOIZIDOU, MARIA A.; HADJISAVVAS, ANDREAS; TANTELES, GEORGE A.; SPANOU-ARISTIDOU, ELENA; KYRIACOU, KYRIACOS; CHRISTOPHIDOU-ANASTASIADOU, VIOLETTA

    2016-01-01

    Fanconi anemia (FA) is a rare disorder characterized by multiple congenital malformations, progressive bone marrow failure and susceptibility to malignancies. Biallelic mutations in the breast cancer 2, early onset (BRCA2) gene are responsible for the FA-D1 subgroup, which accounts for ~3% of all the FA cases. Patients with biallelic BRCA2 mutations generally display a more severe phenotype, with earlier onset and increased incidence of leukaemia and other solid tumors, than other patients with FA. In the present report, the first Cypriot patient with FA-D1 is described, which is the fifth case of a homozygote for the same null allele reported thus far, and the third known case of neuroblastoma in association with FA-D1. PMID:26834852

  3. Fanconi anemia proteins in telomere maintenance.

    PubMed

    Sarkar, Jaya; Liu, Yie

    2016-07-01

    Mammalian chromosome ends are protected by nucleoprotein structures called telomeres. Telomeres ensure genome stability by preventing chromosome termini from being recognized as DNA damage. Telomere length homeostasis is inevitable for telomere maintenance because critical shortening or over-lengthening of telomeres may lead to DNA damage response or delay in DNA replication, and hence genome instability. Due to their repetitive DNA sequence, unique architecture, bound shelterin proteins, and high propensity to form alternate/secondary DNA structures, telomeres are like common fragile sites and pose an inherent challenge to the progression of DNA replication, repair, and recombination apparatus. It is conceivable that longer the telomeres are, greater is the severity of such challenges. Recent studies have linked excessively long telomeres with increased tumorigenesis. Here we discuss telomere abnormalities in a rare recessive chromosomal instability disorder called Fanconi Anemia and the role of the Fanconi Anemia pathway in telomere biology. Reports suggest that Fanconi Anemia proteins play a role in maintaining long telomeres, including processing telomeric joint molecule intermediates. We speculate that ablation of the Fanconi Anemia pathway would lead to inadequate aberrant structural barrier resolution at excessively long telomeres, thereby causing replicative burden on the cell. PMID:27118469

  4. What Are the Signs and Symptoms of Fanconi Anemia?

    MedlinePlus

    ... What Are the Signs and Symptoms of Fanconi Anemia? Major Signs and Symptoms Your doctor may suspect ... sisters also should be tested for the disorder. Anemia The most common symptom of all types of ...

  5. Analysis of the pattern of expression of the Fanconi anemia group C (Facc) gene during murine development

    SciTech Connect

    Krasnoshtein, F.; Buchwald, M.

    1994-09-01

    Fanconi anemia (FA) is an autosomal recessive disorder characterized by a variety of congenital and skeletal malformations, progressive pancytopanenia and predisposition to malignancies. FA cells display chromosomal instability and hypersensitivity to DNA-damaging agents. Both the human and the corresponding murine cDNAs have been cloned in our lab. Here we describe the expression of Facc during mouse development, using mRNA in situ hybridization. Our aim is to obtain clues on the possible function of the Facc gene product during development that may help elucidate basic defect(s) in FA. In addition, knowledge of the exact pattern of Facc expression will assist in interpreting the phenotypes of mutant mice, currently being developed. In embryos the gene is diffusely expressed over the entire embryo, with higher hybridization levels in the mesenchyme and in both upper and lower extremities. Specific expression of Facc is seen in the perichondrium and marrow of long bones of hind limbs/hip; long bones of front limbs/shoulder region; developing digits of front and hind paws; and ribs. The signal is also detected in the following regions: cranial/frontal; facial/periorbital and maxillary/mandibular, hair follicles, diaphragm and lung. In addition, generalized Facc expression is seen during these embryonic stages. The pattern of Facc expression is consistent with the known skeletal abnormalities in FA patients, which include radial ray deformities, metacarpal hypoplasia, and abnormalities of lower limbs, ribs, head and face. The signal in the lung is consistent with the lung lobe absence and abnormal pulmonary drainage that have been detected in some FA patients. The sloped forehead and microcephaly in FA patients may have some association with the signal seen in the frontal region of the mouse cranium. Taken together, our results suggest that Facc is directly involved in the development of various embryonic tissues, particularly bone.

  6. Fanconi Anemia Proteins Function in Mitophagy and Immunity.

    PubMed

    Sumpter, Rhea; Sirasanagandla, Shyam; Fernández, Álvaro F; Wei, Yongjie; Dong, Xiaonan; Franco, Luis; Zou, Zhongju; Marchal, Christophe; Lee, Ming Yeh; Clapp, D Wade; Hanenberg, Helmut; Levine, Beth

    2016-05-01

    Fanconi anemia (FA) pathway genes are important tumor suppressors whose best-characterized function is repair of damaged nuclear DNA. Here, we describe an essential role for FA genes in two forms of selective autophagy. Genetic deletion of Fancc blocks the autophagic clearance of viruses (virophagy) and increases susceptibility to lethal viral encephalitis. Fanconi anemia complementation group C (FANCC) protein interacts with Parkin, is required in vitro and in vivo for clearance of damaged mitochondria, and decreases mitochondrial reactive oxygen species (ROS) production and inflammasome activation. The mitophagy function of FANCC is genetically distinct from its role in genomic DNA damage repair. Moreover, additional genes in the FA pathway, including FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2, are required for mitophagy. Thus, members of the FA pathway represent a previously undescribed class of selective autophagy genes that function in immunity and organellar homeostasis. These findings have implications for understanding the pathogenesis of FA and cancers associated with mutations in FA genes. PMID:27133164

  7. Assembling an orchestra: Fanconi anemia pathway of DNA repair.

    PubMed

    Yuan, Fenghua; Song, Limin; Qian, Liangyue; Hu, Jennifer J; Zhang, Yanbin

    2010-01-01

    Fanconi anemia (FA) is a recessive genetic disorder characterized by developmental defects, bone marrow failure, and cancer susceptibility. The complete set of FA genes has only been identified recently and seems to be uniquely conserved among vertebrates. Fanconi anemia proteins have been implicated in the repair of interstrand DNA crosslinks that block DNA replication and transcription. Although all thirteen FA complementation groups show similar clinical and cellular phenotypes, approximately 85% of patients presented defective FANCA, FANCC, or FANCG. The established DNA interacting components (FANCM, FANCI, FANCD2, and FANCJ) account only for approximately 5% of all FA patients, an observation that raises doubt concerning the roles of FA proteins in DNA repair. In recent years, rapid progress in the area of FA research has provided great insights into the critical roles of FA proteins in DNA repair. However, many FA proteins do not have identifiable domains to indicate how they contribute to biological processes, particularly DNA repair. Therefore, future biochemical studies are warranted to understand the biological functions of FA proteins and their implications in human diseases. PMID:20515746

  8. Effects of ionizing radiation on cells from Fanconi's anemia patients

    SciTech Connect

    Duckworth-Rysiecki, G.; Taylor, A.M.

    1985-01-01

    The lymphocytes from some Fanconi's anemia patients appeared to be more radiosensitive than normal as measured by the number of X-ray-(or bleomycin-) induced chromosome aberrations seen following G2 treatment. Fibroblasts from the same patients, however, all showed the same degree of colony survival as normals following exposure to gamma-rays (Do, 1.13 +/- 0.072 (S.E.) Gy and 1.14 +/- 0.077 Gy for Fanconi's anemia and normal fibroblasts, respectively). The lack of increased radiosensitivity in Fanconi's fibroblasts was also observed by the same degree of inhibition of DNA synthesis as seen in normals following gamma-irradiation. The results show clearly that there is no increase in radiosensitivity common to all cell types from Fanconi's patients, although an apparent increase in chromosomal radiosensitivity may be seen in the lymphocytes from an occasional patient.

  9. Evidence for a founder effect for the IVS4 +4 A{r_arrow}T mutation in the Fanconi anemia gene FACC in a Jewish population

    SciTech Connect

    Verlander, P.C.; Kaporis, A.G.; Qian, L.

    1994-09-01

    Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive disorder defined by hypersensitivity of cells to DNA cross-linking agents; a gene for complementation group C(FACC) has been cloned. Two common mutations, IVS4 +4 A{r_arrow}T and 322delG, and several rare mutations have recently been reported in affected individuals. We now report the development of amplification refractory mutation system (ARMS) assays for rapid, non-radioactive detection of these known mutations in FACC. Primer pairs specific for variant sequences were designed, with the 3{prime} terminal base of one primer matching the variant base. PCR products are separated by electrophoresis on 2.5% agarose gels; mutations are indicated by the presence of a band of a specific size. These ARMS assays can be multiplexed to allow screening for all known mutations in two PCR reactions. We have used these assays for detection of FACC mutations in affected individuals in the International Fanconi Anemia Registry (IFAR), and for carrier detection FACC families. IVS4 +4 A{r_arrow}T is the only FACC mutation found in Jewish FA patients and their families, of both Ashkenazi and Sephardic ancestry. This mutation was not found in any affected individual of non-Jewish origin. In addition, DNA samples from 1596 healthy Jewish individuals primarily of Ashkenazi ancestry were supplied to us by Dor Yeshorim. These samples, ascertained for carrier screening for Tay Sachs, cystic fibrosis, and other genetic diseases with a high frequency in the religious Jewish community served by this organization, were tested for both IVS4 +4 A{r_arrow}T and 322delG mutations; seventeen IVS4 +4 A{r_arrow}T are of Sephardic Jewish ancestry. We hypothesize that IVS4 +4 A{r_arrow}T is a very old mutation, predating the divergence of the Ashkenazi and Sephardic populations. Haplotype analysis with microsatellite markers is in progress.

  10. Evaluation of rare variants in the new fanconi anemia gene ERCC4 (FANCQ) as familial breast/ovarian cancer susceptibility alleles.

    PubMed

    Osorio, Ana; Bogliolo, Massimo; Fernández, Victoria; Barroso, Alicia; de la Hoya, Miguel; Caldés, Trinidad; Lasa, Adriana; Ramón y Cajal, Teresa; Santamariña, Marta; Vega, Ana; Quiles, Francisco; Lázaro, Conxi; Díez, Orland; Fernández, Daniel; González-Sarmiento, Rogelio; Durán, Mercedes; Piqueras, José Fernández; Marín, Maria; Pujol, Roser; Surrallés, Jordi; Benítez, Javier

    2013-12-01

    Recently, it has been reported that biallelic mutations in the ERCC4 (FANCQ) gene cause Fanconi anemia (FA) subtype FA-Q. To investigate the possible role of ERCC4 in breast and ovarian cancer susceptibility, as occurs with other FA genes, we screened the 11 coding exons and exon-intron boundaries of ERCC4 in 1573 index cases from high-risk Spanish familial breast and ovarian cancer pedigrees that had been tested negative for BRCA1 and BRCA2 mutations and 854 controls. The frequency of ERCC4 mutation carriers does not differ between cases and controls, suggesting that ERCC4 is not a cancer susceptibility gene. Interestingly, the prevalence of ERCC4 mutation carriers (one in 288) is similar to that reported for FANCA, whereas there are approximately 100-fold more FA-A than FA-Q patients, indicating that most biallelic combinations of ERCC4 mutations are embryo lethal. Finally, we identified additional bone-fide FA ERCC4 mutations specifically disrupting interstrand cross-link repair. PMID:24027083

  11. Biallelic inactivation of REV7 is associated with Fanconi anemia.

    PubMed

    Bluteau, Dominique; Masliah-Planchon, Julien; Clairmont, Connor; Rousseau, Alix; Ceccaldi, Raphael; Dubois d'Enghien, Catherine; Bluteau, Olivier; Cuccuini, Wendy; Gachet, Stéphanie; Peffault de Latour, Régis; Leblanc, Thierry; Socié, Gérard; Baruchel, André; Stoppa-Lyonnet, Dominique; D'Andrea, Alan D; Soulier, Jean

    2016-09-01

    Fanconi anemia (FA) is a recessive genetic disease characterized by congenital abnormalities, chromosome instability, progressive bone marrow failure (BMF), and a strong predisposition to cancer. Twenty FA genes have been identified, and the FANC proteins they encode cooperate in a common pathway that regulates DNA crosslink repair and replication fork stability. We identified a child with severe BMF who harbored biallelic inactivating mutations of the translesion DNA synthesis (TLS) gene REV7 (also known as MAD2L2), which encodes the mutant REV7 protein REV7-V85E. Patient-derived cells demonstrated an extended FA phenotype, which included increased chromosome breaks and G2/M accumulation upon exposure to DNA crosslinking agents, γH2AX and 53BP1 foci accumulation, and enhanced p53/p21 activation relative to cells derived from healthy patients. Expression of WT REV7 restored normal cellular and functional phenotypes in the patient's cells, and CRISPR/Cas9 inactivation of REV7 in a non-FA human cell line produced an FA phenotype. Finally, silencing Rev7 in primary hematopoietic cells impaired progenitor function, suggesting that the DNA repair defect underlies the development of BMF in FA. Taken together, our genetic and functional analyses identified REV7 as a previously undescribed FA gene, which we term FANCV. PMID:27500492

  12. Fanconi Anemia: A Signal Transduction and DNA Repair Pathway

    PubMed Central

    Kupfer, Gary M.

    2013-01-01

    Fanconi anemia (FA) is a fascinating, rare genetic disorder marked by congenital defects, bone marrow failure, and cancer susceptibility. Research in recent years has led to the elucidation of FA as a DNA repair disorder and involved multiple pathways as well as having wide applicability to common cancers, including breast, ovarian, and head and neck. This review will describe the clinical aspects of FA as well as the current state of its molecular pathophysiology. In particular, work from the Kupfer laboratory will be described that demonstrates how the FA pathway interacts with multiple DNA repair pathways, including the mismatch repair system and signal transduction pathway of the DNA damage response. PMID:24348213

  13. Irreversible repression of DNA synthesis in Fanconi anemia cells is alleviated by the product of a novel cyclin-related gene.

    PubMed Central

    Digweed, M; Günthert, U; Schneider, R; Seyschab, H; Friedl, R; Sperling, K

    1995-01-01

    Primary fibroblasts from patients with the genetic disease Fanconi anemia, which are hypersensitive to cross-linking agents, were used to screen a cDNA library for sequences involved in their abnormal cellular response to a cross-linking challenge. By using library partition and microinjection of in vitro-transcribed RNA, a cDNA clone, pSPHAR (S-phase response), which is able to correct the permanent repression of semiconservative DNA synthesis rates characteristic of these cells, was isolated. Wild-type SPHAR mRNA is expressed in all fibroblasts so far analyzed, including those of Fanconi anemia patients. Correction of the abnormal response in these cells appears therefore to be due to overexpression after cDNA transfer rather than to genetic complementation. The cDNA contains an open reading frame coding for a polypeptide of 7.5 kDa. Rabbit antiserum directed against a SPHAR peptide detects a protein of 7.9 kDa in Western blots (immunoblots) of whole-cell extracts from proliferating, but not resting, fibroblasts. The deduced amino acid sequence of SPHAR contains a motif found in the cyclins, and it is proposed that SPHAR acts within the injected cell by interfering with the cyclin-controlled maintenance of S phase. In agreement with this proposal, normal cells transfected with an antisense SPHAR expression vector have a significantly reduced rate of DNA synthesis during S phase and a prolonged G2 phase, reflecting the need for postreplicative DNA processing before entry into mitosis. PMID:7799938

  14. Primary Ovarian Insufficiency Induced by Fanconi Anemia E Mutation in a Mouse Model

    PubMed Central

    Fu, Chun; Begum, Khurshida; Overbeek, Paul A.

    2016-01-01

    In most cases of primary ovarian insufficiency (POI), the cause of the depletion of ovarian follicles is unknown. Fanconi anemia (FA) proteins are known to play important roles in follicular development. Using random insertional mutagenesis with a lentiviral transgene, we identified a family with reduced fertility in the homozygous transgenic mice. We identified the integration site and found that the lentivirus had integrated into intron 8 of the Fanconi E gene (Fance). By RT-PCR and in situ hybridization, we found that Fance transcript levels were significantly reduced. The Fance homozygous mutant mice were assayed for changes in ovarian development, follicle numbers and estrous cycle. Ovarian dysplasias and a severe lack of follicles were seen in the mutant mice. In addition, the estrous cycle was disrupted in adult females. Our results suggest that POI has been induced by the Fance mutation in this new mouse model. PMID:26939056

  15. Use Massive Parallel Sequencing and Exome Capture Technology to Sequence the Exome of Fanconi Anemia Children and Their Patents

    ClinicalTrials.gov

    2013-11-21

    Fanconi Anemia; Autosomal or Sex Linked Recessive Genetic Disease; Bone Marrow Hematopoiesis Failure, Multiple Congenital Abnormalities, and Susceptibility to Neoplastic Diseases.; Hematopoiesis Maintainance.

  16. A novel diagnostic screen for defects in the Fanconi anemia pathway.

    PubMed

    Shimamura, Akiko; Montes de Oca, Rocio; Svenson, John L; Haining, Nicholas; Moreau, Lisa A; Nathan, David G; D'Andrea, Alan D

    2002-12-15

    Fanconi anemia (FA) is an autosomal recessive chromosomal instability syndrome characterized by congenital abnormalities, progressive bone marrow failure, and cancer predisposition. Although patients with FA are candidates for bone marrow transplantation or gene therapy, their phenotypic heterogeneity can delay or obscure diagnosis. The current diagnostic test for FA consists of cytogenetic quantitation of chromosomal breakage in response to diepoxybutane (DEB) or mitomycin C (MMC). Recent studies have elucidated a biochemical pathway for Fanconi anemia that culminates in the monoubiquitination of the FANCD2 protein. In the current study, we develop a new rapid diagnostic and subtyping FA assay amenable for screening broad populations at risk of FA. Primary lymphocytes were assayed for FANCD2 monoubiquitination by immunoblot. The absence of the monoubiquitinated FANCD2 isoform correlated with the diagnosis of FA by DEB testing in 11 known patients with FA, 37 patients referred for possible FA, and 29 healthy control subjects. Monoubiquitination of FANCD2 was normal in other bone marrow failure syndromes and chromosomal breakage syndromes. A combination of retroviral gene transfer and FANCD2 immunoblotting provides a rapid subtyping assay for patients newly diagnosed with FA. These new FA screening assays would allow efficient testing of broad populations at risk. PMID:12393398

  17. Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations

    PubMed Central

    Castella, Maria; Pujol, Roser; Callén, Elsa; Trujillo, Juan P.; Casado, José A.; Gille, Hans; Lach, Francis P.; Auerbach, Arleen D.; Schindler, Detlev; Benítez, Javier; Porto, Beatriz; Ferro, Teresa; Muñoz, Arturo; Sevilla, Julián; Madero, Luis; Cela, Elena; Beléndez, Cristina; de Heredia, Cristina Díaz; Olivé, Teresa; de Toledo, José Sánchez; Badell, Isabel; Torrent, Montserrat; Estella, Jesús; Dasí, Ángeles; Rodríguez-Villa, Antonia; Gómez, Pedro; Barbot, José; Tapia, María; Molinés, Antonio; Figuera, Ángela; Bueren, Juan A.

    2011-01-01

    Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational “hot-spot” but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations. PMID:21273304

  18. Interstitial lung disease in an adult with Fanconi anemia: Clues to the pathogenesis

    SciTech Connect

    Rubinstein, W.S.; Wenger, S.L.; Hoffman, R.M.

    1997-03-31

    We have studied a 38-year-old man with a prior diagnosis of Holt-Oram syndrome, who presented with diabetes mellitus. He had recently taken prednisone for idiopathic interstitial lung disease and trimethoprim-sulfamethoxazole for sinusitis. Thrombocytopenia progressed to pancytopenia. The patient had skeletal, cardiac, renal, cutaneous, endocrine, hepatic, neurologic, and hematologic manifestations of Fanconi anemia (FA). Chest radiographs showed increased interstitial markings at age 25, dyspnea began in his late 20s, and he stopped smoking at age 32. At age 38, computerized tomography showed bilateral upper lobe fibrosis, lower lobe honeycombing, and bronchiectasis. Pulmonary function tests, compromised at age 29, showed a moderately severe obstructive and restrictive pattern by age 38. Serum alpha-1 antitrypsin level was 224 (normal 85-213) mg/dL and PI phenotype was M1. Karyotype was 46,X-Y with a marked increase in chromosome aberrations induced in vitro by diepoxybutane. The early onset and degree of pulmonary disease in this patient cannot be fully explained by environmental or known genetic causes. The International Fanconi Anemia Registry (IFAR) contains no example of a similar pulmonary presentation. Gene-environment (ecogenetic) interactions in FA seem evident in the final phenotype. The pathogenic mechanism of lung involvement in FA may relate to oxidative injury and cytokine anomalies. 49 refs., 2 figs., 1 tab.

  19. Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations.

    PubMed

    Castella, Maria; Pujol, Roser; Callén, Elsa; Trujillo, Juan P; Casado, José A; Gille, Hans; Lach, Francis P; Auerbach, Arleen D; Schindler, Detlev; Benítez, Javier; Porto, Beatriz; Ferro, Teresa; Muñoz, Arturo; Sevilla, Julián; Madero, Luis; Cela, Elena; Beléndez, Cristina; de Heredia, Cristina Díaz; Olivé, Teresa; de Toledo, José Sánchez; Badell, Isabel; Torrent, Montserrat; Estella, Jesús; Dasí, Angeles; Rodríguez-Villa, Antonia; Gómez, Pedro; Barbot, José; Tapia, María; Molinés, Antonio; Figuera, Angela; Bueren, Juan A; Surrallés, Jordi

    2011-04-01

    Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational "hot-spot" but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations. PMID:21273304

  20. Abnormal response to DNA crosslinking agents of Fanconi anemia fibroblasts can be corrected by transfection with normal human DNA.

    PubMed

    Diatloff-Zito, C; Papadopoulo, D; Averbeck, D; Moustacchi, E

    1986-09-01

    Primary skin fibroblast cell lines from patients with Fanconi anemia were cotransfected with UV-irradiated pSV2neo plasmids and high molecular weight DNA from normal human cells. Restoration of a normal cellular resistance to mitomycin C (MMC) was observed provided that a Fanconi anemia cell line is selected for DNA-mediated transformation (neo gene) and that at least two successive rounds of transfection are performed. Cells were selected by taking advantage of the higher proliferation rate and plating efficiency of the MMC resistant transformants. As estimated from reconstruction experiments, the frequency of transfer of MMC resistance lies between 1 and 30 X 10(-7). The MMC resistance phenotype was maintained for at least 10 generations following transfection. Evidence for DNA-mediated transformation also includes the recovery of a normal pattern of DNA semiconservative synthesis after treatment with 8-methoxypsoralen and 365-nm UV irradiation, and the presence of exogenous pSV2neo DNA sequences was shown by Southern blot analysis. The acquired MMC resistance is probably due to the presence of DNA from normal cells. Indeed, sensitivity to MMC was maintained when Fanconi anemia cells were cotransfected with the UV-irradiated pSV2neo plasmid mixed with their own DNA or with yeast or salmon sperm DNA. These negative results also render unlikely the selection of spontaneous MMC resistant revertants in transfection of Fanconi anemia cells with normal DNA. These experiments establish the prerequisites for the isolation of the gene(s) involved in the response to DNA crosslinking lesions in human cells. PMID:3092225

  1. Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions.

    PubMed

    Velazquez, Isela; Alter, Blanche P

    2004-11-01

    The association between anabolic androgenic steroids and liver tumors was first noted in patients with Fanconi's anemia (FA). The hypotheses which led to this review were as follows: (1) androgen-treated individuals who do not have FA are also at risk of liver tumors; (2) parenteral as well as oral androgens may be responsible for liver tumors; (3) FA patients develop liver tumors after smaller and briefer androgen exposure than non-FA individuals; (4) the risk of hepatic neoplasms may depend on the specific androgen. Medline and Web of Science were searched for all cases of liver tumors associated with androgens. Information from individual cases was entered into a spreadsheet and descriptive statistical analyses were performed. Thirty-six FA cases and 97 non-FA cases with both nonhematologic disorders and acquired aplastic anemia (non-FA AA) were identified. The most common androgens were oxymetholone, methyltestosterone, and danazol. Hepatocellular carcinomas (HCC) were more often associated with oxymetholone and methyltestosterone, while adenomas were associated with danazol. Tumors were reported in six patients who received only parenteral and not oral androgens. FA patients were younger than non-FA patients when androgen use was initiated, and the FA patients developed tumors at younger ages. Non-AA patients were treated with androgens for longer periods of time, compared with FA and non-FA AA patients. All patients on anabolic androgenic steroids are at risk of liver tumors, regardless of underlying diagnosis. The magnitude of the risk cannot be determined from currently available data, because the number of patients receiving androgens is unknown. PMID:15495253

  2. How I treat MDS and AML in Fanconi anemia.

    PubMed

    Peffault de Latour, Régis; Soulier, Jean

    2016-06-16

    Fanconi anemia (FA) is the most frequent inherited cause of bone marrow failure (BMF). Most FA patients experience hematopoietic stem cell attrition and cytopenia during childhood, which along with intrinsic chromosomal instability, favor clonal evolution and the frequent emergence in their teens or young adulthood of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To early identify and further predict bone marrow (BM) clonal progression and enable timely treatment, the follow-up of FA patients includes regular BM morphological and cytogenetic examinations. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment of FA patients with MDS or AML. Although questions remain concerning HSCT itself (including the need for pretransplant chemotherapy, the best conditioning regimen, and the optimal long-term follow-up of such patients especially regarding secondary malignancies), clonal evolution in the absence of significant BM dysplasia and blast cells can be difficult to address in FA patients, for whom the concept of preemptive HSCT is discussed. Illustrated by 3 representative clinical vignettes showing specific features of MDS and AML in FA patients, this paper summarizes our practical approach from diagnosis through treatment in this particular situation. PMID:27020090

  3. Fanconi anemia proteins and the s phase checkpoint.

    PubMed

    Pichierri, Pietro; Rosselli, Filippo

    2004-06-01

    DNA interstrand crosslinks (ICLs) repair represents a formidable task for mammalian cells. Indeed, such DNA lesions, bridging both opposite DNA helices, function as a road-block for every DNA transaction, in particular DNA replication. The eight Fanconi anemia (FA) proteins interact in a common pathway that is thought to be central in ICLs sensing/repair. Interestingly, FA cells, either mutated in one of the proteins composing the FA core complex or in the downstream FA protein FANCD2, exhibited a partial intra-S checkpoint defect in response to crosslinked DNA. Most importantly, the FA proteins work in the ATR-NBS1 branch of the ICL-induced checkpoint pathway as demonstrated by knocking-down CHK1 or MRE11 expression in a FA background. Even though our data disclose a clear functional role for the FA proteins in the intra-S checkpoint response it does not give a definite answer on what FA proteins do in this process and how they participate in the suppression/restart of DNA synthesis. It seems conceivable that FA proteins participate in the process involved in the recovery of stalled replication forks, a common event in proliferating cells, possibly ensuring correct replication fork repair by homologous recombination. PMID:15136767

  4. Alternative donor hematopoietic cell transplantation for Fanconi anemia

    PubMed Central

    DeFor, Todd E.; Young, Jo-Anne H.; Dusenbery, Kathryn E.; Blazar, Bruce R.; Slungaard, Arne; Zierhut, Heather; Weisdorf, Daniel J.; Wagner, John E.

    2015-01-01

    Historically, alternative donor hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) patients resulted in excessive morbidity and mortality. To improve outcomes, we made sequential changes to the HCT conditioning regimen. A total of 130 FA patients (median age, 9.0 years; range, 1-48) underwent alternative donor HCT at the University of Minnesota between 1995 and 2012. All patients received cyclophosphamide (CY), single fraction total body irradiation (TBI), and antithymocyte globulin (ATG) with or without fludarabine (FLU), followed by T-cell–depleted bone marrow or unmanipulated umbilical cord blood transplantation. The addition of FLU enhanced engraftment 3-fold. The incidence of grades 2-4 acute and chronic graft-versus-host disease was 20% and 10%, respectively. Severe toxicity was highest in patients >10 years of age or those with a history of opportunistic infections or transfusions before HCT. Mortality was lowest in patients without a history of opportunistic infection or transfusions and who received conditioning with TBI 300 cGy, CY, FLU, and ATG. These patients had a probability of survival of 94% at 5 years. Alternative donor HCT is now associated with excellent survival for patients without prior opportunistic infections or transfusions and should be considered for all FA patients after the onset of marrow failure. These studies were registered at http://www.clinicaltrials.gov as NCT00005898, NCT00167206, and NCT00352976. PMID:25824692

  5. Fanconi anemia proteins and their interacting partners: a molecular puzzle.

    PubMed

    Kaddar, Tagrid; Carreau, Madeleine

    2012-01-01

    In recent years, Fanconi anemia (FA) has been the subject of intense investigations, primarily in the DNA repair research field. Many discoveries have led to the notion of a canonical pathway, termed the FA pathway, where all FA proteins function sequentially in different protein complexes to repair DNA cross-link damages. Although a detailed architecture of this DNA cross-link repair pathway is emerging, the question of how a defective DNA cross-link repair process translates into the disease phenotype is unresolved. Other areas of research including oxidative metabolism, cell cycle progression, apoptosis, and transcriptional regulation have been studied in the context of FA, and some of these areas were investigated before the fervent enthusiasm in the DNA repair field. These other molecular mechanisms may also play an important role in the pathogenesis of this disease. In addition, several FA-interacting proteins have been identified with roles in these "other" nonrepair molecular functions. Thus, the goal of this paper is to revisit old ideas and to discuss protein-protein interactions related to other FA-related molecular functions to try to give the reader a wider perspective of the FA molecular puzzle. PMID:22737580

  6. A comprehensive strategy for the subtyping of patients with Fanconi anaemia: conclusions from the Spanish Fanconi Anemia Research Network

    PubMed Central

    Casado, José Antonio; Callén, Elsa; Jacome, Ariana; Río, Paula; Castella, Maria; Lobitz, Stephan; Ferro, Teresa; Muñoz, Arturo; Sevilla, Julián; Cantalejo, Ángeles; Cela, Elena; Cervera, José; Sánchez‐Calero, Jesús; Badell, Isabel; Estella, Jesús; Dasí, Ángeles; Olivé, Teresa; Ortega, Juan José; Rodriguez‐Villa, Antonia; Tapia, María; Molinés, Antonio; Madero, Luis; Segovia, José C; Neveling, Kornelia; Kalb, Reinhard; Schindler, Detlev; Hanenberg, Helmut; Surrallés, Jordi; Bueren, Juan A

    2007-01-01

    Background Fanconi anaemia is a heterogeneous genetic disease, where 12 complementation groups have been already described. Identifying the complementation group in patients with Fanconi anaemia constitutes a direct procedure to confirm the diagnosis of the disease and is required for the recruitment of these patients in gene therapy trials. Objective To determine the subtype of Fanconi anaemia patients in Spain, a Mediterranean country with a relatively high population (23%) of Fanconi anaemia patients belonging to the gypsy race. Methods Most patients could be subtyped by retroviral complementation approaches in peripheral blood T cells, although some mosaic patients were subtyped in cultured skin fibroblasts. Other approaches, mainly based on western blot analysis and generation of nuclear RAD51 and FANCJ foci, were required for the subtyping of a minor number of patients. Results and conclusions From a total of 125 patients included in the Registry of Fanconi Anaemia, samples from 102 patients were available for subtyping analyses. In 89 cases the subtype could be determined and in 8 cases exclusions of common complementation groups were made. Compared with other international studies, a skewed distribution of complementation groups was observed in Spain, where 80% of the families belonged to the Fanconi anaemia group A (FA‐A) complementation group. The high proportion of gypsy patients, all of them FA‐A, and the absence of patients with FA‐C account for this characteristic distribution of complementation groups. PMID:17105750

  7. Analysis of 133 meioses places the genes for nevoid basal cell carcinoma (gorlin) syndrome and fanconi anemia group C in a 2.6-cM interval and contributes to the fine map of 9q22.3

    SciTech Connect

    Farndon, P.A.; Hardy, C.; Kilpatrick, M.W.

    1994-09-15

    Four disease genes (NBCCS, ESS1, XPAC, FACC) map to 9q22.3-q31. A fine map of this region was produced by linkage and haplotype analysis using 12 DNA markers. The gene for nevoid basal cell carcinoma syndrome (NBCCS, Gorlin) has an important role in congenital malformations and carcinogenesis. Phase-known recombinants in a study of 133 meioses place NBCCS between (D9S12/D9S151) and D9S176. Haplotype analysis in a two-generation family suggests that NBCCS lies in a smaller interval of 2.6 cM centromeric to D9S287. These flanking markers will be useful clinically for gene tracking. Recombinants also map FACC (Fanconi anemia, group C) to the same region, between (D9S12/D9S151) and D9S287. The recombination rate between (D9S12/D9S151) and D9S53 in males is 8.3% and 13.2% in females, giving a sex-specific male:female ratio of 1:1.6 and a sex-averaged map distance of 10.4 cM. No double recombinants were detected, in agreement with the apparently complete level of interference predicted from the male chiasmata map. 19 refs., 2 figs., 1 tab.

  8. Structure of the FANCI-FANCD2 Complex: Insights into the Fanconi Anemia DNA Repair Pathway

    SciTech Connect

    Joo, Woo; Xu, Guozhou; Persky, Nicole S.; Smogorzewska, Agata; Rudge, Derek G.; Buzovetsky, Olga; Elledge, Stephen J.; Pavletich, Nikola P.

    2011-08-29

    Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the {approx}300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.

  9. Structure of the FANCI-FANCD2 Complex: Insights into the Fanconi Anemia DNA Repair Pathway

    SciTech Connect

    W Joo; G Xu; n Persky; A Smogorzewska; D Rudge; O Buzovetsky; S Elledge; N Pavletich

    2011-12-31

    Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the {approx}300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.

  10. Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology

    PubMed Central

    De Rocco, Daniela; Bottega, Roberta; Cappelli, Enrico; Cavani, Simona; Criscuolo, Maria; Nicchia, Elena; Corsolini, Fabio; Greco, Chiara; Borriello, Adriana; Svahn, Johanna; Pillon, Marta; Mecucci, Cristina; Casazza, Gabriella; Verzegnassi, Federico; Cugno, Chiara; Locasciulli, Anna; Farruggia, Piero; Longoni, Daniela; Ramenghi, Ugo; Barberi, Walter; Tucci, Fabio; Perrotta, Silverio; Grammatico, Paola; Hanenberg, Helmut; Della Ragione, Fulvio; Dufour, Carlo; Savoia, Anna

    2014-01-01

    Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes. PMID:24584348

  11. Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology.

    PubMed

    De Rocco, Daniela; Bottega, Roberta; Cappelli, Enrico; Cavani, Simona; Criscuolo, Maria; Nicchia, Elena; Corsolini, Fabio; Greco, Chiara; Borriello, Adriana; Svahn, Johanna; Pillon, Marta; Mecucci, Cristina; Casazza, Gabriella; Verzegnassi, Federico; Cugno, Chiara; Locasciulli, Anna; Farruggia, Piero; Longoni, Daniela; Ramenghi, Ugo; Barberi, Walter; Tucci, Fabio; Perrotta, Silverio; Grammatico, Paola; Hanenberg, Helmut; Della Ragione, Fulvio; Dufour, Carlo; Savoia, Anna

    2014-06-01

    Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes. PMID:24584348

  12. Identification of de Novo Fanconi Anemia in Younger Patients With Newly Diagnosed Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-05-13

    Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Fanconi Anemia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  13. Oral human papillomavirus is common in individuals with Fanconi anemia

    PubMed Central

    Sauter, Sharon L.; Wells, Susanne I.; Zhang, Xue; Hoskins, Elizabeth E.; Davies, Stella M.; Myers, Kasiani C.; Mueller, Robin; Panicker, Gitika; Unger, Elizabeth R.; Sivaprasad, Umasundari; Brown, Darron R.; Mehta, Parinda A.; Butsch Kovacic, Melinda

    2015-01-01

    Background Fanconi Anemia (FA) is a rare genetic disorder resulting in a loss of function of the FA-related DNA repair pathway. Individuals with FA are predisposed to some cancers including oropharyngeal and gynecological cancers with known associations with human papillomavirus (HPV) in the general population. Since individuals with FA respond poorly to chemotherapy and radiation, prevention of cancer is critical. Methods To determine if individuals with FA are particularly susceptible to oral HPV infection, we analyzed survey-based risk factor data and tested DNA isolated from oral rinses from 126 individuals with FA and 162 unaffected first-degree family members for 37 HPV types. Results Fourteen individuals (11.1%) with FA tested positive, significantly more (p=0.003) than family members (2.5%). While HPV prevalence was even higher for sexually active individuals with FA (17.7% vs. 2.4% in family; p=0.003), HPV positivity also tended to be higher in the sexually inactive (8.7% in FA vs. 2.9% in siblings). Indeed, having FA increased HPV positivity 4.9 fold (95%CI: 1.6–15.4) considering age and sexual experience, but did not differ by other potential risk factors. Conclusion Our studies suggest that oral HPV is more common in individuals with FA. It will be essential to continue to explore associations between risk factors and immune dysfunction on HPV incidence and persistence over time. Impact HPV vaccination should be emphasized in those with FA as a first step to prevent oropharyngeal cancers, although additional studies are needed to determine if the level of protection it offers in this population is adequate. PMID:25809863

  14. Damaged mitochondria in Fanconi anemia – an isolated event or a general phenomenon?

    PubMed Central

    Pagano, Giovanni; Shyamsunder, Pavithra; Verma, Rama S.; Lyakhovich, Alex

    2014-01-01

    Fanconi anemia (FA) is known as an inherited bone marrow failure syndrome associated with cancer predisposition and susceptibility to a number of DNA damaging stimuli, along with a number of clinical features such as upper limb malformations, increased diabetes incidence and typical anomalies in skin pigmentation. The proteins encoded by FA-defective genes (FANC proteins) display well-established roles in DNA damage and repair pathways. Moreover, some independent studies have revealed that mitochondrial dysfunction (MDF) is also involved in FA phenotype. Unconfined to FA, we have shown that other syndromes featuring DNA damage and repair (such as ataxia-telangiectasia, AT, and Werner syndrome, WS) display MDF-related phenotypes, along with oxidative stress (OS) that, altogether, may play major roles in these diseases. Experimental and clinical studies are warranted in the prospect of future therapies to be focused on compounds scavenging reactive oxygen species (ROS) as well as protecting mitochondrial functions. PMID:25594021

  15. The Fanconi anemia ID2 complex: Dueling saxes at the crossroads

    PubMed Central

    Boisvert, Rebecca A; Howlett, Niall G

    2014-01-01

    Fanconi anemia (FA) is a rare recessive genetic disease characterized by congenital abnormalities, bone marrow failure and heightened cancer susceptibility in early adulthood. FA is caused by biallelic germ-line mutation of any one of 16 genes. While several functions for the FA proteins have been ascribed, the prevailing hypothesis is that the FA proteins function cooperatively in the FA-BRCA pathway to repair damaged DNA. A pivotal step in the activation of the FA-BRCA pathway is the monoubiquitination of the FANCD2 and FANCI proteins. Despite their importance for DNA repair, the domain structure, regulation, and function of FANCD2 and FANCI remain poorly understood. In this review, we provide an overview of our current understanding of FANCD2 and FANCI, with an emphasis on their posttranslational modification and common and unique functions. PMID:25486561

  16. Congenital malformations and developmental disabilities in ataxia-telangiectasia, Fanconi anemia, and xeroderma pigmentosum families.

    PubMed

    Welshimer, K; Swift, M

    1982-09-01

    Heterozygous carriers of an ataxia-telangiectasia (A-T), Fanconi anemia (FA), or xeroderma pigmentosum (XP) gene may be predisposed to some of the same congenital malformations or developmental disabilities that are common among homozygotes. To test this hypothesis, medical records, death certificates, and questionnaires from 27 A-T families, 25 FA families, and 31 XP families were reviewed. Eleven XP blood relatives (out of 1,100) were found with moderate or severe unexplained mental retardation, a significant excess compared to the FA and A-T families (3/1,439). There were four microcephalic XP blood relatives and none in the FA or A-T families. In the A-T families, idiopathic scoliosis and vertebral anomalies were in excess, while genitourinary and distal limb malformations were found in the FA families. A-T, FA, or XP heterozygotes may constitute an important proportion of individuals at risk for specific malformations or developmental abnormalities. PMID:7124732

  17. Congenital malformations and developmental disabilities in ataxia-telangiectasia, Fanconi anemia, and xeroderma pigmentosum families.

    PubMed Central

    Welshimer, K; Swift, M

    1982-01-01

    Heterozygous carriers of an ataxia-telangiectasia (A-T), Fanconi anemia (FA), or xeroderma pigmentosum (XP) gene may be predisposed to some of the same congenital malformations or developmental disabilities that are common among homozygotes. To test this hypothesis, medical records, death certificates, and questionnaires from 27 A-T families, 25 FA families, and 31 XP families were reviewed. Eleven XP blood relatives (out of 1,100) were found with moderate or severe unexplained mental retardation, a significant excess compared to the FA and A-T families (3/1,439). There were four microcephalic XP blood relatives and none in the FA or A-T families. In the A-T families, idiopathic scoliosis and vertebral anomalies were in excess, while genitourinary and distal limb malformations were found in the FA families. A-T, FA, or XP heterozygotes may constitute an important proportion of individuals at risk for specific malformations or developmental abnormalities. PMID:7124732

  18. Interplay between Fanconi anemia and homologous recombination pathways in genome integrity.

    PubMed

    Michl, Johanna; Zimmer, Jutta; Tarsounas, Madalena

    2016-05-01

    The Fanconi anemia (FA) pathway plays a central role in the repair of DNA interstrand crosslinks (ICLs) and regulates cellular responses to replication stress. Homologous recombination (HR), the error-free pathway for double-strand break (DSB) repair, is required during physiological cell cycle progression for the repair of replication-associated DNA damage and protection of stalled replication forks. Substantial crosstalk between the two pathways has recently been unravelled, in that key HR proteins such as the RAD51 recombinase and the tumour suppressors BRCA1 and BRCA2 also play important roles in ICL repair. Consistent with this, rare patient mutations in these HR genes cause FA pathologies and have been assigned FA complementation groups. Here, we focus on the clinical and mechanistic implications of the connection between these two cancer susceptibility syndromes and on how these two molecular pathways of DNA replication and repair interact functionally to prevent genomic instability. PMID:27037238

  19. Dearth and Delayed Maturation of Testicular Germ Cells in Fanconi Anemia E Mutant Male Mice

    PubMed Central

    Fu, Chun; Begum, Khurshida; Jordan, Philip W.; He, Yan; Overbeek, Paul A.

    2016-01-01

    After using a self-inactivating lentivirus for non-targeted insertional mutagenesis in mice, we identified a transgenic family with a recessive mutation that resulted in reduced fertility in homozygous transgenic mice. The lentiviral integration site was amplified by inverse PCR. Sequencing revealed that integration had occurred in intron 8 of the mouse Fance gene, which encodes the Fanconi anemia E (Fance) protein. Fanconi anemia (FA) proteins play pivotal roles in cellular responses to DNA damage and Fance acts as a molecular bridge between the FA core complex and Fancd2. To investigate the reduced fertility in the mutant males, we analyzed postnatal development of testicular germ cells. At one week after birth, most tubules in the mutant testes contained few or no germ cells. Over the next 2–3 weeks, germ cells accumulated in a limited number of tubules, so that some tubules contained germ cells around the full periphery of the tubule. Once sufficient numbers of germ cells had accumulated, they began to undergo the later stages of spermatogenesis. Immunoassays revealed that the Fancd2 protein accumulated around the periphery of the nucleus in normal developing spermatocytes, but we did not detect a similar localization of Fancd2 in the Fance mutant testes. Our assays indicate that although Fance mutant males are germ cell deficient at birth, the extant germ cells can proliferate and, if they reach a threshold density, can differentiate into mature sperm. Analogous to previous studies of FA genes in mice, our results show that the Fance protein plays an important, but not absolutely essential, role in the initial developmental expansion of the male germ line. PMID:27486799

  20. Increased radiosensitivity of a subpopulation of T-lymphocyte progenitors from patients with Fanconi's anemia

    SciTech Connect

    Knox, S.J.; Wilson, F.D.; Greenberg, B.R.; Shifrine, M.; Rosenblatt, L.S.; Reeves, J.D.; Misra, H.

    1981-06-01

    In vitro radiation survival of peripheral blood T lymphocytes was studied in 15 clinically normal adults and 4 patients with Fanconi's anemia. Tritiated thymidine incorporation in a whole blood lymphocyte stimulation test (LST) and a newly developed whole blood T-lymphocyte colony assay were used to measure lymphocyte blastogenesis and colony formation in response to phytohemagglutinin (PHA) or concanavalin-A (Con-A) stimulation. Lymphocyte colony formation was found to be consistently more sensitive than the LST for detection of low-level radiation effects using both normal cells and lymphocytes from Fanconi's anemia patients. Lymphocytes from patients with Fanconi's anemia were significantly more sensitive to in vitro x irradiation than lymphocytes from clinically normal individuals as measured by their ability to divide when stimulated by PHA in the LST and colony formation assay. No significant difference in the radiosensitivity of the Con-A response was observed between the two groups. The PHA-responsive T-lymphocyte subpopulation in Fanconi's anemia patients appears to be intrinsically defective. The nature of this defect, significance in the disease process, and relevancy of these findings to the establishment of radiation protection standards are discussed.

  1. Increased radiosensitivity of a subpopulation ot T-lymphocyte progenitors from patients with Fanconi's anemia

    SciTech Connect

    Knox, S.J.; Wilson, F.D.; Greenberg, B.R.; Shifrine, M.; Rosenblatt, L.S.; Reeves, J.D.; Misra, H.

    1981-06-01

    In vitro radiation survival of peripheral blood T lymphocytes was studied in 15 clinically normal adults and 4 patients with Fanconi's anemia. Tritiated thymidine incorporation in a whole blood lymphocyte stimulation test (LST) and a newly developed whole blood T-lymphocyte colony assay were used to measure lymphocyte blastogenesis and colony formation in response to phytohemagglutinin (PHA) or concanavalin-A (Con-A) stimulation. Lymphocyte colony formation was found to be consistently more sensitive than the LST for detection of low-level radiation effects using both normal cells and lymphocytes from Fanconi's anemia patients. Lymphocytes from patients with Fanconi's anemia were significantly more sensitive to in vitro x-irradiation than lymphocytes from clinically normal individuals as measured by their ability to divide when stimulated by PHA in the LST (patients, D37 . 198 R; normals, D37 . 309 R, p . 0.057) and colony formation assay (patients, D37 . 53 R; normals, D37 . 109 R, p . 0.016). No significant difference in the radiosensitivity of the Con-A response was observed between the two groups. The PHA-responsive T-lymphocyte subpopulation in Fanconi's anemia patients appears to be intrinsically defective. The nature of this defect, significance in the disease process, and relevancy of these findings to the establishment of radiation protection standards are discussed.

  2. TGF-β Pathway Inhibition Signals New Hope for Fanconi Anemia.

    PubMed

    Tummala, Hemanth; Dokal, Inderjeet

    2016-05-01

    An improved understanding of the bone marrow failure (BMF) mechanisms in Fanconi anemia (FA) may improve current therapeutic strategies. Zhang et al. identify hyperactive TGF-β signaling as an underlying cause of BMF in FA mice and patient cells, whose inhibition promotes DNA repair and hematopoietic stem and progenitor cell survival. PMID:27152440

  3. The ubiquitin family meets the Fanconi anemia proteins.

    PubMed

    Renaudin, Xavier; Koch Lerner, Leticia; Menck, Carlos Frederico Martins; Rosselli, Filippo

    2016-01-01

    Fanconi anaemia (FA) is a hereditary disorder characterized by bone marrow failure, developmental defects, predisposition to cancer and chromosomal abnormalities. FA is caused by biallelic mutations that inactivate genes encoding proteins involved in replication stress-associated DNA damage responses. The 20 FANC proteins identified to date constitute the FANC pathway. A key event in this pathway involves the monoubiquitination of the FANCD2-FANCI heterodimer by the collective action of at least 10 different proteins assembled in the FANC core complex. The FANC core complex-mediated monoubiquitination of FANCD2-FANCI is essential to assemble the heterodimer in subnuclear, chromatin-associated, foci and to regulate the process of DNA repair as well as the rescue of stalled replication forks. Several recent works have demonstrated that the activity of the FANC pathway is linked to several other protein post-translational modifications from the ubiquitin-like family, including SUMO and NEDD8. These modifications are related to DNA damage responses but may also affect other cellular functions potentially related to the clinical phenotypes of the syndrome. This review summarizes the interplay between the ubiquitin and ubiquitin-like proteins and the FANC proteins that constitute a major pathway for the surveillance of the genomic integrity and addresses the implications of their interactions in maintaining genome stability. PMID:27543315

  4. Fanconi Anemia Proteins, DNA Interstrand Crosslink Repair Pathways, and Cancer Therapy

    PubMed Central

    Andreassen, Paul R.; Ren, Keqin

    2016-01-01

    DNA interstrand crosslinkers, a chemically diverse group of compounds which also induce alkylation of bases and DNA intrastrand crosslinks, are extensively utilized for cancer therapy. Understanding the cellular response to DNA damage induced by these agents is critical for more effective utilization of these compounds and for the identification of novel therapeutic targets. Importantly, the repair of DNA interstrand crosslinks (ICLs) involves many distinct DNA repair pathways, including nucleotide excision repair, translesion synthesis (TLS), and homologous recombination (HR). Additionally, proteins implicated in the pathophysiology of the multigenic disease Fanconi anemia (FA) have a role in the repair of ICLs that is not well understood. Cells from FA patients are hypersensitive to agents that induce ICLs, therefore FA proteins are potentially novel therapeutic targets. Here we will review current research directed at identifying FA genes and understanding the function of FA proteins in DNA damage responses. We will also examine interactions of FA proteins with other repair proteins and pathways, including signaling networks, which are potentially involved in ICL repair. Potential approaches to the modulation of FA protein function to enhance therapeutic outcome will be discussed. Also, mutation of many genes that encode proteins involved in ICL repair, including FA genes, increases susceptibility to cancer. A better understanding of these pathways is therefore critical for the design of individualized therapies tailored to the genetic profile of a particular malignancy. For this purpose, we will also review evidence for the association of mutation of FA genes with cancer in non-FA patients. PMID:19200054

  5. Brief report: human pluripotent stem cell models of fanconi anemia deficiency reveal an important role for fanconi anemia proteins in cellular reprogramming and survival of hematopoietic progenitors.

    PubMed

    Yung, Sun K; Tilgner, Katarzyna; Ledran, Maria H; Habibollah, Saba; Neganova, Irina; Singhapol, Chatchawan; Saretzki, Gabriele; Stojkovic, Miodrag; Armstrong, Lyle; Przyborski, Stefan; Lako, Majlinda

    2013-05-01

    Fanconi anemia (FA) is a genomic instability disorder caused by mutations in genes involved in replication-dependant-repair and removal of DNA cross-links. Mouse models with targeted deletions of FA genes have been developed; however, none of these exhibit the human bone marrow aplasia. Human embryonic stem cell (hESC) differentiation recapitulates many steps of embryonic hematopoietic development and is a useful model system to investigate the early events of hematopoietic progenitor specification. It is now possible to derive patient-specific human-induced pluripotent stem cells (hiPSC); however, this approach has been rather difficult to achieve in FA cells due to a requirement for activation of FA pathway during reprogramming process which can be bypassed either by genetic complementation or reprogramming under hypoxic conditions. In this study, we report that FA-C patient-specific hiPSC lines can be derived under normoxic conditions, albeit at much reduced efficiency. These disease-specific hiPSC lines and hESC with stable knockdown of FANCC display all the in vitro hallmarks of pluripotency. Nevertheless, the disease-specific hiPSCs show a much higher frequency of chromosomal abnormalities compared to parent fibroblasts and are unable to generate teratoma composed of all three germ layers in vivo, likely due to increased genomic instability. Both FANCC-deficient hESC and hiPSC lines are capable of undergoing hematopoietic differentiation, but the hematopoietic progenitors display an increased apoptosis in culture and reduced clonogenic potential. Together these data highlight the critical requirement for FA proteins in survival of hematopoietic progenitors, cellular reprogramming, and maintenance of genomic stability. PMID:23280624

  6. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.

    PubMed

    Bogliolo, Massimo; Schuster, Beatrice; Stoepker, Chantal; Derkunt, Burak; Su, Yan; Raams, Anja; Trujillo, Juan P; Minguillón, Jordi; Ramírez, María J; Pujol, Roser; Casado, José A; Baños, Rocío; Rio, Paula; Knies, Kerstin; Zúñiga, Sheila; Benítez, Javier; Bueren, Juan A; Jaspers, Nicolaas G J; Schärer, Orlando D; de Winter, Johan P; Schindler, Detlev; Surrallés, Jordi

    2013-05-01

    Fanconi anemia (FA) is a rare genomic instability disorder characterized by progressive bone marrow failure and predisposition to cancer. FA-associated gene products are involved in the repair of DNA interstrand crosslinks (ICLs). Fifteen FA-associated genes have been identified, but the genetic basis in some individuals still remains unresolved. Here, we used whole-exome and Sanger sequencing on DNA of unclassified FA individuals and discovered biallelic germline mutations in ERCC4 (XPF), a structure-specific nuclease-encoding gene previously connected to xeroderma pigmentosum and segmental XFE progeroid syndrome. Genetic reversion and wild-type ERCC4 cDNA complemented the phenotype of the FA cell lines, providing genetic evidence that mutations in ERCC4 cause this FA subtype. Further biochemical and functional analysis demonstrated that the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in DNA ICL repair without severely compromising nucleotide excision repair. Our data show that depending on the type of ERCC4 mutation and the resulting balance between both DNA repair activities, individuals present with one of the three clinically distinct disorders, highlighting the multifunctional nature of the XPF endonuclease in genome stability and human disease. PMID:23623386

  7. Finnish Fanconi anemia mutations and hereditary predisposition to breast and prostate cancer.

    PubMed

    Mantere, T; Haanpää, M; Hanenberg, H; Schleutker, J; Kallioniemi, A; Kähkönen, M; Parto, K; Avela, K; Aittomäki, K; von Koskull, H; Hartikainen, J M; Kosma, V-M; Laasanen, S-L; Mannermaa, A; Pylkäs, K; Winqvist, R

    2015-07-01

    Mutations in downstream Fanconi anemia (FA) pathway genes, BRCA2, PALB2, BRIP1 and RAD51C, explain part of the hereditary breast cancer susceptibility, but the contribution of other FA genes has remained questionable. Due to FA's rarity, the finding of recurrent deleterious FA mutations among breast cancer families is challenging. The use of founder populations, such as the Finns, could provide some advantage in this. Here, we have resolved complementation groups and causative mutations of five FA patients, representing the first mutation confirmed FA cases in Finland. These patients belonged to complementation groups FA-A (n = 3), FA-G (n = 1) and FA-I (n = 1). The prevalence of the six FA causing mutations was then studied in breast (n = 1840) and prostate (n = 565) cancer cohorts, and in matched controls (n = 1176 females, n = 469 males). All mutations were recurrent, but no significant association with cancer susceptibility was observed for any: the prevalence of FANCI c.2957_2969del and c.3041G>A mutations was even highest in healthy males (1.7%). This strengthens the exclusive role of downstream genes in cancer predisposition. From a clinical point of view, current results provide fundamental information of the mutations to be tested first in all suspected FA cases in Finland. PMID:24989076

  8. Hypomutability in Fanconi anemia cells is associated with increased deletion frequency at the HPRT locus

    SciTech Connect

    Papadopoulo, D.; Guillouf, C.; Moustacchi, E. ); Mohrenweiser, H. )

    1990-11-01

    Fanconi anemia (FA) is an inherited human disorder associated with a predisposition to cancer and characterized by anomalies in the processing of DNA cross-links and certain monoadducts. The authors reported previously that the frequency of psoralen-photoinduced mutations at the HPRT locus is lower in FA cells than in normal cells. This hypomutability is shown here to be associated with an increased frequency of deletions in the HPRT gene when either a mixture of cross-links and monoadducts or monoadducts alone are induced. Molecular analysis of mutants in the HPRT gene was carried out. In normal cells the majority of spontaneous and induced mutants are point mutations whereas in FA deletion mutations predominate. In that case a majority of mutants were found to lack individual exons or small clusters of exons whereas in normal cells large (complete or major gene loss) and small deletions are almost equally represented. Thus they propose that the FA defect lies in a mutagenic pathway that, in normal cells, involves by passing lesions and subsequent gap filling by a recombinational process during replication.

  9. Dental Perspective of Rare Disease of Fanconi Anemia: Case Report with Review

    PubMed Central

    Goswami, Mridula; Bhushan, Urvashi; Goswami, Manoj

    2016-01-01

    Fanconi anemia is an extremely rare genetic disease characterized by chromosomal instability that induces congenital alterations in individuals. It causes defective hemopoiesis ultimately leading to bone marrow failure. Patients are susceptible to recurrent infections and increased risk of hemorrhage, as well as delayed and poor wound healing. Herein, we report a case of Fanconi anemia in which various classical signs of the disease were present. The patient has been on regular follow-up since three and a half years for management of dental problems. The different aspects of this rare disorder are discussed with emphasis on oral manifestations and their influence on the general health of affected patients. Due to an increased susceptibility to developing cancers in this specific population, it is imperative for pediatric dentists to know about the common oral manifestations and potentially cancerous lesions, in order to make an early diagnosis and provide comprehensive care and maintenance of oral health in affected individuals. PMID:27013901

  10. Homology-directed Fanconi anemia pathway crosslink repair is dependent on DNA replication

    PubMed Central

    Nakanishi, Koji; Cavallo, Francesca; Perrouault, Loïc; Giovannangeli, Carine; Moynahan, Mary Ellen; Barchi, Marco; Brunet, Erika; Jasin, Maria

    2012-01-01

    Homologous recombination (also termed homology-directed repair, HDR) is a major pathway for the repair of DNA interstrand crosslinks (ICLs) in mammalian cells. Cells from Fanconi anemia (FA) patients are characterized by extreme ICL sensitivity, but their reported defect in HDR is mild. Here, we examined ICL-induced HDR using a GFP reporter and observed a profound defect in ICL-induced HDR in FA cells, but only when the reporter could replicate. PMID:21423196

  11. Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia

    PubMed Central

    Lach, Francis P.; Kimble, Danielle C.; Kamat, Aparna; Teer, Jamie K.; Donovan, Frank X.; Flynn, Elizabeth; Sen, Shurjo K.; Thongthip, Supawat; Sanborn, Erica; Smogorzewska, Agata; Ostrander, Elaine A.

    2013-01-01

    Current methods for detecting mutations in Fanconi anemia (FA)–suspected patients are inefficient and often miss mutations. We have applied recent advances in DNA sequencing and genomic capture to the diagnosis of FA. Specifically, we used custom molecular inversion probes or TruSeq-enrichment oligos to capture and sequence FA and related genes, including introns, from 27 samples from the International Fanconi Anemia Registry at The Rockefeller University. DNA sequencing was complemented with custom array comparative genomic hybridization (aCGH) and RNA sequencing (RNA-seq) analysis. aCGH identified deletions/duplications in 4 different FA genes. RNA-seq analysis revealed lack of allele specific expression associated with a deletion and splicing defects caused by missense, synonymous, and deep-in-intron variants. The combination of TruSeq-targeted capture, aCGH, and RNA-seq enabled us to identify the complementation group and biallelic germline mutations in all 27 families: FANCA (7), FANCB (3), FANCC (3), FANCD1 (1), FANCD2 (3), FANCF (2), FANCG (2), FANCI (1), FANCJ (2), and FANCL (3). FANCC mutations are often the cause of FA in patients of Ashkenazi Jewish (AJ) ancestry, and we identified 2 novel FANCC mutations in 2 patients of AJ ancestry. We describe here a strategy for efficient molecular diagnosis of FA. PMID:23613520

  12. Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice

    PubMed Central

    Houghtaling, Scott; Timmers, Cynthia; Noll, Meenakshi; Finegold, Milton J.; Jones, Stephen N.; Meyn, M. Stephen; Grompe, Markus

    2003-01-01

    Fanconi anemia (FA) is a genetic disorder characterized by hypersensitivity to DNA damage, bone marrow failure, congenital defects, and cancer. To further investigate the in vivo function of the FA pathway, mice with a targeted deletion in the distally acting FA gene Fancd2 were created. Similar to human FA patients and other FA mouse models, Fancd2 mutant mice exhibited cellular sensitivity to DNA interstrand cross-links and germ cell loss. In addition, chromosome mispairing was seen in male meiosis. However, Fancd2 mutant mice also displayed phenotypes not observed in other mice with disruptions of proximal FA genes. These include microphthalmia, perinatal lethality, and epithelial cancers, similar to mice with Brca2/Fancd1 hypomorphic mutations. These additional phenotypes were not caused by defects in the ATM-mediated S-phase checkpoint, which was intact in primary Fancd2 mutant fibroblasts. The phenotypic overlap between Fancd2-null and Brca2/Fancd1 hypomorphic mice is consistent with a common function for both proteins in the same pathway, regulating genomic stability. PMID:12893777

  13. Lentiviral-mediated genetic correction of hematopoietic and mesenchymal progenitor cells from Fanconi anemia patients.

    PubMed

    Jacome, Ariana; Navarro, Susana; Río, Paula; Yañez, Rosa M; González-Murillo, Africa; Lozano, M Luz; Lamana, Maria Luisa; Sevilla, Julian; Olive, Teresa; Diaz-Heredia, Cristina; Badell, Isabel; Estella, Jesus; Madero, Luis; Guenechea, Guillermo; Casado, José; Segovia, Jose C; Bueren, Juan A

    2009-06-01

    Previous clinical trials based on the genetic correction of purified CD34(+) cells with gamma-retroviral vectors have demonstrated clinical efficacy in different monogenic diseases, including X-linked severe combined immunodeficiency, adenosine deaminase deficient severe combined immunodeficiency and chronic granulomatous disease. Similar protocols, however, failed to engraft Fanconi anemia (FA) patients with genetically corrected cells. In this study, we first aimed to correlate the hematological status of 27 FA patients with CD34(+) cell values determined in their bone marrow (BM). Strikingly, no correlation between these parameters was observed, although good correlations were obtained when numbers of colony-forming cells (CFCs) were considered. Based on these results, and because purified FA CD34(+) cells might have suboptimal repopulating properties, we investigated the possibility of genetically correcting unselected BM samples from FA patients. Our data show that the lentiviral transduction of unselected FA BM cells mediates an efficient phenotypic correction of hematopoietic progenitor cells and also of CD34(-) mesenchymal stromal cells (MSCs), with a reported role in hematopoietic engraftment. Our results suggest that gene therapy protocols appropriate for the treatment of different monogenic diseases may not be adequate for stem cell diseases like FA. We propose a new approach for the gene therapy of FA based on the rapid transduction of unselected hematopoietic grafts with lentiviral vectors (LVs). PMID:19277017

  14. Lentiviral-mediated Genetic Correction of Hematopoietic and Mesenchymal Progenitor Cells From Fanconi Anemia Patients

    PubMed Central

    Jacome, Ariana; Navarro, Susana; Río, Paula; Yañez, Rosa M; González-Murillo, Africa; Luz Lozano, M; Lamana, Maria Luisa; Sevilla, Julian; Olive, Teresa; Diaz-Heredia, Cristina; Badell, Isabel; Estella, Jesus; Madero, Luis; Guenechea, Guillermo; Casado, José; Segovia, Jose C; Bueren, Juan A

    2009-01-01

    Previous clinical trials based on the genetic correction of purified CD34+ cells with γ-retroviral vectors have demonstrated clinical efficacy in different monogenic diseases, including X-linked severe combined immunodeficiency, adenosine deaminase deficient severe combined immunodeficiency and chronic granulomatous disease. Similar protocols, however, failed to engraft Fanconi anemia (FA) patients with genetically corrected cells. In this study, we first aimed to correlate the hematological status of 27 FA patients with CD34+ cell values determined in their bone marrow (BM). Strikingly, no correlation between these parameters was observed, although good correlations were obtained when numbers of colony-forming cells (CFCs) were considered. Based on these results, and because purified FA CD34+ cells might have suboptimal repopulating properties, we investigated the possibility of genetically correcting unselected BM samples from FA patients. Our data show that the lentiviral transduction of unselected FA BM cells mediates an efficient phenotypic correction of hematopoietic progenitor cells and also of CD34− mesenchymal stromal cells (MSCs), with a reported role in hematopoietic engraftment. Our results suggest that gene therapy protocols appropriate for the treatment of different monogenic diseases may not be adequate for stem cell diseases like FA. We propose a new approach for the gene therapy of FA based on the rapid transduction of unselected hematopoietic grafts with lentiviral vectors (LVs). PMID:19277017

  15. Complementation of a Fanconi anemia group A cell line by UbA{sup 52}

    SciTech Connect

    Moses, R.E.; Heina, J.A.; Jakobs, P.M.

    1994-09-01

    Cells from patients with Fanconi anemia (FA) display chromosomal instability and increased sensitivity to mitomycin C (MMC) and diepoxybutane (DEB) relative to normal cells. Several genes act in this pathway of DNA damage processing based upon four known complementation groups in FA. We have made a cDNA expression library in a vector with a G418 selectable marker to identify FA genes other than the FA-C group. Approximately 1 x 10{sup 6} independent cDNA clones were isolated with an average cDNA size of 1.5 kb. Five cell lines resistant to MMC and DEB were isolated from 6 x 10{sup 6} G418-resistant transfectants from 65 individual transfections of the FA-A fibroblast line GM6914. The isolated cell lines also showed normal chromosome stability. The same cDNA (600 bp) was recovered from three independent cell lines by PCR using flanking sequence primers. The gene has sequence identity with a known gene, the ubiquitin fusion gene, UbA{sub 52}. Interestingly, each of the cDNAs were inserted in antisense orientation relative to the cytomegalovirus (CMV) promoter as determined by sequencing and PCR using UbA{sub 52}-specific internal primers. Southern blot analysis indicated the cell lines had distinct chromosomal insertion sites. Mutation analysis by chemical cleavage showed no reading frame mutations, indicating that UbA{sub 52} is not the FA-A gene. Re-transfection with the UbA{sub 52} gene in antisense gave complementation for MMC, DEB and chromosome stability to varying degrees. Re-transfection of the antisense construct with the CMV promotor removed or with a sense construct did not alter the MMC sensitivity. We conclude that the antisense UbA{sub 52} gene has a non-specific effect, perhaps acting by altering the cell cycle or susceptibility to apoptosis.

  16. Modeling Fanconi Anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs

    PubMed Central

    Montserrat, Nuria; Tarantino, Carolina; Gu, Ying; Yi, Fei; Xu, Xiuling; Zhang, Weiqi; Ruiz, Sergio; Plongthongkum, Nongluk; Zhang, Kun; Masuda, Shigeo; Nivet, Emmanuel; Tsunekawa, Yuji; Soligalla, Rupa Devi; Goebl, April; Aizawa, Emi; Kim, Na Young; Kim, Jessica; Dubova, Ilir; Li, Ying; Ren, Ruotong; Benner, Chris; del Sol, Antonio; Bueren, Juan; Trujillo, Juan Pablo; Surralles, Jordi; Cappelli, Enrico; Dufour, Carlo; Esteban, Concepcion Rodriguez; Belmonte, Juan Carlos Izpisua

    2014-01-01

    Fanconi Anemia (FA) is a recessive disorder characterized by genomic instability, congenital abnormalities, cancer predisposition and bone marrow failure. However, the pathogenesis of FA is not fully understood partly due to the limitations of current disease models. Here, we derive integration-free induced pluripotent stem cells (iPSCs) from an FA patient without genetic complementation and report in situ gene correction in FA-iPSCs as well as the generation of isogenic FANCA deficient human embryonic stem cell (ESC) lines. FA cellular phenotypes are recapitulated in iPSCs/ESCs and their adult stem/progenitor cell derivatives. By using isogenic pathogenic mutation-free controls as well as cellular and genomic tools, our model serves to facilitate the discovery of novel disease features. We validate our model as a drug-screening platform by identifying several compounds that improve hematopoietic differentiation of FA-iPSCs. These compounds are also able to rescue the hematopoietic phenotype of FA-patient bone marrow cells. PMID:24999918

  17. ATM-dependent Phosphorylation of the Fanconi Anemia Protein PALB2 Promotes the DNA Damage Response.

    PubMed

    Guo, Yingying; Feng, Wanjuan; Sy, Shirley M H; Huen, Michael S Y

    2015-11-13

    The Fanconi anemia protein PALB2, also known as FANCN, protects genome integrity by regulating DNA repair and cell cycle checkpoints. Exactly how PALB2 functions may be temporally coupled with detection and signaling of DNA damage is not known. Intriguingly, we found that PALB2 is transformed into a hyperphosphorylated state in response to ionizing radiation (IR). IR treatment specifically triggered PALB2 phosphorylation at Ser-157 and Ser-376 in manners that required the master DNA damage response kinase Ataxia telangiectasia mutated, revealing potential mechanistic links between PALB2 and the Ataxia telangiectasia mutated-dependent DNA damage responses. Consistently, dysregulated PALB2 phosphorylation resulted in sustained activation of DDRs. Full-blown PALB2 phosphorylation also required the breast and ovarian susceptible gene product BRCA1, highlighting important roles of the BRCA1-PALB2 interaction in orchestrating cellular responses to genotoxic stress. In summary, our phosphorylation analysis of tumor suppressor protein PALB2 uncovers new layers of regulatory mechanisms in the maintenance of genome stability and tumor suppression. PMID:26420486

  18. Programmable Bio-Nano-Chip based Cytologic Testing of Oral Potentially Malignant Disorders in Fanconi Anemia

    PubMed Central

    Floriano, Pierre; Abram, Tim; Taylor, Leander; Le, Cathy; Talavera, Humberto; Nguyen, Michael; Raja, Rameez; Gillenwater, Ann; McDevitt, John; Vigneswaran, Nadarajah

    2015-01-01

    Fanconi anemia (FA) is caused by mutations of DNA repair genes. The risk of oral squamous cell carcinoma (OSCC) among FA patients is 800-folds higher than in the general population. Early detection of OSCC, preferably at it precursor stage is critical in FA patients to improve their survival. In an ongoing clinical trial, we are evaluating the effectiveness of the programmable bio-nano-chip (p-BNC)-based oral cytology test in diagnosing oral potentially malignant disorders (OPMD) in non-FA patients. We used this test to compare the cytomorphometric and molecular biomarkers in OSCC cell lines derived from FA patients and non-FA patients and brush biopsy samples of a FA patient’s OPMD and normal mucosa of healthy volunteers. Our data showed that expression patterns of molecular biomarkers were not notably different between sporadic and FA OSCC cell lines. The p-BNC assay revealed significant differences in cytometric parameters and biomarker MCM2 expression between cytobrush samples of the FA patient and cytobrush samples of normal oral mucosa obtained from healthy volunteers. Microscopic examination of the FA patient’s OPMD confirmed the presence of dysplasia. Our pilot data suggests that p-BNC brush biopsy test recognizes dysplastic oral epithelial cells in a brush biopsy sample of a FA patient. PMID:25662766

  19. Shared Copy Number Variation in Simultaneous Nephroblastoma and Neuroblastoma due to Fanconi Anemia

    PubMed Central

    Serra, A.; Eirich, K.; Winkler, A.K.; Mrasek, K.; Göhring, G.; Barbi, G.; Cario, H.; Schlegelberger, B.; Pokora, B.; Liehr, T.; Leriche, C.; Henne-Bruns, D.; Barth, T.F.; Schindler, D.

    2012-01-01

    Concurrent emergence of nephroblastoma (Wilms Tumor; WT) and neuroblastoma (NB) is rare and mostly observed in patients with severe subtypes of Fanconi anemia (FA) with or without VACTER-L association (VL). We investigated the hypothesis that early consequences of genomic instability result in shared regions with copy number variation in different precursor cells that originate distinct embryonal tumors. We observed a newborn girl with FA and VL (aplasia of the thumbs, cloacal atresia (urogenital sinus), tethered cord at L3/L4, muscular ventricular septum defect, and horseshoe-kidney with a single ureter) who simultaneously acquired an epithelial-type WT in the left portion of the kidney and a poorly differentiated adrenal NB in infancy. A novel homozygous germline frameshift mutation in PALB2 (c.1676_c1677delAAinsG) leading to protein truncation (pGln526ArgfsX1) inherited from consanguineous parents formed the genetic basis of FA-N. Spontaneous and induced chromosomal instability was detected in the majority of cells analyzed from peripheral lymphocytes, bone marrow, and cultured fibroblasts. Bone marrow cells also showed complex chromosome rearrangements consistent with the myelodysplastic syndrome at 11 months of age. Array-comparative genomic hybridization analyses of both WT and NB showed shared gains or amplifications within the chromosomal regions 11p15.5 and 17q21.31-q25.3, including genes that are reportedly implicated in tumor development such as IGF2, H19, WT2, BIRC5, and HRAS. PMID:23112754

  20. Twenty years of the Italian Fanconi Anemia Registry: where we stand and what remains to be learned

    PubMed Central

    Risitano, Antonio M.; Marotta, Serena; Calzone, Rita; Grimaldi, Francesco; Zatterale, Adriana

    2016-01-01

    The natural history of Fanconi anemia remains hard to establish because of its rarity and its heterogeneous clinical presentation; since 1994, the Italian Fanconi Anemia Registry has collected clinical, epidemiological and genetic data of Italian Fanconi Anemia patients. This registry includes 180 patients with a confirmed diagnosis of Fanconi anemia who have either been enrolled prospectively, at diagnosis, or later on. After enrollment, follow-up data were periodically collected to assess the clinical course, possible complications and long-term survival; the median follow up was 15.6 years. The main goal of the study was to describe the natural history of Fanconi anemia, focusing on the following variables: family history, disease presentation, development of hematological manifestations, development of malignancies, occurrence of hematopoietic stem cell transplantation and survival. Typical morphological and/or hematological abnormalities and/or growth retardation were the most common manifestations at diagnosis; the majority of patients (77%) exhibited hematological abnormalities at the initial presentation, and almost all (96%) eventually developed hematological manifestations. More than half of the patients (57%) underwent a bone-marrow transplant. The occurrence of cancer was quite rare at diagnosis, whereas the cumulative incidence of malignancies at 10, 20 and 30 years was 5%, 8% and 22%, respectively, for hematological cancers and 1%, 15% and 32%, respectively, for solid tumors. Overall survival at 10, 20 and 30 years were 88%, 56% and 37%, respectively; the main causes of death were cancer, complications of the hematological presentation and complications of transplantation. These data clearly confirm the detrimental outcome of Fanconi anemia, with no major improvement in the past decades. PMID:26635036

  1. RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway.

    PubMed

    Xie, Jenny; Kim, Hyungjin; Moreau, Lisa A; Puhalla, Shannon; Garber, Judy; Al Abo, Muthana; Takeda, Shunichi; D'Andrea, Alan D

    2015-04-01

    The Fanconi anemia/BRCA (FA/BRCA) pathway is a DNA repair pathway that is required for excision of DNA interstrand cross-links. The 17 known FA proteins, along with several FA-associated proteins (FAAPs), cooperate in this pathway to detect, unhook, and excise DNA cross-links and to subsequently repair the double-strand breaks generated in the process. In the current study, we identified a patient with FA with a point mutation in FANCA, which encodes a mutant FANCA protein (FANCAI939S). FANCAI939S failed to bind to the FAAP20 subunit of the FA core complex, leading to decreased stability. Loss of FAAP20 binding exposed a SUMOylation site on FANCA at amino acid residue K921, resulting in E2 SUMO-conjugating enzyme UBC9-mediated SUMOylation, RING finger protein 4-mediated (RNF4-mediated) polyubiquitination, and proteasome-mediated degradation of FANCA. Mutation of the SUMOylation site of FANCA rescued the expression of the mutant protein. Wild-type FANCA was also subject to SUMOylation, RNF4-mediated polyubiquitination, and degradation, suggesting that regulated release of FAAP20 from FANCA is a critical step in the normal FA pathway. Consistent with this model, cells lacking RNF4 exhibited interstrand cross-linker hypersensitivity, and the gene encoding RNF4 was epistatic with the other genes encoding members of the FA/BRCA pathway. Together, the results from our study underscore the importance of analyzing unique patient-derived mutations for dissecting complex DNA repair processes. PMID:25751062

  2. Fanconi anemia (FA) and crosslinker sensitivity: Re-appraising the origins of FA definition.

    PubMed

    Pagano, Giovanni; d'Ischia, Marco; Pallardó, Federico V

    2015-07-01

    The commonly accepted definition of Fanconi anemia (FA) relying on DNA repair deficiency is submitted to a critical review starting from the early reports pointing to mitomycin C bioactivation and to the toxicity mechanisms of diepoxybutane and a group of nitrogen mustards causing DNA crosslinks in FA cells. A critical analysis of the literature prompts revisiting the FA phenotype and crosslinker sensitivity in terms of an oxidative stress (OS) background, redox-related anomalies of FA (FANC) proteins, and mitochondrial dysfunction. This re-appraisal of FA basic defect might lead to innovative approaches both in elucidating FA phenotypes and in clinical management. PMID:25732180

  3. Role of Fanconi Anemia FANCG in Preventing Double-Strand Breakage and Chromosomal Rearrangement during DNA Replication

    SciTech Connect

    Tebbs, R S; Hinz, J M; Yamada, N A; Wilson, J B; Jones, N J; Salazar, E P; Thomas, C B; Jones, I M; Thompson, L H

    2003-10-04

    The Fanconi anemia (FA) proteins overlap with those of homologous recombination through FANCD1/BRCA2, but the biochemical functions of other FA proteins are unknown. By constructing and characterizing a null fancg mutant of hamster CHO cells, we present several new insights for FA. The fancg cells show a broad sensitivity to genotoxic agents, not supporting the conventional concept of sensitivity to only DNA crosslinking agents. The aprt mutation rate is normal, but hprt mutations are reduced, which we ascribe to the lethality of large deletions. CAD and dhfr gene amplification rates are increased, implying excess chromosomal breakage during DNA replication, and suggesting amplification as a contributing factor to cancer-proneness in FA patients. In S-phase cells, both spontaneous and mutagen-induced Rad51 nuclear foci are elevated. These results support a model in which FancG protein helps to prevent collapse of replication forks by allowing translesion synthesis or lesion bypass through homologous recombination.

  4. Secular trends in outcomes for Fanconi anemia patients who receive transplants: implications for future studies.

    PubMed

    Rosenberg, Philip S; Alter, Blanche P; Socié, Gerard; Gluckman, Eliane

    2005-09-01

    Transplantation protocols for patients with Fanconi anemia are being modified continuously. However, it is unclear how outcomes have changed over time. We determined historical adverse event rates from long-term follow-up of 117 Fanconi anemia patients in the Hôpital Saint Louis transplant cohort, who received low-dose cyclophosphamide- and irradiation-based conditioning, in combination with other modalities, between 1976 and October 2002. In high-risk patients with mismatched donors, the peritransplantation mortality rate during 0 to 6 months declined significantly over time (P = .003), from 28%/month (95% confidence interval [CI], 9%-87%/month) during 1985 to 1989 to 3.3%/month (95% CI, 0.8%-13.3%/month) during 2000 to October 2002. The corresponding proportion of patients who developed severe acute graft-versus-host disease also declined significantly over time (P = .003). In low-risk patients with matched sibling donors, the peritransplantation mortality rate was consistently low, 1.4%/month (95% CI, 0.3%-5.3%/month), during 1990 to October 2002. Sample sizes to detect 2-fold reductions from rates and risks observed since the mid-1990s are larger than recently reported case series. To demonstrate further advances in survival, transplant centers may need to coordinate their protocols and engage in multicenter collaborative studies. PMID:16125637

  5. Fanconi anemia complementation group A (FANCA) localizes to centrosomes and functions in the maintenance of centrosome integrity.

    PubMed

    Kim, Sunshin; Hwang, Soo Kyung; Lee, Mihee; Kwak, Heejin; Son, Kook; Yang, Jiha; Kim, Sung Hak; Lee, Chang-Hun

    2013-09-01

    Fanconi anemia (FA) proteins are known to play roles in the cellular response to DNA interstrand cross-linking lesions; however, several reports have suggested that FA proteins play additional roles. To elucidate novel functions of FA proteins, we used yeast two-hybrid screening to identify binding partners of the Fanconi anemia complementation group A (FANCA) protein. The candidate proteins included never-in-mitosis-gene A (NIMA)-related kinase 2 (Nek2), which functions in the maintenance of centrosome integrity. The interaction of FANCA and Nek2 was confirmed in human embryonic kidney (HEK) 293T cells. Furthermore, FANCA interacted with γ-tubulin and localized to centrosomes, most notably during the mitotic phase, confirming that FANCA is a centrosomal protein. Knockdown of FANCA increased the frequency of centrosomal abnormalities and enhanced the sensitivity of U2OS osteosarcoma cells to nocodazole, a microtubule-interfering agent. In vitro kinase assays indicated that Nek2 can phosphorylate FANCA at threonine-351 (T351), and analysis with a phospho-specific antibody confirmed that this phosphorylation occurred in response to nocodazole treatment. Furthermore, U2OS cells overexpressing the phosphorylation-defective T351A FANCA mutant showed numerical centrosomal abnormalities, aberrant mitotic arrest, and enhanced nocodazole sensitivity, implying that the Nek2-mediated T351 phosphorylation of FANCA is important for the maintenance of centrosomal integrity. Taken together, this study revealed that FANCA localizes to centrosomes and is required for the maintenance of centrosome integrity, possibly through its phosphorylation at T351 by Nek2. PMID:23806870

  6. Snm1B/Apollo functions in the Fanconi anemia pathway in response to DNA interstrand crosslinks.

    PubMed

    Mason, Jennifer M; Sekiguchi, JoAnn M

    2011-07-01

    Fanconi anemia (FA) is an inherited chromosomal instability disorder characterized by childhood aplastic anemia, developmental abnormalities and cancer predisposition. One of the hallmark phenotypes of FA is cellular hypersensitivity to agents that induce DNA interstrand crosslinks (ICLs), such as mitomycin C (MMC). FA is caused by mutation in at least 14 genes which function in the resolution of ICLs during replication. The FA proteins act within the context of a protein network in coordination with multiple repair factors that function in distinct pathways. SNM1B/Apollo is a member of metallo-β-lactamase/βCASP family of nucleases and has been demonstrated to function in ICL repair. However, the relationship between SNM1B and the FA protein network is not known. In the current study, we establish that SNM1B functions epistatically to the central FA factor, FANCD2, in cellular survival after ICL damage and homology-directed repair of DNA double-strand breaks. We also demonstrate that MMC-induced chromosomal anomalies are increased in SNM1B-depleted cells, and this phenotype is not further exacerbated upon depletion of either FANCD2 or another key FA protein, FANCI. Furthermore, we find that SNM1B is required for proper localization of critical repair factors, including FANCD2, BRCA1 and RAD51, to MMC-induced subnuclear foci. Our findings demonstrate that SNM1B functions within the FA pathway during the repair of ICL damage. PMID:21478198

  7. [Fanconi anemia animal models - How differences can teach us as much as similarities…].

    PubMed

    Dubois, Émilie L; Béliveau, Mariline; Masson, Jean-Yves

    2016-01-01

    Fanconi Anemia is a rare autosomal recessive genetic disease with heterogenous phenotypes including myelosuppression, congenital malformations and heightened cancer predisposition. FA cells are highly sensitive to cross-linking agents. Since the 90's, at least 19 FANC proteins (FANCA to FANCT) have been identified as working together in a unique pathway detecting and triggering the repair of DNA crosslinks. Since then, the creation of animal models in various species (nematode, fruit fly, zebrafish and mouse) contributed to a better understanding of the physiopathology of the disease. This review aims to summarize the main discoveries made in these in vivo models, as well as to discuss some controversies that arose from these studies. PMID:27406770

  8. How SUMOylation Fine-Tunes the Fanconi Anemia DNA Repair Pathway

    PubMed Central

    Coleman, Kate E.; Huang, Tony T.

    2016-01-01

    Fanconi anemia (FA) is a rare human genetic disorder characterized by developmental defects, bone marrow failure and cancer predisposition, primarily due to a deficiency in the repair of DNA interstrand crosslinks (ICLs). ICL repair through the FA DNA repair pathway is a complicated multi-step process, involving at least 19 FANC proteins and coordination of multiple DNA repair activities, including homologous recombination, nucleotide excision repair and translesion synthesis (TLS). SUMOylation is a critical regulator of several DNA repair pathways, however, the role of this modification in controlling the FA pathway is poorly understood. Here, we summarize recent advances in the fine-tuning of the FA pathway by small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligases (STUbLs) and other SUMO-related interactions, and discuss the implications of these findings in the design of novel therapeutics for alleviating FA-associated condition, including cancer. PMID:27148358

  9. Exploiting the Fanconi Anemia Pathway for Targeted Anti-Cancer Therapy

    PubMed Central

    Jo, Ukhyun; Kim, Hyungjin

    2015-01-01

    Genome instability, primarily caused by faulty DNA repair mechanisms, drives tumorigenesis. Therapeutic interventions that exploit deregulated DNA repair in cancer have made considerable progress by targeting tumor-specific alterations of DNA repair factors, which either induces synthetic lethality or augments the efficacy of conventional chemotherapy and radiotherapy. The study of Fanconi anemia (FA), a rare inherited blood disorder and cancer predisposition syndrome, has been instrumental in understanding the extent to which DNA repair defects contribute to tumorigenesis. The FA pathway functions to resolve blocked replication forks in response to DNA interstrand cross-links (ICLs), and accumulating knowledge of its activation by the ubiquitin-mediated signaling pathway has provided promising therapeutic opportunities for cancer treatment. Here, we discuss recent advances in our understanding of FA pathway regulation and its potential application for designing tailored therapeutics that take advantage of deregulated DNA ICL repair in cancer. PMID:26194820

  10. Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

    PubMed Central

    Kim, Hyungjin; D'Andrea, Alan D.

    2012-01-01

    The maintenance of genome stability is critical for survival, and its failure is often associated with tumorigenesis. The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand cross-links (ICLs), and a germline defect in the pathway results in FA, a cancer predisposition syndrome driven by genome instability. Central to this pathway is the monoubiquitination of FANCD2, which coordinates multiple DNA repair activities required for the resolution of ICLs. Recent studies have demonstrated how the FA pathway coordinates three critical DNA repair processes, including nucleolytic incision, translesion DNA synthesis (TLS), and homologous recombination (HR). Here, we review recent advances in our understanding of the downstream ICL repair steps initiated by ubiquitin-mediated FA pathway activation. PMID:22751496

  11. X ray sensitivity of diploid skin fibroblasts from patients with Fanconi's anemia

    NASA Technical Reports Server (NTRS)

    Kale, Ranjini

    1989-01-01

    Experiments were performed on Fanconi's anemia and normal human fibroblast cell lines growing in culture in an attempt to correlate cell cycle kinetics with genomic damage and determine their bearing on the mechanism of chromosome aberration induction. FA fibroblasts showed a significantly increased susceptibility to chromosomal breakage by x rays in the G2 phase of the cell cycle. No such response was observed in fibroblasts irradiated in the G0 phase. The observed increases in achromatic lesions and in chromatid deletions in FA cells as compared with normal cells appear to indicate that FA cells are deficient in strand break repair and also possibly in base damage excision repair. Experiments are now in progress to further elucidate the mechanisms involved.

  12. Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia

    PubMed Central

    Pulliam-Leath, Anna C.; Ciccone, Samantha L.; Nalepa, Grzegorz; Li, Xiaxin; Si, Yue; Miravalle, Leticia; Smith, Danielle; Yuan, Jin; Li, Jingling; Anur, Praveen; Orazi, Attilio; Vance, Gail H.; Yang, Feng-Chun; Hanenberg, Helmut; Bagby, Grover C.

    2010-01-01

    Fanconi anemia (FA) is an inherited chromosomal instability syndrome characterized by bone marrow failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). Eight FA proteins associate in a nuclear core complex to monoubiquitinate FANCD2/FANCI in response to DNA damage. Additional functions have been described for some of the core complex proteins; however, in vivo genetic proof has been lacking. Here we show that double-mutant Fancc−/−;Fancg−/− mice develop spontaneous hematologic sequelae including bone marrow failure, AML, MDS and complex random chromosomal abnormalities that the single-mutant mice do not. This genetic model provides evidence for unique core complex protein function independent of their ability to monoubiquitinate FANCD2/FANCI. Importantly, this model closely recapitulates the phenotypes found in FA patients and may be useful as a preclinical platform to evaluate the molecular pathogenesis of spontaneous bone marrow failure, MDS and AML in FA. PMID:20606166

  13. The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription.

    PubMed

    Schwab, Rebekka A; Nieminuszczy, Jadwiga; Shah, Fenil; Langton, Jamie; Lopez Martinez, David; Liang, Chih-Chao; Cohn, Martin A; Gibbons, Richard J; Deans, Andrew J; Niedzwiedz, Wojciech

    2015-11-01

    DNA replication stress can cause chromosomal instability and tumor progression. One key pathway that counteracts replication stress and promotes faithful DNA replication consists of the Fanconi anemia (FA) proteins. However, how these proteins limit replication stress remains largely elusive. Here we show that conflicts between replication and transcription activate the FA pathway. Inhibition of transcription or enzymatic degradation of transcription-associated R-loops (DNA:RNA hybrids) suppresses replication fork arrest and DNA damage occurring in the absence of a functional FA pathway. Furthermore, we show that simple aldehydes, known to cause leukemia in FA-deficient mice, induce DNA:RNA hybrids in FA-depleted cells. Finally, we demonstrate that the molecular mechanism by which the FA pathway limits R-loop accumulation requires FANCM translocase activity. Failure to activate a response to physiologically occurring DNA:RNA hybrids may critically contribute to the heightened cancer predisposition and bone marrow failure of individuals with mutated FA proteins. PMID:26593718

  14. FANCJ suppresses microsatellite instability and lymphomagenesis independent of the Fanconi anemia pathway.

    PubMed

    Matsuzaki, Kenichiro; Borel, Valerie; Adelman, Carrie A; Schindler, Detlev; Boulton, Simon J

    2015-12-15

    Microsatellites are short tandem repeat sequences that are highly prone to expansion/contraction due to their propensity to form non-B-form DNA structures, which hinder DNA polymerases and provoke template slippage. Although error correction by mismatch repair plays a key role in preventing microsatellite instability (MSI), which is a hallmark of Lynch syndrome, activities must also exist that unwind secondary structures to facilitate replication fidelity. Here, we report that Fancj helicase-deficient mice, while phenotypically resembling Fanconi anemia (FA), are also hypersensitive to replication inhibitors and predisposed to lymphoma. Whereas metabolism of G4-DNA structures is largely unaffected in Fancj(-/-) mice, high levels of spontaneous MSI occur, which is exacerbated by replication inhibition. In contrast, MSI is not observed in Fancd2(-/-) mice but is prevalent in human FA-J patients. Together, these data implicate FANCJ as a key factor required to counteract MSI, which is functionally distinct from its role in the FA pathway. PMID:26637282

  15. Ubiquitin-SUMO circuitry controls activated fanconi anemia ID complex dosage in response to DNA damage.

    PubMed

    Gibbs-Seymour, Ian; Oka, Yasuyoshi; Rajendra, Eeson; Weinert, Brian T; Passmore, Lori A; Patel, Ketan J; Olsen, Jesper V; Choudhary, Chunaram; Bekker-Jensen, Simon; Mailand, Niels

    2015-01-01

    We show that central components of the Fanconi anemia (FA) DNA repair pathway, the tumor suppressor proteins FANCI and FANCD2 (the ID complex), are SUMOylated in response to replication fork stalling. The ID complex is SUMOylated in a manner that depends on the ATR kinase, the FA ubiquitin ligase core complex, and the SUMO E3 ligases PIAS1/PIAS4 and is antagonized by the SUMO protease SENP6. SUMOylation of the ID complex drives substrate selectivity by triggering its polyubiquitylation by the SUMO-targeted ubiquitin ligase RNF4 to promote its removal from sites of DNA damage via the DVC1-p97 ubiquitin segregase complex. Deregulation of ID complex SUMOylation compromises cell survival following replication stress. Our results uncover a regulatory role for SUMOylation in the FA pathway, and we propose that ubiquitin-SUMO signaling circuitry is a mechanism that contributes to the balance of activated ID complex dosage at sites of DNA damage. PMID:25557546

  16. Targeted therapy for genetic cancer syndromes: Fanconi anemia, medullary thyroid cancer, tuberous sclerosis, and RASopathies.

    PubMed

    Agarwal, Rishi; Liebe, Sarah; Turski, Michelle L; Vidwans, Smruti J; Janku, Filip; Garrido-Laguna, Ignacio; Munoz, Javier; Schwab, Richard; Rodon, Jordi; Kurzrock, Razelle; Subbiah, Vivek

    2015-02-01

    With the advent of genomics-based treatment in recent years, the use of targeted therapies in the treatment of various malignancies has increased exponentially. Though much data is available regarding the efficacy of targeted therapies for common malignancies, genetic cancer syndromes remain a somewhat unexplored topic with comparatively less published literature. This review seeks to characterize targeted therapy options for the following genetic cancer syndromes: Fanconi anemia, inherited medullary thyroid cancer, tuberous sclerosis, and RASopathies. By understanding the pathophysiology of these conditions as well as available molecularly targeted therapies, oncologists, in collaboration with geneticists and genetic counsellors, can begin to develop effective clinical management options and therapy regimens for the patients with these genetic syndromes that they may encounter in their practice. PMID:25725224

  17. Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.

    PubMed

    Kashiyama, Kazuya; Nakazawa, Yuka; Pilz, Daniela T; Guo, Chaowan; Shimada, Mayuko; Sasaki, Kensaku; Fawcett, Heather; Wing, Jonathan F; Lewin, Susan O; Carr, Lucinda; Li, Tao-Sheng; Yoshiura, Koh-ichiro; Utani, Atsushi; Hirano, Akiyoshi; Yamashita, Shunichi; Greenblatt, Danielle; Nardo, Tiziana; Stefanini, Miria; McGibbon, David; Sarkany, Robert; Fassihi, Hiva; Takahashi, Yoshito; Nagayama, Yuji; Mitsutake, Norisato; Lehmann, Alan R; Ogi, Tomoo

    2013-05-01

    Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF. PMID:23623389

  18. Malfunction of Nuclease ERCC1-XPF Results in Diverse Clinical Manifestations and Causes Cockayne Syndrome, Xeroderma Pigmentosum, and Fanconi Anemia

    PubMed Central

    Kashiyama, Kazuya; Nakazawa, Yuka; Pilz, Daniela T.; Guo, Chaowan; Shimada, Mayuko; Sasaki, Kensaku; Fawcett, Heather; Wing, Jonathan F.; Lewin, Susan O.; Carr, Lucinda; Li, Tao-Sheng; Yoshiura, Koh-ichiro; Utani, Atsushi; Hirano, Akiyoshi; Yamashita, Shunichi; Greenblatt, Danielle; Nardo, Tiziana; Stefanini, Miria; McGibbon, David; Sarkany, Robert; Fassihi, Hiva; Takahashi, Yoshito; Nagayama, Yuji; Mitsutake, Norisato; Lehmann, Alan R.; Ogi, Tomoo

    2013-01-01

    Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders—CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF. PMID:23623389

  19. Radiologic Differences between Bone Marrow Stromal and Hematopoietic Progenitor Cell Lines from Fanconi Anemia (Fancd2−/−) Mice

    PubMed Central

    Berhane, Hebist; Epperly, Michael W.; Goff, Julie; Kalash, Ronny; Cao, Shaonan; Franicola, Darcy; Zhang, Xichen; Shields, Donna; Houghton, Frank; Wang, Hong; Wipf, Peter; Parmar, Kalindi; Greenberger, Joel S.

    2014-01-01

    FancD2 plays a central role in the human Fanconi anemia DNA damage response (DDR) pathway. Fancd2−/− mice exhibit many features of human Fanconi anemia including cellular DNA repair defects. Whether the DNA repair defect in Fancd2−/− mice results in radiologic changes in all cell lineages is unknown. We measured stress of hematopoiesis in long-term marrow cultures and radiosensitivity in clonogenic survival curves, as well as comet tail intensity, total antioxidant stores and radiation-induced gene expression in hematopoietic progenitor compared to bone marrow stromal cell lines. We further evaluated radioprotection by a mitochondrial-targeted antioxidant GS-nitroxide, JP4-039. Hematopoiesis longevity in Fancd2−/− mouse long-term marrow cultures was diminished and bone marrow stromal cell lines were radiosensitive compared to Fancd2+/+ stromal cells (Fancd2−/− D0 = 1.4 ± 0.1 Gy, ñ = 5.0 ± 0.6 vs. Fancd2+/+ D0 = 1.6 ± 0.1 Gy, ñ = 6.7 ± 1.6), P = 0.0124 for D0 and P = 0.0023 for ñ, respectively). In contrast, Fancd2−/− IL-3-dependent hematopoietic progenitor cells were radioresistant (D0 = 1.71 ± 0.04 Gy and ñ = 5.07 ± 0.52) compared to Fancd2+/+ (D0 = 1.39 ± 0.09 Gy and ñ = 2.31 ± 0.85, P = 0.001 for D0). CFU-GM from freshly explanted Fancd2−/− marrow was also radioresistant. Consistent with radiosensitivity, irradiated Fancd2−/− stromal cells had higher DNA damage by comet tail intensity assay compared to Fancd2+/+ cells (P < 0.0001), slower DNA damage recovery, lower baseline total antioxidant capacity, enhanced radiation-induced depletion of antioxidants, and increased CDKN1A-p21 gene transcripts and protein. Consistent with radioresistance, Fancd2−/− IL-3-dependent hematopoietic cells had higher baseline and post irradiation total antioxidant capacity. While, there was no detectable alteration of radiation-induced cell cycle arrest with Fancd2−/− stromal cells, hematopoietic progenitor cells showed reduced G2/M

  20. Radiologic differences between bone marrow stromal and hematopoietic progenitor cell lines from Fanconi Anemia (Fancd2(-/-)) mice.

    PubMed

    Berhane, Hebist; Epperly, Michael W; Goff, Julie; Kalash, Ronny; Cao, Shaonan; Franicola, Darcy; Zhang, Xichen; Shields, Donna; Houghton, Frank; Wang, Hong; Wipf, Peter; Parmar, Kalindi; Greenberger, Joel S

    2014-01-01

    FancD2 plays a central role in the human Fanconi anemia DNA damage response (DDR) pathway. Fancd2(-/-) mice exhibit many features of human Fanconi anemia including cellular DNA repair defects. Whether the DNA repair defect in Fancd2(-/-) mice results in radiologic changes in all cell lineages is unknown. We measured stress of hematopoiesis in long-term marrow cultures and radiosensitivity in clonogenic survival curves, as well as comet tail intensity, total antioxidant stores and radiation-induced gene expression in hematopoietic progenitor compared to bone marrow stromal cell lines. We further evaluated radioprotection by a mitochondrial-targeted antioxidant GS-nitroxide, JP4-039. Hematopoiesis longevity in Fancd2(-/-) mouse long-term marrow cultures was diminished and bone marrow stromal cell lines were radiosensitive compared to Fancd2(+/+) stromal cells (Fancd2(-/-) D0 = 1.4 ± 0.1 Gy, ñ = 5.0 ± 0.6 vs. Fancd2(+/+) D0 = 1.6 ± 0.1 Gy, ñ = 6.7 ± 1.6), P = 0.0124 for D0 and P = 0.0023 for ñ, respectively). In contrast, Fancd2(-/-) IL-3-dependent hematopoietic progenitor cells were radioresistant (D0 = 1.71 ± 0.04 Gy and ñ = 5.07 ± 0.52) compared to Fancd2(+/+) (D0 = 1.39 ± 0.09 Gy and ñ = 2.31 ± 0.85, P = 0.001 for D0). CFU-GM from freshly explanted Fancd2(-/-) marrow was also radioresistant. Consistent with radiosensitivity, irradiated Fancd2(-/-) stromal cells had higher DNA damage by comet tail intensity assay compared to Fancd2(+/+) cells (P < 0.0001), slower DNA damage recovery, lower baseline total antioxidant capacity, enhanced radiation-induced depletion of antioxidants, and increased CDKN1A-p21 gene transcripts and protein. Consistent with radioresistance, Fancd2(-/-) IL-3-dependent hematopoietic cells had higher baseline and post irradiation total antioxidant capacity. While, there was no detectable alteration of radiation-induced cell cycle arrest with Fancd2(-/-) stromal cells, hematopoietic progenitor cells showed reduced G2/M cell cycle

  1. Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia.

    PubMed

    Rickman, Kimberly A; Lach, Francis P; Abhyankar, Avinash; Donovan, Frank X; Sanborn, Erica M; Kennedy, Jennifer A; Sougnez, Carrie; Gabriel, Stacey B; Elemento, Olivier; Chandrasekharappa, Settara C; Schindler, Detlev; Auerbach, Arleen D; Smogorzewska, Agata

    2015-07-01

    Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT. PMID:26119737

  2. Fanconi anemia in brothers initially diagnosed with VACTERL association with hydrocephalus, and subsequently with Baller-Gerold syndrome

    SciTech Connect

    Rossbach, H.C.; Granan, N.H.; Rossi, A.R.; Barbosa, J.L.

    1996-01-02

    Two brothers with presumed Baller-Gerold syndrome, one of whom was previously diagnosed with the association of vertebral, cardiac, renal, limb anomalies, anal atresia, tracheo-esophageal fistula (VACTERL) association with hydrocephalus, were evaluated for chromosome breakage because of severe thrombo cytopenia in one of them. Spontaneous and clastogen-induced breakage was markedly increased in both patients as compared to control individuals. Clinical manifestations and chromosome breakage, consistent with Fanconi anemia, in patients with a prior diagnosis of either Baller-Gerold syndrome, reported earlier in one other patient, or with VACTERL association with hydrocephalus, recently reported in 3 patients, underline the clinical heterogeneity of Fanconi anemia and raise the question of whether these syndromes are distinct disorders or phenotypic variations of the same disease. 12 refs., 3 figs., 1 tab.

  3. Late effects in patients with Fanconi anemia following allogeneic hematopoietic stem cell transplantation from alternative donors.

    PubMed

    Anur, P; Friedman, D N; Sklar, C; Oeffinger, K; Castiel, M; Kearney, J; Singh, B; Prockop, S E; Kernan, N A; Scaradavou, A; Kobos, R; Curran, K; Ruggiero, J; Zakak, N; O'Reilly, R J; Boulad, F

    2016-07-01

    Hematopoietic stem cell transplantation (HSCT) is curative for hematological manifestations of Fanconi anemia (FA). We performed a retrospective analysis of 22 patients with FA and aplastic anemia, myelodysplastic syndrome or acute myelogenous leukemia who underwent a HSCT at Memorial Sloan Kettering Cancer Center and survived at least 1 year post HSCT. Patients underwent either a TBI- (N=18) or busulfan- (N=4) based cytoreduction followed by T-cell-depleted transplants from alternative donors. Twenty patients were alive at time of the study with a 5- and 10-year overall survival of 100 and 84% and no evidence of chronic GvHD. Among the 18 patients receiving a TBI-based regimen, 11 (61%) had persistent hemochromatosis, 4 (22%) developed hypothyroidism, 7 (39%) had insulin resistance and 5 (27%) developed hypertriglyceridemia after transplant. Eleven of 16 evaluable patients (68%), receiving TBI, developed gonadal dysfunction. Two patients who received a TBI-based regimen died of squamous cell carcinoma. One patient developed hemochromatosis, hypothyroidism and gonadal dysfunction after busulfan-based cytoreduction. TBI appears to be a risk factor for malignant and endocrine late effects in the FA host. Multidisciplinary follow-up of patients with FA (including cancer screening) is essential for early detection and management of late complications, and improving long-term outcomes. PMID:26999465

  4. Identification of point mutations and large intragenic deletions in Fanconi anemia using next-generation sequencing technology.

    PubMed

    Nicchia, Elena; Greco, Chiara; De Rocco, Daniela; Pecile, Vanna; D'Eustacchio, Angela; Cappelli, Enrico; Corti, Paola; Marra, Nicoletta; Ramenghi, Ugo; Pillon, Marta; Farruggia, Piero; Dufour, Carlo; Pallavicini, Alberto; Torelli, Lucio; Savoia, Anna

    2015-11-01

    Fanconi anemia (FA) is a rare bone marrow failure disorder characterized by clinical and genetic heterogeneity with at least 17 genes involved, which make molecular diagnosis complex and time-consuming. Since next-generation sequencing technologies could greatly improve the genetic testing in FA, we sequenced DNA samples with known and unknown mutant alleles using the Ion PGM (™) system (IPGM). The molecular target of 74.2 kb in size covered 96% of the FA-coding exons and their flanking regions. Quality control testing revealed high coverage. Comparing the IPGM and Sanger sequencing output of FANCA,FANCC, and FANCG we found no false-positive and a few false-negative variants, which led to high sensitivity (95.58%) and specificity (100%) at least for these two most frequently mutated genes. The analysis also identified novel mutant alleles, including those in rare complementation groups FANCF and FANCL. Moreover, quantitative evaluation allowed us to characterize large intragenic deletions of FANCA and FANCD2, suggesting that IPGM is suitable for identification of not only point mutations but also copy number variations. PMID:26740942

  5. Investigation of FANCA gene in Fanconi anaemia patients in Iran

    PubMed Central

    Saffar Moghadam, Ali Akbar; Mahjoubi, Frouzandeh; Reisi, Nahid; Vosough, Parvaneh

    2016-01-01

    Background & objectives: Fanconi anaemia (FA) is a syndrome with a predisposition to bone marrow failure, congenital anomalies and malignancies. It is characterized by cellular hypersensitivity to cross-linking agents such as mitomycin C (MMC). In the present study, a new approach was selected to investigate FANCA (Fanconi anaemia complementation group A) gene in patients clinically diagnosed with cellular hypersensitivity to DNA cross-linking agent MMC. Methods: Chromosomal breakage analysis was performed to prove the diagnosis of Fanconi anaemia in 318 families. Of these, 70 families had a positive result. Forty families agreed to molecular genetic testing. In total, there were 27 patients with unknown complementary types. Genomic DNA was extracted and total RNA was isolated from fresh whole blood of the patients. The first-strand cDNA was synthesized and the cDNA of each patient was then tested with 21 pairs of overlapping primers. High resolution melting curve analysis was used to screen FANCA, and LinReg software version 1.7 was utilized for analysis of expression. Results: In total, six sequence alterations were identified, which included two stop codons, two frames-shift mutations, one large deletion and one amino acid exchange. FANCA expression was downregulated in patients who had sequence alterations. Interpretation & conclusions: The results of the present study show that high resolution melting (HRM) curve analysis may be useful in the detection of sequence alteration. It is simpler and more costeffective than the multiplex ligation-dependent probe amplification (MLPA) procedure. PMID:27121516

  6. A Human Orthologue of Archaeal DNA Repair Protein Hef is Defective in Fanconi Anemia Complementation Group M

    PubMed Central

    Meetei, Amom Ruhikanta; Medhurst, Annette L.; Ling, Chen; Xue, Yutong; Singh, Thiyam Ramsing; Bier, Patrick; Steltenpool, Jurgen; Stone, Stacie; Dokal, Inderjeet; Mathew, Christopher G.; Hoatlin, Maureen; Joenje, Hans; de Winter, Johan P.; Wang, Weidong

    2005-01-01

    Fanconi anemia (FA) is a genetic disease featuring genomic instability and cancer predisposition1. Nine FA genes have been identified, and their products participate in a DNA damage response network involving BRCA1 and BRCA22,3. We have previously purified a FA core complex containing the FANCL ubiquitin ligase and 6 other FA proteins4–6. Each protein in this complex is essential for monoubiquitination of FANCD2, a key reaction in the FA DNA damage response pathway2,7. Here we show that another component of this complex, FAAP250, is mutated in FA patients of a new complementation group (FA-M). FAAP250, renamed FANCM, has sequence similarity to known DNA repair proteins, including archaeal Hef, yeast Mph1 and human ERCC4/XPF. FANCM can dissociate DNA triplex, possibly due to its ability to translocate on duplex DNA. FANCM is essential for FANCD2 monoubiquitination and becomes hyperphosphorylated in response to DNA damage. Our data suggest an evolutionary link between FA proteins and DNA repair; FANCM may act as an engine that translocates the FA core complex along DNA. PMID:16116422

  7. The Fanconi Anemia C Protein Binds to and Regulates Stathmin-1 Phosphorylation

    PubMed Central

    Magron, Audrey; Elowe, Sabine; Carreau, Madeleine

    2015-01-01

    The Fanconi anemia (FA) proteins are involved in a signaling network that assures the safeguard of chromosomes. To understand the function of FA proteins in cellular division events, we investigated the interaction between Stathmin-1 (STMN1) and the FA group C (FANCC) protein. STMN1 is a ubiquitous cytosolic protein that regulates microtubule dynamics. STMN1 activities are regulated through phosphorylation-dephosphorylation mechanisms that control assembly of the mitotic spindle, and dysregulation of STMN1 phosphorylation is associated with mitotic aberrancies leading to chromosome instability and cancer progression. Using different biochemical approaches, we showed that FANCC interacts and co-localizes with STMN1 at centrosomes during mitosis. We also showed that FANCC is required for STMN1 phosphorylation, as mutations in FANCC reduced serine 16- and 38-phosphorylated forms of STMN1. Phosphorylation of STMN1 at serine 16 is likely an event dependent on a functional FA pathway, as it is reduced in FANCA- and FANCD2-mutant cells. Furthermore, FA-mutant cells exhibited mitotic spindle anomalies such as supernumerary centrosomes and shorter mitotic spindles. These results suggest that FA proteins participate in the regulation of cellular division via the microtubule-associated protein STMN1. PMID:26466335

  8. The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription

    PubMed Central

    Schwab, Rebekka A.; Nieminuszczy, Jadwiga; Shah, Fenil; Langton, Jamie; Lopez Martinez, David; Liang, Chih-Chao; Cohn, Martin A.; Gibbons, Richard J.; Deans, Andrew J.; Niedzwiedz, Wojciech

    2015-01-01

    Summary DNA replication stress can cause chromosomal instability and tumor progression. One key pathway that counteracts replication stress and promotes faithful DNA replication consists of the Fanconi anemia (FA) proteins. However, how these proteins limit replication stress remains largely elusive. Here we show that conflicts between replication and transcription activate the FA pathway. Inhibition of transcription or enzymatic degradation of transcription-associated R-loops (DNA:RNA hybrids) suppresses replication fork arrest and DNA damage occurring in the absence of a functional FA pathway. Furthermore, we show that simple aldehydes, known to cause leukemia in FA-deficient mice, induce DNA:RNA hybrids in FA-depleted cells. Finally, we demonstrate that the molecular mechanism by which the FA pathway limits R-loop accumulation requires FANCM translocase activity. Failure to activate a response to physiologically occurring DNA:RNA hybrids may critically contribute to the heightened cancer predisposition and bone marrow failure of individuals with mutated FA proteins. PMID:26593718

  9. Endocrinopathies, Bone Health, and Insulin Resistance in Patients with Fanconi Anemia after Hematopoietic Cell Transplantation.

    PubMed

    Barnum, Jessie L; Petryk, Anna; Zhang, Lei; DeFor, Todd E; Baker, K Scott; Steinberger, Julia; Nathan, Brandon; Wagner, John E; MacMillan, Margaret L

    2016-08-01

    A number of endocrinopathies have been described after hematopoietic cell transplantation (HCT), but data are limited in patients with Fanconi anemia (FA). We report several endocrine-based disorders in a cohort of 44 patients with FA after HCT compared with both 74 patients who received HCT for hematologic malignancies and with 275 healthy controls. Endocrinopathies assessed included hypothyroidism, hypogonadism, short stature, dyslipidemia, insulin resistance, abnormalities in body composition, and bone health. Most (86%) patients with FA had at least 1 endocrinopathy, with 11% having 3 or more. Hypothyroidism was seen in 57%, hypogonadism in 27%, short stature in 50%, and reduced total body and lumbar spine bone mineral density (BMD) (height adjusted Z-score < -1) in 57% and 21%, respectively. Vitamin D deficiency was seen in 71%. Short stature was associated with younger age at HCT and gonadal failure was associated with older age at HCT. Insulin resistance was associated with increased percent fat mass and increased android/gynoid ratio by dual energy X-ray absorptiometry. Hypothyroidism, short stature, and reduced total body BMD were more prevalent in patients with FA compared with patients with hematologic malignancies. We recommend an assessment before transplantation and close follow-up afterwards to ensure proper clinical management. Future studies should continue to explore the impact of HCT on endocrinopathies in FA patients. PMID:27180116

  10. TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia.

    PubMed

    Zhang, Haojian; Kozono, David E; O'Connor, Kevin W; Vidal-Cardenas, Sofia; Rousseau, Alix; Hamilton, Abigail; Moreau, Lisa; Gaudiano, Emily F; Greenberger, Joel; Bagby, Grover; Soulier, Jean; Grompe, Markus; Parmar, Kalindi; D'Andrea, Alan D

    2016-05-01

    Fanconi anemia (FA) is an inherited DNA repair disorder characterized by progressive bone marrow failure (BMF) from hematopoietic stem and progenitor cell (HSPC) attrition. A greater understanding of the pathogenesis of BMF could improve the therapeutic options for FA patients. Using a genome-wide shRNA screen in human FA fibroblasts, we identify transforming growth factor-β (TGF-β) pathway-mediated growth suppression as a cause of BMF in FA. Blocking the TGF-β pathway improves the survival of FA cells and rescues the proliferative and functional defects of HSPCs derived from FA mice and FA patients. Inhibition of TGF-β signaling in FA HSPCs results in elevated homologous recombination (HR) repair with a concomitant decrease in non-homologous end-joining (NHEJ), accounting for the improvement in cellular growth. Together, our results suggest that elevated TGF-β signaling contributes to BMF in FA by impairing HSPC function and may be a potential therapeutic target for the treatment of FA. PMID:27053300

  11. Significance of the Fanconi Anemia FANCD2 Protein in Sporadic and Metastatic Human Breast Cancer

    PubMed Central

    Rudland, Philip S.; Platt-Higgins, Angela M.; Davies, Lowri M.; de Silva Rudland, Suzete; Wilson, James B.; Aladwani, Abdulaziz; Winstanley, John H.R.; Barraclough, Dong L.; Barraclough, Roger; West, Christopher R.; Jones, Nigel J.

    2010-01-01

    FANCD2, a pivotal protein in the Fanconi anemia and BRCA pathway/network, is monoubiquitylated in the nucleus in response to DNA damage. This study examines the subcellular location and relationship with prognostic factors and patient survival of FANCD2 in breast cancer. Antibodies to FANCD2 were used to immunocytochemically stain 16 benign and 20 malignant breast specimens as well as 314 primary breast carcinomas to assess its association with subcellular compartment and prognostic factors using Fisher’s Exact test or with patient survival over 20 years using Wilcoxon-Gehan statistics. Immunoreactive FANCD2 was found in the nucleus and cytoplasm of all 16 benign tissues, but nuclear staining was lost from a significant 19/20 malignant carcinomas (P < 0.0001). Antibodies to FANCD2 stained the cytoplasm of 196 primary carcinomas, leaving 118 as negatively stained. Negative cytoplasmic staining was significantly associated with positive staining for the metastasis-inducing proteins S100A4, S100P, osteopontin, and AGR2 (P ≤ 0.002). Survival of patients with FANCD2-negative carcinomas was significantly worse (P < 0.0001) than those with positively stained carcinomas, and only 4% were alive at the census date. Multivariate regression analysis identified negative staining for cytoplasmic FANCD2 as the most significant indicator of patient death (P = 0.001). Thus FANCD2’s cytoplasmic loss in the primary carcinomas may allow the selection of cells overexpressing proteins that can induce metastases before surgery. PMID:20363922

  12. Fanconi anemia proteins FANCD2 and FANCI exhibit different DNA damage responses during S-phase

    PubMed Central

    Sareen, Archana; Chaudhury, Indrajit; Adams, Nicole; Sobeck, Alexandra

    2012-01-01

    Fanconi anemia (FA) pathway members, FANCD2 and FANCI, contribute to the repair of replication-stalling DNA lesions. FA pathway activation relies on phosphorylation of FANCI by the ataxia telangiectasia and Rad3-related (ATR) kinase, followed by monoubiquitination of FANCD2 and FANCI by the FA core complex. FANCD2 and FANCI are thought to form a functional heterodimer during DNA repair, but it is unclear how dimer formation is regulated or what the functions of the FANCD2–FANCI complex versus the monomeric proteins are. We show that the FANCD2–FANCI complex forms independently of ATR and FA core complex, and represents the inactive form of both proteins. DNA damage-induced FA pathway activation triggers dissociation of FANCD2 from FANCI. Dissociation coincides with FANCD2 monoubiquitination, which significantly precedes monoubiquitination of FANCI; moreover, monoubiquitination responses of FANCD2 and FANCI exhibit distinct DNA substrate specificities. A phosphodead FANCI mutant fails to dissociate from FANCD2, whereas phosphomimetic FANCI cannot interact with FANCD2, indicating that FANCI phosphorylation is the molecular trigger for FANCD2–FANCI dissociation. Following dissociation, FANCD2 binds replicating chromatin prior to—and independently of—FANCI. Moreover, the concentration of chromatin-bound FANCD2 exceeds that of FANCI throughout replication. Our results suggest that FANCD2 and FANCI function separately at consecutive steps during DNA repair in S-phase. PMID:22753026

  13. Diagnostic Overlap between Fanconi Anemia and the Cohesinopathies: Roberts Syndrome and Warsaw Breakage Syndrome

    PubMed Central

    van der Lelij, Petra; Oostra, Anneke B.; Rooimans, Martin A.; Joenje, Hans; de Winter, Johan P.

    2010-01-01

    Fanconi anemia (FA) is a recessively inherited disease characterized by multiple symptoms including growth retardation, skeletal abnormalities, and bone marrow failure. The FA diagnosis is complicated due to the fact that the clinical manifestations are both diverse and variable. A chromosomal breakage test using a DNA cross-linking agent, in which cells from an FA patient typically exhibit an extraordinarily sensitive response, has been considered the gold standard for the ultimate diagnosis of FA. In the majority of FA patients the test results are unambiguous, although in some cases the presence of hematopoietic mosaicism may complicate interpretation of the data. However, some diagnostic overlap with other syndromes has previously been noted in cases with Nijmegen breakage syndrome. Here we present results showing that misdiagnosis may also occur with patients suffering from two of the three currently known cohesinopathies, that is, Roberts syndrome (RBS) and Warsaw breakage syndrome (WABS). This complication may be avoided by scoring metaphase chromosomes—in addition to chromosomal breakage—for spontaneously occurring premature centromere division, which is characteristic for RBS and WABS, but not for FA. PMID:21490908

  14. Second Allogeneic Hematopoietic Cell Transplantation for Patients with Fanconi Anemia and Bone Marrow Failure.

    PubMed

    Ayas, Mouhab; Eapen, Mary; Le-Rademacher, Jennifer; Carreras, Jeanette; Abdel-Azim, Hisham; Alter, Blanche P; Anderlini, Paolo; Battiwalla, Minoo; Bierings, Marc; Buchbinder, David K; Bonfim, Carmem; Camitta, Bruce M; Fasth, Anders L; Gale, Robert Peter; Lee, Michelle A; Lund, Troy C; Myers, Kasiani C; Olsson, Richard F; Page, Kristin M; Prestidge, Tim D; Radhi, Mohamed; Shah, Ami J; Schultz, Kirk R; Wirk, Baldeep; Wagner, John E; Deeg, H Joachim

    2015-10-01

    A second allogeneic hematopoietic cell transplantation (HCT) is the sole salvage option for individuals who develop graft failure after their first HCT. Data on outcomes after second HCT in patients with Fanconi anemia (FA) are scarce. Here we report outcomes after second allogeneic HCT for FA (n = 81). The indication for second HCT was graft failure after the first HCT. Transplantations were performed between 1990 and 2012. The timing of the second HCT predicted subsequent graft failure and survival. Graft failure was high when the second HCT was performed less than 3 months from the first. The 3-month probability of graft failure was 69% when the interval between the first HCT and second HCT was less than 3 months, compared with 23% when the interval was longer (P < .001). Consequently, the 1-year survival rate was substantially lower when the interval between the first and second HCTs was less than 3 months compared with longer (23% vs 58%; P = .001). The corresponding 5-year probability of survival was 16% and 45%, respectively (P = .006). Taken together, these data suggest that fewer than one-half of patients with FA undergoing a second HCT for graft failure are long-term survivors. There is an urgent need to develop strategies to reduce the rate of graft failure after first HCT. PMID:26116087

  15. The Fanconi Anemia Pathway Protects Genome Integrity from R-loops

    PubMed Central

    García-Rubio, María L.; Pérez-Calero, Carmen; Barroso, Sonia I.; Tumini, Emanuela; Herrera-Moyano, Emilia; Rosado, Iván V.; Aguilera, Andrés

    2015-01-01

    Co-transcriptional RNA-DNA hybrids (R loops) cause genome instability. To prevent harmful R loop accumulation, cells have evolved specific eukaryotic factors, one being the BRCA2 double-strand break repair protein. As BRCA2 also protects stalled replication forks and is the FANCD1 member of the Fanconi Anemia (FA) pathway, we investigated the FA role in R loop-dependent genome instability. Using human and murine cells defective in FANCD2 or FANCA and primary bone marrow cells from FANCD2 deficient mice, we show that the FA pathway removes R loops, and that many DNA breaks accumulated in FA cells are R loop-dependent. Importantly, FANCD2 foci in untreated and MMC-treated cells are largely R loop dependent, suggesting that the FA functions at R loop-containing sites. We conclude that co-transcriptional R loops and R loop-mediated DNA damage greatly contribute to genome instability and that one major function of the FA pathway is to protect cells from R loops. PMID:26584049

  16. Regulation of Fanconi anemia protein FANCD2 monoubiquitination by miR-302.

    PubMed

    Suresh, Bharathi; Kumar, A Madhan; Jeong, Hoe-Su; Cho, Youl-Hee; Ramakrishna, Suresh; Kim, Kye-Seong

    2015-10-16

    Fanconi anemia (FA) is a recessively inherited multigene disease characterized by congenital defects, progressive bone marrow failure, and heightened cancer susceptibility. Monoubiquitination of the FA pathway member FANCD2 contributes to the repair of replication stalling DNA lesions. However, cellular regulation of FANCD2 monoubiquitination remains poorly understood. In the present study, we identified the miR-302 cluster as a potential regulator of FANCD2 by bioinformatics analysis. MicroRNAs (miRNAs) are the major posttranscriptional regulators of a wide variety of biological processes, and have been implicated in a number of diseases. Expression of the exogenous miR-302 cluster (without miR-367) reduced FANCD2 monoubiquitination and nuclear foci formation. Furthermore, miR-302 cells showed extensive chromosomal breakage upon MMC treatment when compared to mock control cells. Taken together, our results suggest that overexpression of miR-302 plays a critical role in the regulation of FANCD2 monoubiquitination, resulting in characteristic defects in DNA repair within cells. PMID:26343459

  17. Plasma ultrafiltrates from Fanconi Anemia patients induces chromosomal breakages in donor lymphocytes

    SciTech Connect

    Emerit, I.; Levy, A.; Pagano, G.

    1994-09-01

    The present study investigated the occurrence, if any, of transferable clastogenic activity in the plasma from Fanconi Anemia (FA) patients and their families. A total of 13 FA homozygotes, 25 parents, and 12 siblings were studied for their: (a) spontaneous and DEB-induced chromosomal instability, and (b) induction of chromosomal breaks in peripheral blood lymphocytes (PBL) from healthy donors, following exposure to plasma ultrafiltrates from FA subjects, their parents or siblings. Plasma was ultrafiltered through membranes with a cutoff at 10,000 daltons (YM 10 Amicon) and 0.25 ml-aliquote added to PBL from 14 healthy donors. DEB test provided FA confirmatory diagnosis. The occurrence of clastogenic factors (CF) was evident in all FA patients, except for one. In two out of three patients, who died during this study, very high CF levels were observed. Clastogenic activity was significantly higher in male than in female patients (p<0.05). No correlation was observed between CF data and spontaneous or DEB-induced chromosomal instability. Ultrafiltrates from parents and siblings showed less CF than FA homozygotes; however, concentration by ultrafiltration through YM 2 (3x to 5x) led to excess clastogenic activity. The control plasmas were lacking CF even after an 8x concentration. The present data suggest that CF formation in the plasma of FA patients is consistent with an in vivo prooxident state in FA.

  18. FANCJ suppresses microsatellite instability and lymphomagenesis independent of the Fanconi anemia pathway

    PubMed Central

    Matsuzaki, Kenichiro; Borel, Valerie; Adelman, Carrie A.; Schindler, Detlev; Boulton, Simon J.

    2015-01-01

    Microsatellites are short tandem repeat sequences that are highly prone to expansion/contraction due to their propensity to form non-B-form DNA structures, which hinder DNA polymerases and provoke template slippage. Although error correction by mismatch repair plays a key role in preventing microsatellite instability (MSI), which is a hallmark of Lynch syndrome, activities must also exist that unwind secondary structures to facilitate replication fidelity. Here, we report that Fancj helicase-deficient mice, while phenotypically resembling Fanconi anemia (FA), are also hypersensitive to replication inhibitors and predisposed to lymphoma. Whereas metabolism of G4-DNA structures is largely unaffected in Fancj−/− mice, high levels of spontaneous MSI occur, which is exacerbated by replication inhibition. In contrast, MSI is not observed in Fancd2−/− mice but is prevalent in human FA-J patients. Together, these data implicate FANCJ as a key factor required to counteract MSI, which is functionally distinct from its role in the FA pathway. PMID:26637282

  19. Replication Protein A (RPA) deficiency activates the Fanconi anemia DNA repair pathway.

    PubMed

    Jang, Seok-Won; Jung, Jin Ki; Kim, Jung Min

    2016-09-01

    The Fanconi anemia (FA) pathway regulates DNA inter-strand crosslink (ICL) repair. Despite our greater understanding of the role of FA in ICL repair, its function in the preventing spontaneous genome instability is not well understood. Here, we show that depletion of replication protein A (RPA) activates the FA pathway. RPA1 deficiency increases chromatin recruitment of FA core complex, leading to FANCD2 monoubiquitination (FANCD2-Ub) and foci formation in the absence of DNA damaging agents. Importantly, ATR depletion, but not ATM, abolished RPA1 depletion-induced FANCD2-Ub, suggesting that ATR activation mediated FANCD2-Ub. Interestingly, we found that depletion of hSSB1/2-INTS3, a single-stranded DNA-binding protein complex, induces FANCD2-Ub, like RPA1 depletion. More interestingly, depletion of either RPA1 or INTS3 caused increased accumulation of DNA damage in FA pathway deficient cell lines. Taken together, these results indicate that RPA deficiency induces activation of the FA pathway in an ATR-dependent manner, which may play a role in the genome maintenance. PMID:27398742

  20. Ubiquitin-SUMO Circuitry Controls Activated Fanconi Anemia ID Complex Dosage in Response to DNA Damage

    PubMed Central

    Gibbs-Seymour, Ian; Oka, Yasuyoshi; Rajendra, Eeson; Weinert, Brian T.; Passmore, Lori A.; Patel, Ketan J.; Olsen, Jesper V.; Choudhary, Chunaram; Bekker-Jensen, Simon; Mailand, Niels

    2015-01-01

    Summary We show that central components of the Fanconi anemia (FA) DNA repair pathway, the tumor suppressor proteins FANCI and FANCD2 (the ID complex), are SUMOylated in response to replication fork stalling. The ID complex is SUMOylated in a manner that depends on the ATR kinase, the FA ubiquitin ligase core complex, and the SUMO E3 ligases PIAS1/PIAS4 and is antagonized by the SUMO protease SENP6. SUMOylation of the ID complex drives substrate selectivity by triggering its polyubiquitylation by the SUMO-targeted ubiquitin ligase RNF4 to promote its removal from sites of DNA damage via the DVC1-p97 ubiquitin segregase complex. Deregulation of ID complex SUMOylation compromises cell survival following replication stress. Our results uncover a regulatory role for SUMOylation in the FA pathway, and we propose that ubiquitin-SUMO signaling circuitry is a mechanism that contributes to the balance of activated ID complex dosage at sites of DNA damage. PMID:25557546

  1. Fanconi anemia pathway regulates convergent transcription-induced cell death at trinucleotide repeats in human cells

    PubMed Central

    Chatterjee, Nimrat; Lin, Yunfu; Wilson, John H.

    2016-01-01

    Almost 20 incurable neurodegenerative disorders are caused by trinucleotide repeat (TNR) expansion beyond a certain threshold, with disease time of onset and severity positively correlating with repeat length. Typically, long TNRs display a bias toward further expansion and repeats continue to expand not only during germline transmissions from parents to offspring, but also remain highly unstable in somatic tissues of patients. Hence, understanding TNR instability mechanisms sheds light on underlying disease pathology. Recently, we showed that activated ATR is the major signal for convergent-transcription-induced cell death at CAG repeats and is regulated by the mismatch repair (MMR) pathway. Additionally, components of other DNA repair pathways such as transcription-coupled nucleotide excision repair (TC-NER) and R-loop resolution by RNaseH reduce cell death. Because activated ATR signals the Fanconi anemia (FA) pathway of interstrand crosslink DNA repair, we asked whether the FA pathway also modulates convergent-transcription-induced cell death at expanded CAG repeats. We show here that siRNA knockdown of FA components—FANCI, FANCJ, FANCM, FANCA, and FANCD2—decreases cell death, suggesting that FA proteins, like MMR proteins, are activators of cell death during convergent transcription.

  2. Bone mineral density in children with fanconi anemia after hematopoietic cell transplantation.

    PubMed

    Petryk, Anna; Polgreen, Lynda E; Barnum, Jessie L; Zhang, Lei; Hodges, James S; Baker, K Scott; Wagner, John E; Steinberger, Julia; MacMillan, Margaret L

    2015-05-01

    Fanconi anemia (FA) is an inherited DNA repair disorder associated with short stature and bone marrow failure, usually requiring hematopoietic cell transplantation (HCT). Although low bone mineral density (BMD) has been reported in leukemia patients after HCT, little is known about BMD in FA children after HCT (FA HCT). This study's goals were to compare BMD in FA HCT to BMD in healthy controls and in children who received HCT for hematologic malignancy (cancer HCT), and to test for associations between BMD and risk factors for bone loss. This cross-sectional study included 20 FA HCT, 13 cancer HCT, and 90 healthy controls, age-matched and <18 years old at evaluation. BMD Z-scores for total body (TBMD) and lumbar spine (LBMD) were measured by dual energy x-ray absorptiometry and adjusted for height-for-age Z-score (HAZ). FA HCT had lower mean TBMDHAZ Z-score (by .8 SD) and higher fraction with Z-score ≤ -1 than healthy controls (42% versus 11%). No LBMD deficits were detected. FA HCT and cancer HCT groups did not differ significantly in TBMD or LBMD Z-scores. In FA HCT patients, lower body mass index and lower percent fat were associated with lower BMD. This study highlights the importance of monitoring BMD to optimize bone health in FA patients. PMID:25591848

  3. Long-term Survival, Organ Function, and Malignancy after Hematopoietic Stem Cell Transplantation for Fanconi Anemia.

    PubMed

    Bonfim, Carmem; Ribeiro, Lisandro; Nichele, Samantha; Bitencourt, Marco; Loth, Gisele; Koliski, Adriana; Funke, Vaneuza A M; Pilonetto, Daniela V; Pereira, Noemi F; Flowers, Mary E D; Velleuer, Eunike; Dietrich, Ralf; Fasth, Anders; Torres-Pereira, Cassius C; Pedruzzi, Paola; Eapen, Mary; Pasquini, Ricardo

    2016-07-01

    We report on long-term survival in 157 patients with Fanconi anemia (FA) who survived 2 years or longer after their first transplantation with a median follow-up of 9 years. Marrow failure (80%) was the most common indication for transplantation. There were 20 deaths beyond 2 years after transplantation, with 12 of the deaths occurring beyond 5 years after transplantation. Donor chimerism was available for 149 patients: 112 (76%) reported > 95% chimerism, 27 (18%) reported 90% to 95% chimerism, and 8 (5%) reported 20% to 89% donor chimerism. Two patients have < 20% donor chimerism. The 10- and 15-year probabilities of survival were 90% and 79%, respectively. Results of multivariate analysis showed higher mortality risks for transplantations before 2003 (hazard ratio [HR], 7.87; P = .001), chronic graft-versus-host disease (GVHD) (HR, 3.80; P = .004) and squamous cell carcinoma after transplantation (HR, 38.17; P < .0001). The predominant cause of late mortality was squamous cell carcinoma, with an incidence of 8% and 14% at 10 and 15 years after transplantation, respectively, and was more likely to occur in those with chronic GVHD. Other causes of late mortality included chronic GVHD, infection, graft failure, other cancers, and hemorrhage. Although most patients are disease free and functional long term, our data support aggressive surveillance for long periods to identify those at risk for late mortality. PMID:26976241

  4. Fanconi Syndrome Secondary to Deferasirox in Diamond-Blackfan Anemia: Case Series and Recommendations for Early Diagnosis.

    PubMed

    Papneja, Koyelle; Bhatt, Mihir D; Kirby-Allen, Melanie; Arora, Steven; Wiernikowski, John T; Athale, Uma H

    2016-08-01

    Deferasirox is an oral iron chelator used to treat patients with transfusion-related iron overload. We report, from two institutions, two children with Diamond-Blackfan anemia who developed Fanconi syndrome secondary to deferasirox administration, along with a review of the literature. The current recommendation for the laboratory monitoring of patients receiving deferasirox does not include serum electrolytes or urine analysis. Thus, despite routine clinic visits and bloodwork, these two patients presented with life-threatening electrolyte abnormalities requiring hospitalization. Hence, we propose the inclusion of serum electrolytes and urine analysis as part of routine monitoring to facilitate the early diagnosis of Fanconi syndrome in the context of high doses of deferasirox therapy. PMID:27082377

  5. Rejection of the second allogeneic graft in a child with Fanconi anemia reversed by antilymphocyte globulin and donor lymphocyte infusion.

    PubMed

    Abdelkefi, Abderrahman; Ben Othman, T; Ladeb, S; Torjman, L; Ben Abdeladhim, A

    2003-01-01

    Rejection after allogeneic bone marrow transplantation for Fanconi anemia (FA) is a complication with a high risk of mortality. We describe a patient who, following a second episode of rejection after a second allogeneic stem cell transplantation, was successfully treated with antilymphocyte globulin, followed by donor lymphocyte infusion. At three and a half years after donor lymphocyte infusion, she is alive with a Karnofsky score of 90%. Her molecular chimerism is of donor origin. Thus, donor lymphocyte infusion can be considered as a therapy option for rejection after allogeneic bone marrow transplantation for FA. PMID:14671621

  6. Anti-Müllerian Hormone Deficiency in Females With Fanconi Anemia

    PubMed Central

    Sklavos, Martha M.; Giri, Neelam; Stratton, Pamela; Alter, Blanche P.

    2014-01-01

    Context: In females with Fanconi anemia (FA), infertility is often accompanied by diminished ovarian reserve and hypergonadotropic amenorrhea before the age of 30 years, suggesting primary ovarian insufficiency (POI). POI is typically diagnosed only after perimenopausal symptoms are observed. Objective: The objective of the study was to assess whether serum anti-Müllerian hormone (AMH) levels can serve as a cycle-independent marker for the diagnosis of POI in patients with FA. Design and Setting: This observational study used the National Cancer Institute's inherited bone marrow failure syndrome cohort at the National Institutes of Health Clinical Center. Participants: The study included 22 females with FA, 20 unaffected female relatives of patients with FA, and 21 unrelated healthy females under 41 years of age. Main Outcome Measure: Serum AMH, a marker of ovarian reserve, was measured in all participants. Results: Females with FA had very low AMH levels (median 0.05 ng/mL; range 0–2.32 ng/mL; P < .001) when compared with unaffected relatives (median 2.10 ng/mL; range 0.04–4.73 ng/mL) and unrelated healthy females (median 1.92 ng/mL; range 0.31–6.64 ng/mL). All patients with FA older than 25 years of age were diagnosed with POI and had undetectable AMH levels. Conclusions: AMH deficiency appears to be a shared trait across this heterogeneous FA cohort. Substantially reduced AMH levels in females with FA suggest a primary ovarian defect associated with reduced fertility. Measurement of AMH at the time of FA diagnosis and subsequent monitoring of AMH levels at regular intervals may be useful for the timely management of complications related to POI such as subfertility/infertility, osteoporosis, and menopausal symptoms. PMID:24438373

  7. Oral manifestations compatible with chronic graft-versus-host disease in patients with Fanconi anemia.

    PubMed

    Grein Cavalcanti, Laura; Fuentes Araújo, Renata L; Bonfim, Carmem; Torres-Pereira, Cassius C

    2015-02-01

    Fanconi anemia (FA) is a genetic disease that is characterized by several congenital abnormalities and progressive bone marrow failure and is associated with an increased susceptibility to malignant disorders. Currently, the only potential cure for hematological disorders is hematopoietic stem cell transplantation (HSCT). However, 1 of the most common complications after HSCT is the development of oral chronic graft-versus-host disease (cGVHD), which is also a risk factor for the development of cancer, particularly oral squamous cell carcinoma. Therefore, the purpose of this study was to describe the prevalence and characteristics of oral manifestations compatible with cGVHD in patients diagnosed with FA according to the National Institutes of Health (NIH) consensus criteria. A total of 96 patients (51 females, 45 males; median age, 16 years) with FA, who were in medical follow-up after HSCT at the outpatient clinic of the bone marrow transplantation unit (Hospital de Clínicas from the Universidade Federal do Paraná) underwent an oral evaluation between January 2013 and December 2013. Post-HSCT periods varied from 1 to 261 months and were divided into 3 periods: immediate post-HSCT period; intermediate post-HSC period, and late post-HSCT period. Among the evaluated patients, 40 of 96 (42%) presented with oral manifestations of cGVHD, with 29 of 40 (73%) of these patients in the late post-HSCT period. NIH scale scores varied from 0 to 10, and lichenoid and hyperkeratotic lesions were the abnormalities most frequently observed (100%). Overall, a high prevalence of oral manifestations was observed for cGVHD patients with FA. These data highlight the importance of monitoring oral manifestations compatible with cGVHD to identify and treat individuals with a higher risk of developing oral cancer. PMID:25316110

  8. Disseminated Medulloblastoma in a Child with Germline BRCA2 6174delT Mutation and without Fanconi Anemia.

    PubMed

    Xu, Jingying; Margol, Ashley Sloane; Shukla, Anju; Ren, Xiuhai; Finlay, Jonathan L; Krieger, Mark D; Gilles, Floyd H; Couch, Fergus J; Aziz, Meraj; Fung, Eric T; Asgharzadeh, Shahab; Barrett, Michael T; Erdreich-Epstein, Anat

    2015-01-01

    Medulloblastoma, the most common malignant brain tumor in children, occurs with increased frequency in individuals with Fanconi anemia who have biallelic germline mutations in BRCA2. We describe an 8-year-old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented 8 months after diagnosis as malignant pleural and peritoneal effusions. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here, we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization, and next generation sequencing analysis. In addition to the BRCA2 6174delT, the medulloblastoma cells had amplification of MYC, deletion at Xp11.2, and isochromosome 17, but no structural variations or overexpression of GFI1 or GFI1B. To our knowledge, this is the first pair of diagnosis/recurrence medulloblastoma cell lines, the only medulloblastoma cell lines with BRCA2 6174delT described to date, and the first reported case of a child with medulloblastoma associated with a germline BRCA2 6174delT who did not also have Fanconi anemia. PMID:26380221

  9. Fanconi anemia with biallelic FANCD1/BRCA2 mutations - Case report of a family with three affected children.

    PubMed

    Svojgr, Karel; Sumerauer, David; Puchmajerova, Alena; Vicha, Ales; Hrusak, Ondrej; Michalova, Kyra; Malis, Josef; Smisek, Petr; Kyncl, Martin; Novotna, Drahuse; Machackova, Eva; Jencik, Jan; Pycha, Karel; Vaculik, Miroslav; Kodet, Roman; Stary, Jan

    2016-03-01

    Fanconi anemia, complementation group D1 with bi-allelic FANCD1 (BRCA2) mutations, is a very rare genetic disorder characterized by early onset of childhood malignancies, including acute leukemia, brain cancer and nephroblastoma. Here, we present a case report of a family with 3 affected children in terms of treatment outcome, toxicity and characterization of the malignancies using comprehensive cytogenetic analysis. The first child was diagnosed with T-cell acute lymphoblastic leukemia when he was 11 months old. During chemotherapy, he suffered from repeated pancytopenia, sepsis and severe vincristine polyneuropathy, and 18 months after primary diagnosis, he succumbed to secondary acute monocytic leukemia. The second child was diagnosed with stage 2 triphasic nephroblastoma (Wilms tumor), when he was 3 years and 11 months old. During chemotherapy, he suffered from vincristine polyneuropathy. Currently, he is in complete remission, 29 months following the initial diagnosis. The third child was diagnosed with medulloblastoma with classical histology, when she was 4 years and 5 months old. After the first cycle of chemotherapy, she suffered from prolonged pancytopenia, sepsis and severe skin and mucosal toxicity. Six weeks after primary diagnosis, a first relapse in the posterior fossa was diagnosed, and at 7 and half months after primary diagnosis, a second relapse was diagnosed that led to the patient's death. Our case report underscores tumor heterogeneity, treatment toxicity and poor outcome in Fanconi anemia patients of complementation group D1. PMID:26657402

  10. Disseminated Medulloblastoma in a Child with Germline BRCA2 6174delT Mutation and without Fanconi Anemia

    PubMed Central

    Xu, Jingying; Margol, Ashley Sloane; Shukla, Anju; Ren, Xiuhai; Finlay, Jonathan L.; Krieger, Mark D.; Gilles, Floyd H.; Couch, Fergus J.; Aziz, Meraj; Fung, Eric T.; Asgharzadeh, Shahab; Barrett, Michael T.; Erdreich-Epstein, Anat

    2015-01-01

    Medulloblastoma, the most common malignant brain tumor in children, occurs with increased frequency in individuals with Fanconi anemia who have biallelic germline mutations in BRCA2. We describe an 8-year-old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented 8 months after diagnosis as malignant pleural and peritoneal effusions. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here, we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization, and next generation sequencing analysis. In addition to the BRCA2 6174delT, the medulloblastoma cells had amplification of MYC, deletion at Xp11.2, and isochromosome 17, but no structural variations or overexpression of GFI1 or GFI1B. To our knowledge, this is the first pair of diagnosis/recurrence medulloblastoma cell lines, the only medulloblastoma cell lines with BRCA2 6174delT described to date, and the first reported case of a child with medulloblastoma associated with a germline BRCA2 6174delT who did not also have Fanconi anemia. PMID:26380221

  11. Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs.

    PubMed

    Liu, Guang-Hui; Suzuki, Keiichiro; Li, Mo; Qu, Jing; Montserrat, Nuria; Tarantino, Carolina; Gu, Ying; Yi, Fei; Xu, Xiuling; Zhang, Weiqi; Ruiz, Sergio; Plongthongkum, Nongluk; Zhang, Kun; Masuda, Shigeo; Nivet, Emmanuel; Tsunekawa, Yuji; Soligalla, Rupa Devi; Goebl, April; Aizawa, Emi; Kim, Na Young; Kim, Jessica; Dubova, Ilir; Li, Ying; Ren, Ruotong; Benner, Chris; del Sol, Antonio; Bueren, Juan; Trujillo, Juan Pablo; Surralles, Jordi; Cappelli, Enrico; Dufour, Carlo; Esteban, Concepcion Rodriguez; Izpisua Belmonte, Juan Carlos

    2014-01-01

    Fanconi anaemia (FA) is a recessive disorder characterized by genomic instability, congenital abnormalities, cancer predisposition and bone marrow (BM) failure. However, the pathogenesis of FA is not fully understood partly due to the limitations of current disease models. Here, we derive integration free-induced pluripotent stem cells (iPSCs) from an FA patient without genetic complementation and report in situ gene correction in FA-iPSCs as well as the generation of isogenic FANCA-deficient human embryonic stem cell (ESC) lines. FA cellular phenotypes are recapitulated in iPSCs/ESCs and their adult stem/progenitor cell derivatives. By using isogenic pathogenic mutation-free controls as well as cellular and genomic tools, our model serves to facilitate the discovery of novel disease features. We validate our model as a drug-screening platform by identifying several compounds that improve hematopoietic differentiation of FA-iPSCs. These compounds are also able to rescue the hematopoietic phenotype of FA patient BM cells. PMID:24999918

  12. GS-nitroxide (JP4-039)-mediated radioprotection of human Fanconi anemia cell lines.

    PubMed

    Bernard, Mark E; Kim, Hyun; Berhane, Hebist; Epperly, Michael W; Franicola, Darcy; Zhang, Xichen; Houghton, Frank; Shields, Donna; Wang, Hong; Bakkenist, Christopher J; Frantz, Marie-Celine; Forbeck, Erin M; Goff, Julie P; Wipf, Peter; Greenberger, Joel S

    2011-11-01

    Fanconi anemia (FA) is an inherited disorder characterized by defective DNA repair and cellular sensitivity to DNA crosslinking agents. Clinically, FA is associated with high risk for marrow failure, leukemia and head and neck squamous cell carcinoma (HNSCC). Radiosensitivity in FA patients compromises the use of total-body irradiation for hematopoietic stem cell transplantation and radiation therapy for HNSCC. A radioprotector for the surrounding tissue would therefore be very valuable during radiotherapy for HNSCC. Clonogenic radiation survival curves were determined for pre- or postirradiation treatment with the parent nitroxide Tempol or JP4-039 in cells of four FA patient-derived cell lines and two transgene-corrected subclonal lines. FancG(-/-) (PD326) and FancD2(-/-) (PD20F) patient lines were more sensitive to the DNA crosslinking agent mitomycin C (MMC) than their transgene-restored subclonal cell lines (both P < 0.0001). FancD2(-/-) cells were more radiosensitive than the transgene restored subclonal cell line (ñ = 2.0 ± 0.7 and 4.7 ± 2.2, respectively, P = 0.03). In contrast, FancG(-/-) cells were radioresistant relative to the transgene-restored subclonal cell line (ñ = 9.4 ± 1.5 and 2.2 ± 05, respectively, P = 0.001). DNA strand breaks measured by the comet assay correlated with radiosensitivity. Cell lines from a Fanc-C and Fanc-A patients showed radiosensitivity similar to that of Fanc-D2(-/-) cells. A fluorophore-tagged JP4-039 (BODIPY-FL) analog targeted the mitochondria of the cell lines. Preirradiation or postirradiation treatment with JP4-039 at a lower concentration than Tempol significantly increased the radioresistance and stabilized the antioxidant stores of all cell lines. Tempol increased the toxicity of MMC in FancD2(-/-) cells. These data provide support for the potential clinical use of JP4-039 for normal tissue radioprotection during chemoradiotherapy in FA patients. PMID:21939290

  13. GS-Nitroxide (JP4-039)-Mediated Radioprotection of Human Fanconi Anemia Cell Lines

    PubMed Central

    Bernard, Mark E.; Kim, Hyun; Berhane, Hebist; Epperly, Michael W.; Franicola, Darcy; Zhang, Xichen; Houghton, Frank; Shields, Donna; Wang, Hong; Bakkenist, Christopher J.; Frantz, Marie-Celine; Forbeck, Erin M.; Goff, Julie P.; Wipf, Peter; Greenberger, Joel S.

    2011-01-01

    Fanconi anemia (FA) is an inherited disorder characterized by defective DNA repair and cellular sensitivity to DNA crosslinking agents. Clinically, FA is associated with high risk for marrow failure, leukemia and head and neck squamous cell carcinoma (HNSCC). Radiosensitivity in FA patients compromises the use of total-body irradiation for hematopoietic stem cell transplantation and radiation therapy for HNSCC. A radioprotector for the surrounding tissue would therefore be very valuable during radiotherapy for HNSCC. Clonogenic radiation survival curves were determined for pre- or postirradiation treatment with the parent nitroxide Tempol or JP4-039 in cells of four FA patient-derived cell lines and two transgene-corrected subclonal lines. FancG–/– (PD326) and FancD2–/– (PD20F) patient lines were more sensitive to the DNA crosslinking agent mitomycin C (MMC) than their transgene-restored subclonal cell lines (both P < 0.0001). FancD2–/– cells were more radiosensitive than the transgene restored subclonal cell line (ñ = 2.0 ± 0.7 and 4.7 ± 2.2, respectively, P = 0.03). In contrast, FancG–/– cells were radioresistant relative to the transgene-restored subclonal cell line (ñ = 9.4 ± 1.5 and 2.2 ± 05, respectively, P = 0.001). DNA strand breaks measured by the comet assay correlated with radiosensitivity. Cell lines from a Fanc-C and Fanc-A patients showed radiosensitivity similar to that of Fanc-D2–/– cells. A fluorophore-tagged JP4-039 (BODIPY-FL) analog targeted the mitochondria of the cell lines. Preirradiation or postirradiation treatment with JP4-039 at a lower concentration than Tempol significantly increased the radioresistance and stabilized the antioxidant stores of all cell lines. Tempol increased the toxicity of MMC in FancD2–/– cells. These data provide support for the potential clinical use of JP4-039 for normal tissue radioprotection during chemoradiotherapy in FA patients. PMID:21939290

  14. Fanconi Anemia Repair Pathway Dysfunction, a Potential Therapeutic Target in Lung Cancer

    PubMed Central

    Duan, Wenrui; Gao, Li; Aguila, Brittany; Kalvala, Arjun; Otterson, Gregory A.; Villalona-Calero, Miguel A.

    2014-01-01

    The Fanconi anemia (FA) pathway is a major mechanism of homologous recombination DNA repair. The functional readout of the pathway is activation through mono-ubiquitination of FANCD2 leading to nuclear foci of repair. We have recently developed an FA triple-staining immunofluorescence based method (FATSI) to evaluate FANCD2 foci formation in formalin fixed paraffin-embedded (FFPE) tumor samples. DNA-repair deficiencies have been considered of interest in lung cancer prevention, given the persistence of damage produced by cigarette smoke in this setting, as well as in treatment, given potential increased efficacy of DNA-damaging drugs. We screened 139 non-small cell lung cancer (NSCLC) FFPE tumors for FANCD2 foci formation by FATSI analysis. Among 104 evaluable tumors, 23 (22%) were FANCD2 foci negative, thus repair deficient. To evaluate and compare novel-targeted agents in the background of FA deficiency, we utilized RNAi technology to render several lung cancer cell lines FANCD2 deficient. Successful FANCD2 knockdown was confirmed by reduction in the FANCD2 protein. Subsequently, we treated the FA defective H1299D2-down and A549D2-down NSCLC cells and their FA competent counterparts (empty vector controls) with the PARP inhibitors veliparib (ABT-888) (5 μM) and BMN673 (0.5 μM), as well as the CHK1 inhibitor Arry-575 at a dose of 0.5 μM. We also treated the FA defective small cell lung cancer cell lines H719D2-down and H792D2-down and their controls with the BCL-2/XL inhibitor ABT-263 at a dose of 2 μM. The treated cells were harvested at 24, 48, and 72 h post treatment. MTT cell viability analysis showed that each agent was more cytotoxic to the FANCD2 knock-down cells. In all tests, the FA defective lung cancer cells had less viable cells as comparing to controls 72 h post treatment. Both MTT and clonogenic analyses comparing the two PARP inhibitors, showed that BMN673 was more potent compared to veliparib. Given that FA pathway plays essential

  15. Factors affecting the outcome of related allogeneic hematopoietic cell transplantation in patients with Fanconi Anemia.

    PubMed

    Ayas, Mouhab; Siddiqui, Khawar; Al-Jefri, Abdullah; El-Solh, Hassan; Al-Ahmari, Ali; Khairy, Ashraf; Markiz, Samer; Shahin, Hasan; Al-Musa, Abdulrahman; Al-Seraihy, Amal

    2014-10-01

    Hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi Anemia (FA), and it is generally accepted that these patients should receive low-intensity conditioning because of the underlying DNA repair defect in their cells. Outcomes for recipients of matched related HCT have generally been favorable, but only a few studies have scrutinized the factors that may affect the eventual outcome of these patients. This retrospective analysis of 94 pediatric patients with FA who underwent related HCT at King Faisal Specialist Hospital & Research Center was carried out to attempt to identify factors that may affect outcome. Results showed overall survival (OS) probabilities of 92.5%, 89%, and 86% at 1, 5, and 10 years, respectively. In univariate analysis, use of higher dose cyclophosphamide (CY) (60 mg/kg) conditioning was associated with a better 10-year OS than lower dose CY (20 mg/kg) conditioning (91% versus 82%, respectively; P = .035), and use of radiation-containing regimens was associated with a significantly lower 10-year OS than nonradiation regimens (76% versus 91%, respectively; P = .005). Of the 4 regimens used in this study, the fludarabine-based regimen was associated with the highest survival (95.2%; P = .034). The use of the higher dose CY (60 mg/kg) was associated with a significantly increased incidence of hemorrhagic cystitis (HC) (20% versus 5.6% respectively; P = .049). Three patients (3%) developed squamous cell carcinoma (2 oropharyngeal and 1 genitourinary), at 9.4, 5.4, and 13.3 years after HCT; 2 of them had radiation-containing conditioning. In conclusion, our data suggest that although using a higher dose CY (60 mg/kg) conditioning regimen may be associated with better survival, it is also associated with a significantly increased risk of HC. The addition of fludarabine to the low-dose CY (20 mg/kg) is associated with the best survival. On the other hand, radiation-containing regimens are associated with

  16. Living related liver transplantation in an adult patient with hepatocellular adenoma and carcinoma 13 years after bone marrow transplantation for Fanconi anemia: a case report

    PubMed Central

    Colle, Isabelle; Laureys, Geneviève; Raevens, Sarah; Libbrecht, Louis; Reyntjens, Koen; Geerts, Anja; Rogiers, Xavier; Troisi, Roberto; Hoehn, Holger; Schindler, Detlev; Hanenberg, Helmut; De Wilde, Vincent; Van Vlierberghe, Hans

    2013-01-01

    Fanconi anemia is an inherited bone marrow failure syndrome, characterised by failing DNA repair. Hematopoetic stem cell transplantation, known to be curative for the bone marrow failure, does neither prevent or cure other manifestations such as the development of malignancies. We describe a 26-year-old male patient with known Fanconi anemia and Marfan syndrome who in 1994 underwent a successful bone marrow transplantation of stem cells from his HLA-identical sister. In 2006, three hepatocellular carcinoma (HCC) lesions in the liver were detected and promptly resected. The resection specimen contained 3 lesions, all showing activation of the beta-catenin pathway: a well differentiated steatotic HCC with remnants of the underlying adenoma from which it arose, an adenoma with small foci of well differentiated HCC and a cholestatic adenoma. Known risk factors for developing HCC include Fanconi anemia itself and the use of androgens (oxymetholone) for a period of 3 years preceeding transplantation. Because of the increased risk of developing additional HCC’s, liver transplantation was proposed, taking into account that immunosuppression increases the risk of other malignancies. By using part of the liver of the HLA-identical sister, already acting as bone marrow donor 13 years before, immunosuppression could be avoided. A left lobe liver transplantation was performed without immediate complications for donor and acceptor on July 2, 2007. Nine months after liver transplantation the recipient developed an anastomotic biliary stricture that had to be dilated by percutaneous transhepatic cholangiography. Two months later however, the stenosis recurred, necessitating a surgical reanastomosis (hepaticojejunostomy). Five years after liver transplantation the patient is still doing well. This case report is twofold special being the first case reporting Fanconi anemia linked to Marfan syndrome and being the first reported case of Fanconi anemia who was treated for

  17. Fanconi anemia protein FANCD2 inhibits TRF1 polyADP-ribosylation through tankyrase1-dependent manner

    PubMed Central

    2011-01-01

    Background Fanconi anemia (FA) is a rare autosomal recessive syndrome characterized by developmental abnormalities, progressive bone marrow failure, and predisposition to cancer. The key FA protein FANCD2 crosstalks with members of DNA damage and repair pathways that also play a role at telomeres. Therefore, we investigated whether FANCD2 has a similar involvement at telomeres. Results We reveal that FANCD2 may perform a novel function separate to the FANCD2/BRCA pathway. This function includes FANCD2 interaction with one of the telomere components, the PARP family member tankyrase-1. Moreover, FANCD2 inhibits tankyrase-1 activity in vitro. In turn, FANCD2 deficiency increases the polyADP-ribosylation of telomere binding factor TRF1. Conclusions FANCD2 binding and inhibiting tankyrase-1PARsylation at telomeres may provide an additional step within the FA pathway for the regulation of genomic integrity. PMID:21314979

  18. Haploidentical stem cell transplantation as a salvage therapy for cord blood engraftment failure in a patient with Fanconi anemia.

    PubMed

    Rihani, Rawad; Lataifeh, Isam; Halalsheh, Hadeel; Hussein, Ayad Ahmed; Al-Zaben, Abdulhadi; Abdel-Rahman, Fawzi; Sarhan, Mahmoud

    2010-09-01

    A 7-year-old male with Fanconi Anemia who developed primary graft failure following one antigen-mismatched unrelated cord blood transplantation and a nonradiation-based conditioning, underwent a second hematopoietic stem cell transplantation (HSCT) from his 2-loci mismatched haploidentical father, using a nonradiation-based regimen, 79 days after the first HSCT. A sustained hematological engraftment was achieved at 9 days post-second HSCT. At 15 months post-second HSCT; the patient demonstrated normal blood counts, sustained donor chimerism, and no evidence of GVHD. Haploidentical HSCTs as primary or secondary sources of stem cells, with appropriate T-cell depletion, may be a readily available option in the absence of HLA-matched related or unrelated donors. PMID:20658637

  19. Insight into the Roles of Helicase Motif Ia by Characterizing Fanconi Anemia Group J Protein (FANCJ) Patient Mutations*

    PubMed Central

    Guo, Manhong; Vidhyasagar, Venkatasubramanian; Ding, Hao; Wu, Yuliang

    2014-01-01

    Helicases are molecular motors that couple the energy of ATP hydrolysis to the unwinding and remodeling of structured DNA or RNA, which is coordinated by conserved helicase motifs. FANCJ is a DNA helicase that is genetically linked to Fanconi anemia, breast cancer, and ovarian cancer. Here, we characterized two Fanconi anemia patient mutations, R251C and Q255H, that are localized in helicase motif Ia. Our genetic complementation analysis revealed that both the R251C and Q255H alleles failed to rescue cisplatin sensitivity of a FANCJ null cell line as detected by cell survival or γ-H2AX foci formation. Furthermore, our biochemical assays demonstrated that both purified recombinant proteins abolished DNA helicase activity and failed to disrupt the DNA-protein complex. Intriguingly, R251C impaired DNA binding ability to single-strand DNA and double-strand DNA, whereas Q255H retained higher binding activity to these DNA substrates compared with wild-type FANCJ protein. Consequently, R251C abolished its DNA-dependent ATP hydrolysis activity, whereas Q255H retained normal ATPase activity. Physically, R251C had reduced ATP binding ability, whereas Q255H had normal ATP binding ability and could translocate on single-strand DNA. Although both proteins were recruited to damage sites in our laser-activated confocal assays, they lost their DNA repair function, which explains why they exerted a domain negative effect when expressed in a wild-type background. Taken together, our work not only reveals the structural function of helicase motif Ia but also provides the molecular pathology of FANCJ in related diseases. PMID:24573678

  20. ΔNp63 activates the Fanconi anemia DNA repair pathway and limits the efficacy of cisplatin treatment in squamous cell carcinoma.

    PubMed

    Bretz, Anne Catherine; Gittler, Miriam P; Charles, Joël P; Gremke, Niklas; Eckhardt, Ines; Mernberger, Marco; Mandic, Robert; Thomale, Jürgen; Nist, Andrea; Wanzel, Michael; Stiewe, Thorsten

    2016-04-20

    TP63, a member of the p53 gene family gene, encodes the ΔNp63 protein and is one of the most frequently amplified genes in squamous cell carcinomas (SCC) of the head and neck (HNSCC) and lungs (LUSC). Using an epiallelic series of siRNAs with intrinsically different knockdown abilities, we show that the complete loss of ΔNp63 strongly impaired cell proliferation, whereas partial ΔNp63 depletion rendered cells hypersensitive to cisplatin accompanied by an accumulation of DNA damage. Expression profiling revealed wide-spread transcriptional regulation of DNA repair genes and in particular Fanconi anemia (FA) pathway components such as FANCD2 and RAD18 - known to be crucial for the repair of cisplatin-induced interstrand crosslinks. In SCC patients ΔNp63 levels significantly correlate with FANCD2 and RAD18 expression confirming ΔNp63 as a key activator of the FA pathwayin vivo Mechanistically, ΔNp63 bound an upstream enhancer of FANCD2 inactive in primary keratinocytes but aberrantly activated by ΔNp63 in SCC. Consistently, depletion of FANCD2 sensitized to cisplatin similar to depletion of ΔNp63. Together, our results demonstrate that ΔNp63 directly activates the FA pathway in SCC and limits the efficacy of cisplatin treatment. Targeting ΔNp63 therefore would not only inhibit SCC proliferation but also sensitize tumors to chemotherapy. PMID:26819410

  1. ΔNp63 activates the Fanconi anemia DNA repair pathway and limits the efficacy of cisplatin treatment in squamous cell carcinoma

    PubMed Central

    Bretz, Anne Catherine; Gittler, Miriam P.; Charles, Joël P.; Gremke, Niklas; Eckhardt, Ines; Mernberger, Marco; Mandic, Robert; Thomale, Jürgen; Nist, Andrea; Wanzel, Michael; Stiewe, Thorsten

    2016-01-01

    TP63, a member of the p53 gene family gene, encodes the ΔNp63 protein and is one of the most frequently amplified genes in squamous cell carcinomas (SCC) of the head and neck (HNSCC) and lungs (LUSC). Using an epiallelic series of siRNAs with intrinsically different knockdown abilities, we show that the complete loss of ΔNp63 strongly impaired cell proliferation, whereas partial ΔNp63 depletion rendered cells hypersensitive to cisplatin accompanied by an accumulation of DNA damage. Expression profiling revealed wide-spread transcriptional regulation of DNA repair genes and in particular Fanconi anemia (FA) pathway components such as FANCD2 and RAD18 - known to be crucial for the repair of cisplatin-induced interstrand crosslinks. In SCC patients ΔNp63 levels significantly correlate with FANCD2 and RAD18 expression confirming ΔNp63 as a key activator of the FA pathway in vivo. Mechanistically, ΔNp63 bound an upstream enhancer of FANCD2 inactive in primary keratinocytes but aberrantly activated by ΔNp63 in SCC. Consistently, depletion of FANCD2 sensitized to cisplatin similar to depletion of ΔNp63. Together, our results demonstrate that ΔNp63 directly activates the FA pathway in SCC and limits the efficacy of cisplatin treatment. Targeting ΔNp63 therefore would not only inhibit SCC proliferation but also sensitize tumors to chemotherapy. PMID:26819410

  2. Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid.

    PubMed

    Burgos-Morón, Estefanía; Calderón-Montaño, José Manuel; Orta, Manuel Luis; Guillén-Mancina, Emilio; Mateos, Santiago; López-Lázaro, Miguel

    2016-01-01

    Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee. PMID:27399778

  3. Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid

    PubMed Central

    Burgos-Morón, Estefanía; Calderón-Montaño, José Manuel; Orta, Manuel Luis; Guillén-Mancina, Emilio; Mateos, Santiago; López-Lázaro, Miguel

    2016-01-01

    Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee. PMID:27399778

  4. An Indian girl with Fanconi-Bickel syndrome without SLC2A2 gene mutation

    PubMed Central

    Dayal, Devi; Dekate, Parag; Sharda, Sheetal; Das, Ashim; Attri, Savita

    2013-01-01

    Fanconi-Bickel syndrome is a rare autosomal-recessive disorder caused by defects in the facilitative glucose transporter 2 (GLUT2) gene. It is characterized by hepatorenal glycogen accumulation, tubular nephropathy and impaired utilization of glucose and galactose. In this communication, we present the case of a 5-year-old girl who presented with deforming rickets and massive hepatomegaly. Liver biopsy confirmed the diagnosis of glycogen storage disorder. However, the mutation of the SLC2A2 (GLUT2) gene was not found. Mutation negative patients with characteristic Fanconi-Bickel syndrome phenotype suggest additional underlying mechanisms that need exploration.

  5. Loss of Dependence on Continued Expression of the Human Papillomavirus 16 E7 Oncogene in Cervical Cancers and Precancerous Lesions Arising in Fanconi Anemia Pathway-Deficient Mice

    PubMed Central

    Park, Soyeong; Park, Jung Wook; Pitot, Henry C.

    2016-01-01

    ABSTRACT   Fanconi anemia (FA) is a rare genetic disorder caused by defects in DNA damage repair. FA patients often develop squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) are known to cause cancer, including the cervix. However, SCCs found in human FA patients are often HPV negative, even though the majority of female FA patients with anogenital cancers had preexisting HPV-positive dysplasia. We hypothesize that HPVs contribute to the development of SCCs in FA patients but that the continued expression of HPV oncogenes is not required for the maintenance of the cancer state because FA deficiency leads to an accumulation of mutations in cellular genes that render the cancer no longer dependent upon viral oncogenes. We tested this hypothesis, making use of Bi-L E7 transgenic mice in which we temporally controlled expression of HPV16 E7, the dominant viral oncogene in HPV-associated cancers. As seen before, the persistence of cervical neoplastic disease was highly dependent upon the continued expression of HPV16 E7 in FA-sufficient mice. However, in mice with FA deficiency, cervical cancers persisted in a large fraction of the mice after HPV16 E7 expression was turned off, indicating that these cancers had escaped from their dependency on E7. Furthermore, the severity of precancerous lesions also failed to be reduced significantly in the mice with FA deficiency upon turning off expression of E7. These findings confirm our hypothesis and may explain the fact that, while FA patients have a high frequency of infections by HPVs and HPV-induced precancerous lesions, the cancers are frequently HPV negative. Importance   Fanconi anemia (FA) patients are at high risk for developing squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) frequently cause cancer. Yet these SCCs are often HPV negative. FA patients have a genetic defect in their capacity to repair damaged DNA. HPV oncogenes cause an

  6. Loss of Dependence on Continued Expression of the Human Papillomavirus 16 E7 Oncogene in Cervical Cancers and Precancerous Lesions Arising in Fanconi Anemia Pathway-Deficient Mice.

    PubMed

    Park, Soyeong; Park, Jung Wook; Pitot, Henry C; Lambert, Paul F

    2016-01-01

    Fanconi anemia (FA) is a rare genetic disorder caused by defects in DNA damage repair. FA patients often develop squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) are known to cause cancer, including the cervix. However, SCCs found in human FA patients are often HPV negative, even though the majority of female FA patients with anogenital cancers had preexisting HPV-positive dysplasia. We hypothesize that HPVs contribute to the development of SCCs in FA patients but that the continued expression of HPV oncogenes is not required for the maintenance of the cancer state because FA deficiency leads to an accumulation of mutations in cellular genes that render the cancer no longer dependent upon viral oncogenes. We tested this hypothesis, making use of Bi-L E7 transgenic mice in which we temporally controlled expression of HPV16 E7, the dominant viral oncogene in HPV-associated cancers. As seen before, the persistence of cervical neoplastic disease was highly dependent upon the continued expression of HPV16 E7 in FA-sufficient mice. However, in mice with FA deficiency, cervical cancers persisted in a large fraction of the mice after HPV16 E7 expression was turned off, indicating that these cancers had escaped from their dependency on E7. Furthermore, the severity of precancerous lesions also failed to be reduced significantly in the mice with FA deficiency upon turning off expression of E7. These findings confirm our hypothesis and may explain the fact that, while FA patients have a high frequency of infections by HPVs and HPV-induced precancerous lesions, the cancers are frequently HPV negative. IMPORTANCE  : Fanconi anemia (FA) patients are at high risk for developing squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) frequently cause cancer. Yet these SCCs are often HPV negative. FA patients have a genetic defect in their capacity to repair damaged DNA. HPV oncogenes cause an accumulation of DNA

  7. Correction of both spontaneous and DEB-induced chromosome instability in Fanconi anemia FA-C cells by FACC cDNA

    SciTech Connect

    Stavropoulos, D.J.; Tomkins, D.J.; Allingham-Hawkins, D.J.; Buchwald, M.

    1994-09-01

    Cells from all four Fanconi anemia complementation groups show hypersensitivity to cell-killing by mitomycin C (MMC), diepoxybutane (DEB) and other DNA cross-linking agents, and increased spontaneous and DEB-induced chromosome aberrations (CA). The extent of these phenotypes varies between lymphoblastoid cell lines from different complementation groups. Our data showed that the difference in MMC hypersensitivity and DEB-CA was not always coupled. While 230N (FA-B) had higher DEB-induced CA/cell than 536N (FA-C) (7.42 vs. 4.46 respectively), that latter was much more sensitive to cell-killing by MMC (dose at 10% survival, D{sub 10}: 5.2 vs. 1.2 ng/ml respectively). Strathdes et al. (1992) cloned a cDNA Fanconi anemia complementation group C (FACC) which complemented the hypersensitivity to MMC and DEB cell-killing of FA-C cells (536N) but not cells from the other three complementation groups. The present study was initiated to determine whether chromosome instability in 536N is also complemented by the FACC (FAC3) cDNA. The pREP4-FAC3 vector was transfected into 536N and transfectants selected with hygromycin B. The DEB D{sub 10} of 536N (1.0 {mu}M) was corrected to the control level (16.2 {mu}M for 3TO) by FACC (15.1 {mu}M for 536N-FACC), as previously demonstrated. Chromosome instability (cab, cse, ctb, cte) was determined without and with 0.1 {mu}g/ml DEB treatment. Spontaneous CA of 536N (0.30 aberrations/cell) was corrected to the control level (0.04 for 3TO) by FACC (0.06 for 536N-FACC). Similarly, the DEB-induced CA was corrected (2.74 for 536N vs. 0.06 and 0.02 for 3TO and 536N-FACC respectively). Thus, at least for FA complementation group C, hypersensitivity to cell-killing and chromosome instability are not dissociated and are most likely caused by the same gene defect.

  8. In vitro and in vivo inhibition of human Fanconi anemia head and neck squamous carcinoma by a phytonutrient combination.

    PubMed

    Roomi, M W; Kalinovsky, T; Roomi, N W; Niedzwiecki, A; Rath, M

    2015-05-01

    Head and neck squamous cell carcinoma (HNSCC) and acute myeloid leukemia are the major causes of mortality and morbidity in Fanconi anemia (FA) patients. The objective of this study was to investigate the antineoplastic activity of PB, an antineoplastic nutrient mixture (containing quercetin, curcumin, green tea, cruciferex and resveratrol) on human FA HNSCC in vitro and in vivo. Human FA HNSCC cell line OHSU-974 (Fanconi Anemia Research Fund) was cultured in RPMI medium supplemented with 20% FBS and anti-biotics. At near confluence, cells were treated in triplicate with different concentrations of PB: 0, 10, 25, 50, 75 and 100 µg/ml. Cells were also treated with PMA to induce MMP-9 activity. Cell proliferation was detected by MTT assay, secretion of MMPs by gelatinase zymography, invasion through Matrigel, migration by scratch test and morphology by hematoxylin and eosin (H&E) staining. In vivo, athymic male nude mice (n=12) were inoculated with 3x106 OHSU-974 cells subcutaneously and randomly divided into two groups: group A was fed a regular diet and group B a regular diet supplemented with 1% PB. Four weeks later, the mice were sacrificed and their tumors were excised, weighed and processed for histology. NM inhibited the growth of OHSU-974 tumor by 67.6% (p<0.0001) and tumor burden by 63.6% (p<0.0001). PB demonstrated dose-dependent inhibition of cell proliferation, with 27% (p=0.0003) and 48% (p=0.0004) toxicity at 75 and 100 µg/ml, respectively. Zymography revealed MMP-2 and PMA-induced MMP-9 secretion. PB suppressed secretion of both MMPs in a dose-dependent manner, with total block of both at 50 µg/ml. PB inhibited cell migration (by scratch test) and OHSU-974 invasion through Matrigel in a dose-dependent fashion with total block at 50 µg/ml. H&E staining showed no morphological changes below 50 µg/ml. The results suggest that PB has potential therapeutic use in the treatment of human FA HNSCC. PMID:25695860

  9. IL-6, IL-8, MMP-2, MMP-9 are overexpressed in Fanconi anemia cells through a NF-κB/TNF-α dependent mechanism.

    PubMed

    Epanchintsev, Alexey; Shyamsunder, Pavithra; Verma, Rama S; Lyakhovich, Alex

    2015-12-01

    Fanconi anemia (FA) is a rare autosomal recessive genetic disorder associated with a bone-marrow failure, genome instability, hypersensitivity to DNA crosslinking agents and a predisposition to cancer. Mutations have been documented in 16 FA genes that participate in the FA-BRCA DNA repair pathway, a fundamental pathway in the development of the disease and the presentation of its symptoms. FA cells have been characterized by an overproduction of cytokines, MAPKs, and Interleukins. Through this study we have identified the overexpression of additional secretory factors such as IL-6, IL-8, MMP-2, and MMP-9 in FA cells and in cells depleted of FANCA or FANCC and proved that their expression is under the control of NF-κB/TNF-α signaling pathways. We also demonstrated that these overexpressed secretory factors were effective in promoting the proliferation, migration, and invasion of surrounding tumor cells a fundamental event in the process of epithelial mesenchymal transition (EMT) and that they also modulated the expression of EMT markers such as E-cadherin and SNAIL. Overall our data suggest that the upregulation of EMT promoting factors in FA may contribute to predisposing FA patients to cancer, thereby providing new insights into possible therapeutic interventions. PMID:25358651

  10. The Fanconi anemia pathway is required for efficient repair of stress-induced DNA damage in haematopoietic stem cells

    PubMed Central

    Kaschutnig, Paul; Bogeska, Ruzhica; Walter, Dagmar; Lier, Amelie; Huntscha, Sina; Milsom, Michael D

    2015-01-01

    Within regenerating tissues, aging is characterized by a progressive general deterioration of organ function, thought to be driven by the gradual depletion of functional adult stem cells. Although there are probably multifactorial mechanisms that result in compromized stem cell functionality with advancing age, the accumulation of DNA damage within the stem cell compartment is likely to make a major contribution to this process. However, the physiologic source of DNA damage within the different tissue specific stem cell compartments remains to be determined, as does the fate of stem cells exposed to such damage. Using the haematopoietic system as a model organ, we have recently shown that certain forms of physiologic stress, such as infection-associated inflammation and extensive blood loss, leads to the induction of biologically relevant levels of DNA damage in haematopoietic stem cells (HSCs) by dramatically increasing the proliferative index of this normally quiescent cell population.1 We were also able to demonstrate that such stress-associated DNA damage was sufficient to completely deplete HSCs and promote severe aplastic anemia (SAA) in the Fanconi anemia (FA) knockout mouse model, which has compromized replication-associated DNA repair. In this “Extra Views” article, we extend this previous work to show that FA mice do not spontaneously develop a haematopoietic phenotype consistent with SAA, even at extreme old age. This suggests that HSC quiescence restricts the acquisition of DNA damage during aging and preserves the functional integrity of the stem cell pool. In line with this hypothesis, we provide an extended time course analysis of the response of FA knockout mice to chronic inflammatory stress and show that enforced HSC proliferation leads to a highly penetrant SAA phenotype, which closely resembles the progression of the disease in FA patients. PMID:26178207

  11. Advances in the understanding of Fanconi Anemia Complementation Group D2 Protein (FANCD2) in human cancer

    PubMed Central

    Shen, Yihang; Zhang, Jun; Yu, Herbert; Fei, Peiwen

    2015-01-01

    Fanconi anemia (FA) is a rare human genetic disease, resulting from dysfunction in any of 17 known complementation proteins: FANC-A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q & S, and other unknowns. Besides the severe bone marrow failure, an extremely high incidence of cancer as well as many other clinic symptoms associated with FA patients, FA cells are known of insufficiency in homologous recombination, DNA mismatch repair, nucleotide excision repair, translesion DNA synthesis, and other molecular defects, leading to genome instability. Those similar molecular and cellular/tissue features show that all FA proteins function in one common signaling pathway, namely, the FA pathway. The monoubiquitination of FANCD2 is the central step of the FA pathway activation upon DNA damage or during DNA replication. The molecular functions of FANCD2 emerge as a very attractive filed of investigation in cancer research. Herein, we review the recent progresses in FANCD2 functions at these rapidly progressed aspects. PMID:26640811

  12. Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of the Fanconi Anemia pathway in vivo

    PubMed Central

    Yang, Yang; Poe, Jonathan C.; Yang, Lisong; Fedoriw, Andrew; Desai, Siddhi; Magnuson, Terry; Li, Zhiguo; Fedoriw, Yuri; Araki, Kimi; Gao, Yanzhe; Tateishi, Satoshi; Sarantopoulos, Stefanie; Vaziri, Cyrus

    2016-01-01

    In cultured cancer cells the E3 ubiquitin ligase Rad18 activates Trans-Lesion Synthesis (TLS) and the Fanconi Anemia (FA) pathway. However, physiological roles of Rad18 in DNA damage tolerance and carcinogenesis are unknown and were investigated here. Primary hematopoietic stem and progenitor cells (HSPC) co-expressed RAD18 and FANCD2 proteins, potentially consistent with a role for Rad18 in FA pathway function during hematopoiesis. However, hematopoietic defects typically associated with fanc-deficiency (decreased HSPC numbers, reduced engraftment potential of HSPC, and Mitomycin C (MMC) -sensitive hematopoiesis), were absent in Rad18−/− mice. Moreover, primary Rad18−/− mouse embryonic fibroblasts (MEF) retained robust Fancd2 mono-ubiquitination following MMC treatment. Therefore, Rad18 is dispensable for FA pathway activation in untransformed cells and the Rad18 and FA pathways are separable in hematopoietic cells. In contrast with responses to crosslinking agents, Rad18−/− HSPC were sensitive to in vivo treatment with the myelosuppressive agent 7,12 Dimethylbenz[a]anthracene (DMBA). Rad18-deficient fibroblasts aberrantly accumulated DNA damage markers after DMBA treatment. Moreover, in vivo DMBA treatment led to increased incidence of B cell malignancy in Rad18−/− mice. These results identify novel hematopoietic functions for Rad18 and provide the first demonstration that Rad18 confers DNA damage tolerance and tumor-suppression in a physiological setting. PMID:26883629

  13. Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production.

    PubMed

    Brégnard, Christelle; Guerra, Jessica; Déjardin, Stéphanie; Passalacqua, Frank; Benkirane, Monsef; Laguette, Nadine

    2016-06-01

    Fanconi Anemia (FA) is a genetic disorder characterized by elevated cancer susceptibility and pro-inflammatory cytokine production. Using SLX4(FANCP) deficiency as a working model, we questioned the trigger for chronic inflammation in FA. We found that absence of SLX4 caused cytoplasmic DNA accumulation, including sequences deriving from active Long INterspersed Element-1 (LINE-1), triggering the cGAS-STING pathway to elicit interferon (IFN) expression. In agreement, absence of SLX4 leads to upregulated LINE-1 retrotransposition. Importantly, similar results were obtained with the FANCD2 upstream activator of SLX4. Furthermore, treatment of FA cells with the Tenofovir reverse transcriptase inhibitor (RTi), that prevents endogenous retrotransposition, decreased both accumulation of cytoplasmic DNA and pro-inflammatory signaling. Collectively, our data suggest a contribution of endogenous RT activities to the generation of immunogenic cytoplasmic nucleic acids responsible for inflammation in FA. The additional observation that RTi decreased pro-inflammatory cytokine production induced by DNA replication stress-inducing drugs further demonstrates the contribution of endogenous RTs to sustaining chronic inflammation. Altogether, our data open perspectives in the prevention of adverse effects of chronic inflammation in tumorigenesis. PMID:27428429

  14. Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of the Fanconi Anemia pathway in vivo.

    PubMed

    Yang, Yang; Poe, Jonathan C; Yang, Lisong; Fedoriw, Andrew; Desai, Siddhi; Magnuson, Terry; Li, Zhiguo; Fedoriw, Yuri; Araki, Kimi; Gao, Yanzhe; Tateishi, Satoshi; Sarantopoulos, Stefanie; Vaziri, Cyrus

    2016-05-19

    In cultured cancer cells the E3 ubiquitin ligase Rad18 activates Trans-Lesion Synthesis (TLS) and the Fanconi Anemia (FA) pathway. However, physiological roles of Rad18 in DNA damage tolerance and carcinogenesis are unknown and were investigated here. Primary hematopoietic stem and progenitor cells (HSPC) co-expressed RAD18 and FANCD2 proteins, potentially consistent with a role for Rad18 in FA pathway function during hematopoiesis. However, hematopoietic defects typically associated with fanc-deficiency (decreased HSPC numbers, reduced engraftment potential of HSPC, and Mitomycin C (MMC) -sensitive hematopoiesis), were absent in Rad18(-/-) mice. Moreover, primary Rad18(-/-) mouse embryonic fibroblasts (MEF) retained robust Fancd2 mono-ubiquitination following MMC treatment. Therefore, Rad18 is dispensable for FA pathway activation in untransformed cells and the Rad18 and FA pathways are separable in hematopoietic cells. In contrast with responses to crosslinking agents, Rad18(-/-) HSPC were sensitive to in vivo treatment with the myelosuppressive agent 7,12 Dimethylbenz[a]anthracene (DMBA). Rad18-deficient fibroblasts aberrantly accumulated DNA damage markers after DMBA treatment. Moreover, in vivo DMBA treatment led to increased incidence of B cell malignancy in Rad18(-/-) mice. These results identify novel hematopoietic functions for Rad18 and provide the first demonstration that Rad18 confers DNA damage tolerance and tumor-suppression in a physiological setting. PMID:26883629

  15. Forkhead transcription factor FoxF1 interacts with Fanconi anemia protein complexes to promote DNA damage response

    PubMed Central

    Pradhan, Arun; Ustiyan, Vladimir; Zhang, Yufang; Kalin, Tanya V.; Kalinichenko, Vladimir V.

    2016-01-01

    Forkhead box F1 (Foxf1) transcription factor is an important regulator of embryonic development but its role in tumor cells remains incompletely understood. While 16 proteins were characterized in Fanconi anemia (FA) core complex, its interactions with cellular transcriptional machinery remain poorly characterized. Here, we identified FoxF1 protein as a novel interacting partner of the FA complex proteins. Using multiple human and mouse tumor cell lines and Foxf1+/− mice we demonstrated that FoxF1 physically binds to and increases stability of FA proteins. FoxF1 co-localizes with FANCD2 in DNA repair foci in cultured cells and tumor tissues obtained from cisplatin-treated mice. In response to DNA damage, FoxF1-deficient tumor cells showed significantly reduced FANCD2 monoubiquitination and FANCM phosphorylation, resulting in impaired formation of DNA repair foci. FoxF1 knockdown caused chromosomal instability, nuclear abnormalities, and increased tumor cell death in response to DNA-damaging agents. Overexpression of FoxF1 in DNA-damaged cells improved stability of FA proteins, decreased chromosomal and nuclear aberrations, restored formation of DNA repair foci and prevented cell death after DNA damage. These findings demonstrate that FoxF1 is a key component of FA complexes and a critical mediator of DNA damage response in tumor cells. PMID:26625197

  16. AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia

    PubMed Central

    Virts, Elizabeth L.; Jankowska, Anna; Mackay, Craig; Glaas, Marcel F.; Wiek, Constanze; Kelich, Stephanie L.; Lottmann, Nadine; Kennedy, Felicia M.; Marchal, Christophe; Lehnert, Erik; Scharf, Rüdiger E.; Dufour, Carlo; Lanciotti, Marina; Farruggia, Piero; Santoro, Alessandra; Savasan, Süreyya; Scheckenbach, Kathrin; Schipper, Jörg; Wagenmann, Martin; Lewis, Todd; Leffak, Michael; Farlow, Janice L.; Foroud, Tatiana M.; Honisch, Ellen; Niederacher, Dieter; Chakraborty, Sujata C.; Vance, Gail H.; Pruss, Dmitry; Timms, Kirsten M.; Lanchbury, Jerry S.; Alpi, Arno F.; Hanenberg, Helmut

    2015-01-01

    Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2–6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2–6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2–6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene. PMID:26085575

  17. AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia.

    PubMed

    Virts, Elizabeth L; Jankowska, Anna; Mackay, Craig; Glaas, Marcel F; Wiek, Constanze; Kelich, Stephanie L; Lottmann, Nadine; Kennedy, Felicia M; Marchal, Christophe; Lehnert, Erik; Scharf, Rüdiger E; Dufour, Carlo; Lanciotti, Marina; Farruggia, Piero; Santoro, Alessandra; Savasan, Süreyya; Scheckenbach, Kathrin; Schipper, Jörg; Wagenmann, Martin; Lewis, Todd; Leffak, Michael; Farlow, Janice L; Foroud, Tatiana M; Honisch, Ellen; Niederacher, Dieter; Chakraborty, Sujata C; Vance, Gail H; Pruss, Dmitry; Timms, Kirsten M; Lanchbury, Jerry S; Alpi, Arno F; Hanenberg, Helmut

    2015-09-15

    Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene. PMID:26085575

  18. Aplastic Anemia

    MedlinePlus

    Aplastic anemia is a rare but serious blood disorder. If you have it, your bone marrow doesn't make ... blood cells. There are different types, including Fanconi anemia. Causes include Toxic substances, such as pesticides, arsenic, ...

  19. Low-Dose Total-Body Irradiation and Fludarabine Phosphate Followed by Unrelated Donor Stem Cell Transplant in Treating Patients With Fanconi Anemia

    ClinicalTrials.gov

    2016-03-01

    Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; Fanconi Anemia; Previously Treated Myelodysplastic Syndromes

  20. Preventing over-resection by DNA2 helicase/nuclease suppresses repair defects in Fanconi anemia cells

    PubMed Central

    Karanja, Kenneth K; Lee, Eu Han; Hendrickson, Eric A; Campbell, Judith L

    2014-01-01

    FANCD2 is required for the repair of DNA damage by the FA (Fanconi anemia) pathway, and, consequently, FANCD2-deficient cells are sensitive to compounds such as cisplatin and formaldehyde that induce DNA:DNA and DNA:protein crosslinks, respectively. The DNA2 helicase/nuclease is required for RNA/DNA flap removal from Okazaki fragments during DNA replication and for the resection of DSBs (double-strand breaks) during HDR (homology-directed repair) of replication stress-induced damage. A knockdown of DNA2 renders normal cells as sensitive to cisplatin (in the absence of EXO1) and to formaldehyde (even in the presence of EXO1) as FANCD2−/− cells. Surprisingly, however, the depletion of DNA2 in FANCD2-deficient cells rescues the sensitivity of FANCD2−/− cells to cisplatin and formaldehyde. We previously showed that the resection activity of DNA2 acts downstream of FANCD2 to insure HDR of the DSBs arising when replication forks encounter ICL (interstrand crosslink) damage. The suppression of FANCD2−/− by DNA2 knockdowns suggests that DNA2 and FANCD2 also have antagonistic roles: in the absence of FANCD2, DNA2 somehow corrupts repair. To demonstrate that DNA2 is deleterious to crosslink repair, we used psoralen-induced ICL damage to trigger the repair of a site-specific crosslink in a GFP reporter and observed that “over-resection” can account for reduced repair. Our work demonstrates that excessive resection can lead to genome instability and shows that strict regulatory processes have evolved to inhibit resection nucleases. The suppression of FANCD2−/− phenotypes by DNA2 depletion may have implications for FA therapies and for the use of ICL-inducing agents in chemotherapy. PMID:24626199

  1. EGFR activating mutations correlate with a Fanconi anemia-like cellular phenotype that includes PARP inhibitor sensitivity

    PubMed Central

    Pfäffle, Heike N.; Wang, Meng; Gheorghiu, Liliana; Ferraiolo, Natalie; Greninger, Patricia; Borgmann, Kerstin; Settleman, Jeffrey; Benes, Cyril H.; Sequist, Lecia V.; Zou, Lee; Willers, Henning

    2013-01-01

    In lung cancer patients whose tumors harbor activating mutations in the epidermal growth factor receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared to wild-type cancers. However, the mechanisms underlying this association have remained elusive. Here, we describe a cellular phenotype of crosslinker sensitivity in a subset of EGFR-mutant lung cancer cell lines that is reminiscent of the defects seen in cells impaired in the Fanconi Anemia pathway, including a pronounced G2/M cell-cycle arrest and chromosomal radial formation. We identified a defect downstream of FANCD2 at the level of recruitment of FAN1 nuclease and DNA interstrand crosslink (ICL) unhooking. The effect of EGFR mutation was epistatic with FANCD2. Consistent with the known role of FANCD2 in promoting RAD51 foci formation and homologous recombination repair (HRR), EGFR-mutant cells also exhibited an impaired RAD51 foci response to ICLs, but not to DNA double-strand breaks. EGFR kinase inhibition affected RAD51 foci formation neither in EGFR mutant nor wild-type cells. In contrast, EGFR depletion or overexpression of mutant EGFR in wild-type cells suppressed RAD51 foci, suggesting an EGFR kinase-independent regulation of DNA repair. Interestingly, EGFR-mutant cells treated with the PARP inhibitor olaparib also displayed decreased FAN1 foci induction, coupled with a putative block in a late HRR step. As a result, EGFR-mutant lung cancer cells exhibited olaparib sensitivity in-vitro and in-vivo. Our findings provide insight into the mechanisms of cisplatin and PARP inhibitor sensitivity of EGFR-mutant cells, yielding potential therapeutic opportunities for further treatment individualization in this genetically defined subset of lung cancer. PMID:23966292

  2. What Causes Aplastic Anemia?

    MedlinePlus

    ... to aplastic anemia. Examples include Fanconi anemia , Shwachman-Diamond syndrome, dyskeratosis (DIS-ker-ah-TO-sis) congenita, and Diamond-Blackfan anemia. Rate This Content: NEXT >> Featured Video ...

  3. Lung Cancer Cell Line Screen Links Fanconi Anemia/BRCA Pathway Defects to Increased Relative Biological Effectiveness of Proton Radiation

    SciTech Connect

    Liu, Qi; Ghosh, Priyanjali; Magpayo, Nicole; Testa, Mauro; Tang, Shikui; Gheorghiu, Liliana; Biggs, Peter; Paganetti, Harald; Efstathiou, Jason A.; Lu, Hsiao-Ming; Held, Kathryn D.; Willers, Henning

    2015-04-01

    Purpose: Growing knowledge of genomic heterogeneity in cancer, especially when it results in altered DNA damage responses, requires re-examination of the generic relative biological effectiveness (RBE) of 1.1 of protons. Methods and Materials: For determination of cellular radiosensitivity, we irradiated 17 lung cancer cell lines at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer, 2.5 keV/μm). For comparison, 250-kVp X rays and {sup 137}Cs γ-rays were used. To estimate the RBE of protons relative to {sup 60}Co (Co60eq), we assigned an RBE(Co60Eq) of 1.1 to X rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor damage responses. FANCD2 was depleted using RNA interference. Results: Five lung cancer cell lines (29.4%) exhibited reduced clonogenic survival after proton irradiation compared with X-irradiation with the same physical doses. This was confirmed in a 3-dimensional sphere assay. Corresponding proton RBE(Co60Eq) estimates were statistically significantly different from 1.1 (P≤.05): 1.31 to 1.77 (for a survival fraction of 0.5). In 3 of these lines, increased RBE was correlated with alterations in the Fanconi anemia (FA)/BRCA pathway of DNA repair. In Calu-6 cells, the data pointed toward an FA pathway defect, leading to a previously unreported persistence of proton-induced RAD51 foci. The FA/BRCA-defective cells displayed a 25% increase in the size of subnuclear 53BP1 foci 18 hours after proton irradiation. Conclusions: Our cell line screen has revealed variations in proton RBE that are partly due to FA/BRCA pathway defects, suggesting that the use of a generic RBE for cancers should be revisited. We propose that functional biomarkers, such as size of residual 53BP1 foci, may be used to identify cancers with increased sensitivity to proton radiation.

  4. The Fanconi Anemia Protein FANCC Binds to and Facilitates the Activation of STAT1 by Gamma Interferon and Hematopoietic Growth Factors

    PubMed Central

    Pang, Qishen; Fagerlie, Sara; Christianson, Tracy A.; Keeble, Winifred; Faulkner, Greg; Diaz, Jane; Rathbun, R. Keaney; Bagby, Grover C.

    2000-01-01

    Hematopoietic progenitor cells from Fanconi anemia (FA) group C (FA-C) patients display hypersensitivity to the apoptotic effects of gamma interferon (IFN-γ) and constitutively express a variety of IFN-dependent genes. Paradoxically, however, STAT1 activation is suppressed in IFN-stimulated FA cells, an abnormality corrected by transduction of normal FANCC cDNA. We therefore sought to define the specific role of FANCC protein in signal transduction through receptors that activate STAT1. Expression and phosphorylation of IFN-γ receptor α chain (IFN-γRα) and JAK1 and JAK2 tyrosine kinases were equivalent in both normal and FA-C cells. However, in coimmunoprecipitation experiments STAT1 did not dock at the IFN-γR of FA-C cells, an abnormality corrected by transduction of the FANCC gene. In addition, glutathione S-transferase fusion genes encoding normal FANCC but not a mutant FANCC bearing an inactivating point mutation (L554P) bound to STAT1 in lysates of IFN-γ-stimulated B cells and IFN-, granulocyte-macrophage colony-stimulating factor- and stem cell factor-stimulated MO7e cells. Kinetic studies revealed that the initial binding of FANCC was to nonphosphorylated STAT1 but that subsequently the complex moved to the receptor docking site, at which point STAT1 became phosphorylated. The STAT1 phosphorylation defect in FA-C cells was functionally significant in that IFN induction of IFN response factor 1 was suppressed and STAT1-DNA complexes were not detected in nuclear extracts of FA-C cells. We also determined that the IFN-γ hypersensitivity of FA-C hematopoietic progenitor cells does not derive from STAT1 activation defects because granulocyte-macrophage CFU and erythroid burst-forming units from STAT1−/− mice were resistant to IFN-γ. However, BFU-E responses to SCF and erythropoietin were suppressed in STAT−/− mice. Consequently, because the FANCC protein is involved in the activation of STAT1 through receptors for at least three hematopoietic

  5. Fludarabine, low-dose busulfan and antithymocyte globulin as conditioning for Fanconi anemia patients receiving bone marrow transplantation from HLA-compatible related donors.

    PubMed

    Maschan, A A; Trakhtman, P E; Balashov, D N; Shipicina, I P; Skorobogatova, E V; Skvortsova, Y V; Dyshlevaja, Z M; Samochatova, E V; Rumiantsev, A G

    2004-08-01

    Allogeneic hematopoietic stem cell transplantation (SCT) from unaffected donors remains the only modality for the correction of hematological abnormalities in Fanconi anemia (FA) patients. We performed four HLA-matched related donor SCT using a novel irradiation and cyclophosphamide-free conditioning regimen. The protocol included fludarabine 150 mg/m(2), busulfan 4 mg/kg, and antithymocyte globulin 90 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A, MTX, and daclizumab. The engraftment and occurrence of full stable donor hemopoiesis was rapid in all cases with minimal short-term toxic complications. There were no infections or febrile episodes during the inpatient phase. Three patients developed acute GVHD grade I-II involving gut and skin and one patient progressed to extensive chronic GVHD. The preparative conditioning regimen is safe and associated with low organ toxicity and effective immunosupression for the stable engraftment in FA patients undergoing SCT with matched related donors. PMID:15195080

  6. Repair pathways independent of the Fanconi anemia nuclear core complex play a predominant role in mitigating formaldehyde-induced DNA damage

    SciTech Connect

    Noda, Taichi; Takahashi, Akihisa; Kondo, Natsuko; Mori, Eiichiro; Okamoto, Noritomo; Nakagawa, Yosuke; Ohnishi, Ken; Zdzienicka, Malgorzata Z.; Thompson, Larry H.; Helleday, Thomas; Asada, Hideo; and others

    2011-01-07

    The role of the Fanconi anemia (FA) repair pathway for DNA damage induced by formaldehyde was examined in the work described here. The following cell types were used: mouse embryonic fibroblast cell lines FANCA{sup -/-}, FANCC{sup -/-}, FANCA{sup -/-}C{sup -/-}, FANCD2{sup -/-} and their parental cells, the Chinese hamster cell lines FANCD1 mutant (mt), FANCGmt, their revertant cells, and the corresponding wild-type (wt) cells. Cell survival rates were determined with colony formation assays after formaldehyde treatment. DNA double strand breaks (DSBs) were detected with an immunocytochemical {gamma}H2AX-staining assay. Although the sensitivity of FANCA{sup -/-}, FANCC{sup -/-} and FANCA{sup -/-}C{sup -/-} cells to formaldehyde was comparable to that of proficient cells, FANCD1mt, FANCGmt and FANCD2{sup -/-} cells were more sensitive to formaldehyde than the corresponding proficient cells. It was found that homologous recombination (HR) repair was induced by formaldehyde. In addition, {gamma}H2AX foci in FANCD1mt cells persisted for longer times than in FANCD1wt cells. These findings suggest that formaldehyde-induced DSBs are repaired by HR through the FA repair pathway which is independent of the FA nuclear core complex. -- Research highlights: {yields} We examined to clarify the repair pathways of formaldehyde-induced DNA damage. Formaldehyde induces DNA double strand breaks (DSBs). {yields} DSBs are repaired through the Fanconi anemia (FA) repair pathway. {yields} This pathway is independent of the FA nuclear core complex. {yields} We also found that homologous recombination repair was induced by formaldehyde.

  7. Anemia

    MedlinePlus

    ... anemia Idiopathic aplastic anemia Megaloblastic anemia Pernicious anemia Sickle cell anemia Thalassemia Causes Although many parts of the body ... Some forms of anemia, such as thalassemia or sickle cell anemia, which can be inherited Pregnancy Problems with bone ...

  8. Anemia

    MedlinePlus

    ... anemia Idiopathic aplastic anemia Megaloblastic anemia Pernicious anemia Sickle cell anemia Thalassemia ... Some forms of anemia, such as thalassemia or sickle cell anemia, which can be inherited Pregnancy Problems with bone ...

  9. What Is Fanconi Anemia?

    MedlinePlus

    ... children may have serious health and developmental problems. Bone Marrow and Blood Bone marrow is the spongy tissue inside the large bones of your body. Healthy bone marrow contains stem cells that develop into the three ...

  10. Amelioration of Radiation-Induced Oral Cavity Mucositis and Distant Bone Marrow Suppression in Fanconi Anemia Fancd2−/− (FVB/N) Mice by Intraoral GS-Nitroxide JP4-039

    PubMed Central

    Berhane, Hebist; Shinde, Ashwin; Kalash, Ronny; Xu, Karen; Epperly, Michael W.; Goff, Julie; Franicola, Darcy; Zhang, Xichen; Dixon, Tracy; Shields, Donna; Wang, Hong; Wipf, Peter; Li, Song; Gao, Xiang; Greenberger, Joel S.

    2014-01-01

    The altered DNA damage response pathway in patients with Fanconi anemia (FA) may increase the toxicity of clinical radiotherapy. We quantitated oral cavity mucositis in irradiated Fanconi anemia Fancd2−/− mice, comparing this to Fancd2+/− and Fancd2+/+ mice, and we measured distant bone marrow suppression and quantitated the effect of the intraoral radioprotector GS-nitroxide, JP4-039 in F15 emulsion. We found that FA mice were more susceptible to radiation injury and that protection from radiation injury by JP4-039/F15 was observed at all radiation doses. Adult 10–12-week-old mice, of FVB/N background Fancd2−/−, Fancd2+/− and Fancd2+/+ were head and neck irradiated with 24, 26, 28 or 30 Gy (large fraction sizes typical of stereotactic radiosurgery treatments) and subgroups received intraoral JP4-039 (0.4 mg/mouse in 100 μL F15 liposome emulsion) preirradiation. On day 2 or 5 postirradiation, mice were sacrificed, tongue tissue and femur marrow were excised for quantitation of radiation-induced stress response, inflammatory and antioxidant gene transcripts, histopathology and assay for femur marrow colony-forming hematopoietic progenitor cells. Fancd2−/− mice had a significantly higher percentage of oral mucosal ulceration at day 5 after 26 Gy irradiation (59.4 ± 8.2%) compared to control Fancd2+/+ mice (21.7 ± 2.9%, P = 0.0063). After 24 Gy irradiation, Fancd2−/− mice had a higher oral cavity percentage of tongue ulceration compared to Fancd2+/+ mice irradiated with higher doses of 26 Gy (P = 0.0123). Baseline and postirradiation oral cavity gene transcripts were altered in Fancd2−/− mice compared to Fancd2+/+ controls. Fancd2−/− mice had decreased baseline femur marrow CFU-GM, BFUe and CFU-GEMM, which further decreased after 24 or 26 Gy head and neck irradiation. These changes were not seen in head- and neck-irradiated Fancd2+/+ mice. In radiosensitive Fancd2−/− mice, biomarkers of both local oral cavity and distant marrow

  11. Amelioration of radiation-induced oral cavity mucositis and distant bone marrow suppression in fanconi anemia Fancd2-/- (FVB/N) mice by intraoral GS-nitroxide JP4-039.

    PubMed

    Berhane, Hebist; Shinde, Ashwin; Kalash, Ronny; Xu, Karen; Epperly, Michael W; Goff, Julie; Franicola, Darcy; Zhang, Xichen; Dixon, Tracy; Shields, Donna; Wang, Hong; Wipf, Peter; Li, Song; Gao, Xiang; Greenberger, Joel S

    2014-07-01

    The altered DNA damage response pathway in patients with Fanconi anemia (FA) may increase the toxicity of clinical radiotherapy. We quantitated oral cavity mucositis in irradiated Fanconi anemia Fancd2(-/-) mice, comparing this to Fancd2(+/-) and Fancd2(+/+) mice, and we measured distant bone marrow suppression and quantitated the effect of the intraoral radioprotector GS-nitroxide, JP4-039 in F15 emulsion. We found that FA mice were more susceptible to radiation injury and that protection from radiation injury by JP4-039/F15 was observed at all radiation doses. Adult 10-12-week-old mice, of FVB/N background Fancd2(-/-), Fancd2(+/-) and Fancd2(+/+) were head and neck irradiated with 24, 26, 28 or 30 Gy (large fraction sizes typical of stereotactic radiosurgery treatments) and subgroups received intraoral JP4-039 (0.4 mg/mouse in 100 μL F15 liposome emulsion) preirradiation. On day 2 or 5 postirradiation, mice were sacrificed, tongue tissue and femur marrow were excised for quantitation of radiation-induced stress response, inflammatory and antioxidant gene transcripts, histopathology and assay for femur marrow colony-forming hematopoietic progenitor cells. Fancd2(-/-) mice had a significantly higher percentage of oral mucosal ulceration at day 5 after 26 Gy irradiation (59.4 ± 8.2%) compared to control Fancd2(+/+) mice (21.7 ± 2.9%, P = 0.0063). After 24 Gy irradiation, Fancd2(-/-) mice had a higher oral cavity percentage of tongue ulceration compared to Fancd2(+/+) mice irradiated with higher doses of 26 Gy (P = 0.0123). Baseline and postirradiation oral cavity gene transcripts were altered in Fancd2(-/-) mice compared to Fancd2(+/+) controls. Fancd2(-/-) mice had decreased baseline femur marrow CFU-GM, BFUe and CFU-GEMM, which further decreased after 24 or 26 Gy head and neck irradiation. These changes were not seen in head- and neck-irradiated Fancd2(+/+) mice. In radiosensitive Fancd2(-/-) mice, biomarkers of both local oral cavity and distant marrow

  12. Histone chaperone activity of Fanconi anemia proteins, FANCD2 and FANCI, is required for DNA crosslink repair

    PubMed Central

    Sato, Koichi; Ishiai, Masamichi; Toda, Kazue; Furukoshi, Satoshi; Osakabe, Akihisa; Tachiwana, Hiroaki; Takizawa, Yoshimasa; Kagawa, Wataru; Kitao, Hiroyuki; Dohmae, Naoshi; Obuse, Chikashi; Kimura, Hiroshi; Takata, Minoru; Kurumizaka, Hitoshi

    2012-01-01

    Fanconi anaemia (FA) is a rare hereditary disorder characterized by genomic instability and cancer susceptibility. A key FA protein, FANCD2, is targeted to chromatin with its partner, FANCI, and plays a critical role in DNA crosslink repair. However, the molecular function of chromatin-bound FANCD2-FANCI is still poorly understood. In the present study, we found that FANCD2 possesses nucleosome-assembly activity in vitro. The mobility of histone H3 was reduced in FANCD2-knockdown cells following treatment with an interstrand DNA crosslinker, mitomycin C. Furthermore, cells harbouring FANCD2 mutations that were defective in nucleosome assembly displayed impaired survival upon cisplatin treatment. Although FANCI by itself lacked nucleosome-assembly activity, it significantly stimulated FANCD2-mediated nucleosome assembly. These observations suggest that FANCD2-FANCI may regulate chromatin dynamics during DNA repair. PMID:22828868

  13. Hyper-active non-homologous end joining selects for synthetic lethality resistant and pathological Fanconi anemia hematopoietic stem and progenitor cells

    PubMed Central

    Du, Wei; Amarachintha, Surya; Wilson, Andrew F.; Pang, Qishen

    2016-01-01

    The prominent role of Fanconi anemia (FA) proteins involves homologous recombination (HR) repair. Poly[ADP-ribose] polymerase1 (PARP1) functions in multiple cellular processes including DNA repair and PARP inhibition is an emerging targeted therapy for cancer patients deficient in HR. Here we show that PARP1 activation in hematopoietic stem and progenitor cells (HSPCs) in response to genotoxic or oxidative stress attenuates HSPC exhaustion. Mechanistically, PARP1 controls the balance between HR and non-homologous end joining (NHEJ) in double strand break (DSB) repair by preventing excessive NHEJ. Disruption of the FA core complex skews PARP1 function in DSB repair and led to hyper-active NHEJ in Fanca−/− or Fancc−/− HSPCs. Re-expression of PARP1 rescues the hyper-active NHEJ phenotype in Brca1−/−Parp1−/− but less effective in Fanca−/−Parp1−/− cells. Inhibition of NHEJ prevents myeloid/erythroid pathologies associated with synthetic lethality. Our results suggest that hyper-active NHEJ may select for “synthetic lethality” resistant and pathological HSPCs. PMID:26916217

  14. Hyper-active non-homologous end joining selects for synthetic lethality resistant and pathological Fanconi anemia hematopoietic stem and progenitor cells.

    PubMed

    Du, Wei; Amarachintha, Surya; Wilson, Andrew F; Pang, Qishen

    2016-01-01

    The prominent role of Fanconi anemia (FA) proteins involves homologous recombination (HR) repair. Poly[ADP-ribose] polymerase1 (PARP1) functions in multiple cellular processes including DNA repair and PARP inhibition is an emerging targeted therapy for cancer patients deficient in HR. Here we show that PARP1 activation in hematopoietic stem and progenitor cells (HSPCs) in response to genotoxic or oxidative stress attenuates HSPC exhaustion. Mechanistically, PARP1 controls the balance between HR and non-homologous end joining (NHEJ) in double strand break (DSB) repair by preventing excessive NHEJ. Disruption of the FA core complex skews PARP1 function in DSB repair and led to hyper-active NHEJ in Fanca(-/-) or Fancc(-/-) HSPCs. Re-expression of PARP1 rescues the hyper-active NHEJ phenotype in Brca1(-/-)Parp1(-/-) but less effective in Fanca(-/-)Parp1(-/-) cells. Inhibition of NHEJ prevents myeloid/erythroid pathologies associated with synthetic lethality. Our results suggest that hyper-active NHEJ may select for "synthetic lethality" resistant and pathological HSPCs. PMID:26916217

  15. Bone marrow transplantation from matched related donors for patients with Fanconi anemia using low-dose busulfan and cyclophosphamide as conditioning.

    PubMed

    Torjemane, L; Ladeb, S; Ben Othman, T; Abdelkefi, A; Lakhal, A; Ben Abdeladhim, A

    2006-04-01

    Seventeen patients with Fanconi anemia (FA) underwent allogeneic bone marrow transplantation (BMT) from matched related donors (MRD) between January 1999 and June 2003. Median age at BMT was 11 years. Conditioning regimen consisted of low-dose cyclophosphamide (CY; 40 mg/kg) and busulfan (BU; 6 mg/kg) with the addition of lymphoglobulin (20 mg/kg) in two patients. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A (CsA) and methotrexate (MTX; 5 mg/m(2) at day 1, 3, 6). All patients engrafted (for an absolute neutrophil count >0.5 x 10(9)/L) after a median time of 12 days (range 10-16 days). Fourteen patients (82%) had sustained grafts, whereas three others (18%) rejected grafts between day +39 and +80 after transplantation. Two of them are still alive after successful second PBSC transplantation and one died. Acute and chronic GVHD occurred in 23% and 13% of patients, respectively. With a median follow-up of 16 months (range 3-53 months), survival rate was 72% and Karnofsky score was at least 90%. The low-dose BU/CY regimen, in FA patients allografted from an HLA-matched related donor, allowed engraftment with relative low toxicity. Early graft failure (GF) remains a problem and may require modification of this regimen. PMID:16333862

  16. A High-Throughput Screening Strategy to Identify Protein-Protein Interaction Inhibitors That Block the Fanconi Anemia DNA Repair Pathway.

    PubMed

    Voter, Andrew F; Manthei, Kelly A; Keck, James L

    2016-07-01

    Induction of the Fanconi anemia (FA) DNA repair pathway is a common mechanism by which tumors evolve resistance to DNA crosslinking chemotherapies. Proper execution of the FA pathway requires interaction between the FA complementation group M protein (FANCM) and the RecQ-mediated genome instability protein (RMI) complex, and mutations that disrupt FANCM/RMI interactions sensitize cells to DNA crosslinking agents. Inhibitors that block FANCM/RMI complex formation could be useful therapeutics for resensitizing tumors that have acquired chemotherapeutic resistance. To identify such inhibitors, we have developed and validated high-throughput fluorescence polarization and proximity assays that are sensitive to inhibitors that disrupt interactions between the RMI complex and its binding site on FANCM (a peptide referred to as MM2). A pilot screen of 74,807 small molecules was performed using the fluorescence polarization assay. Hits from the primary screen were further tested using the proximity assay, and an orthogonal proximity assay was used to assess inhibitor selectivity. Direct physical interaction between the RMI complex and the most selective inhibitor identified through the screening process was measured by surface plasmon resonance and isothermal titration calorimetry. Observation of direct binding by this small molecule validates the screening protocol. PMID:26962873

  17. The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL*

    PubMed Central

    Miles, Jennifer A.; Frost, Mark G.; Carroll, Eilis; Rowe, Michelle L.; Howard, Mark J.; Sidhu, Ateesh; Chaugule, Viduth K.; Alpi, Arno F.; Walden, Helen

    2015-01-01

    The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). Inefficient repair of these ICL can lead to leukemia and bone marrow failure. A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain. The ELF domain is found in all FANCL homologues, yet the function of the domain remains unknown. We report here that the ELF domain of FANCL is required to mediate a non-covalent interaction between FANCL and ubiquitin. The interaction involves the canonical Ile44 patch on ubiquitin, and a functionally conserved patch on FANCL. We show that the interaction is not necessary for the recognition of the core complex, it does not enhance the interaction between FANCL and Ube2T, and is not required for FANCD2 monoubiquitination in vitro. However, we demonstrate that the ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of ubiquitin binding by FANCL in vivo. PMID:26149689

  18. HLA-MATCHED SIBLING HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR FANCONI ANEMIA: COMPARISON OF IRRADIATION AND NON-IRRADIATION CONTAINING CONDITIONING REGIMENS

    PubMed Central

    Pasquini, Ricardo; Carreras, Jeanette; Pasquini, Marcelo C.; Camitta, Bruce M.; Fasth, Anders L.; Hale, Gregory A.; Harris, Richard E.; Marsh, Judith C.; Robinson, Anibal J.; PhD, Mei-Jie Zhang; Eapen, Mary; Wagner, John E.

    2008-01-01

    Related to the underlying DNA repair defect that is the hallmark of Fanconi anemia (FA), preparatory regimen related toxicities have been obstacles to hematopoietic cell transplantation (HCT). In an attempt to decrease the risk and severity of regimen-related toxicities, non-irradiation regimens have been explored. The aim of this study is to compare outcomes after irradiation and non-irradiation regimens in 148 FA patients and identify risk factors impacting upon HCT outcomes. Hematopoietic recovery, acute and chronic graft-versus-host disease and mortality were similar after irradiation and non-irradiation regimens. In both groups recipient aged >10 years, prior use of androgens and cytomegalovirus seropositivity in either the donor or recipient were associated with higher mortality. With median follow ups >5 years, the 5-year probability of overall survival, adjusted for factors impacting overall mortality was 78% and 81% after irradiation and non-irradiation regimens, p=0.61. In view of the high risk of cancer and other radiation related effects on growth and development, these results support the use of non-irradiation preparatory regimens. As the peak time for developing solid tumors after HCT is 8–9 years, longer follow up is required before definitive statements can be made regarding the impact of non-irradiation regimens on cancer risk. PMID:18804044

  19. The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL.

    PubMed

    Miles, Jennifer A; Frost, Mark G; Carroll, Eilis; Rowe, Michelle L; Howard, Mark J; Sidhu, Ateesh; Chaugule, Viduth K; Alpi, Arno F; Walden, Helen

    2015-08-21

    The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). Inefficient repair of these ICL can lead to leukemia and bone marrow failure. A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain. The ELF domain is found in all FANCL homologues, yet the function of the domain remains unknown. We report here that the ELF domain of FANCL is required to mediate a non-covalent interaction between FANCL and ubiquitin. The interaction involves the canonical Ile44 patch on ubiquitin, and a functionally conserved patch on FANCL. We show that the interaction is not necessary for the recognition of the core complex, it does not enhance the interaction between FANCL and Ube2T, and is not required for FANCD2 monoubiquitination in vitro. However, we demonstrate that the ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of ubiquitin binding by FANCL in vivo. PMID:26149689

  20. Successful hematopoietic stem cell transplantation for Fanconi anemia from an unaffected HLA-genotype-identical sibling selected using preimplantation genetic diagnosis.

    PubMed

    Grewal, Satkiran S; Kahn, Jeffrey P; MacMillan, Margaret L; Ramsay, Norma K C; Wagner, John E

    2004-02-01

    The only proven cure for Fanconi anemia (FA)-associated bone marrow failure is successful allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT with donors other than HLA-identical siblings is associated with high morbidity and poor survival. Therefore, we used preimplantation genetic diagnosis (PGD) to select an embryo produced by in vitro fertilization (IVF) that was unaffected by FA and was HLA-identical to the proband. The patient was a 6-year-old girl with FA and myelodysplasia previously treated with oxymetholone and prednisone. After her parents underwent 5 cycles of IVF with intrauterine transfer of 7 embryos over a span of 4 years, successful pregnancy ensued. Twenty-eight days after delivery, the patient underwent transplantation with her newborn sibling donor's HLA-identical umbilical cord blood hematopoietic stem cells (HSCs). Neutrophil recovery occurred on day 17 without subsequent acute or chronic graft-versus-host disease. Currently, 2.5 years after transplantation, the patient is well and hematopoiesis is normal. In summary, we have described the first successful transplantation, using IVF and PGD, of HSCs from a donor selected on the basis of specific, desirable disease and HLA characteristics. The medical, legal, and ethical issues involved with this approach are discussed. PMID:14504102

  1. The Q motif of Fanconi anemia group J protein (FANCJ) DNA helicase regulates its dimerization, DNA binding, and DNA repair function.

    PubMed

    Wu, Yuliang; Sommers, Joshua A; Loiland, Jason A; Kitao, Hiroyuki; Kuper, Jochen; Kisker, Caroline; Brosh, Robert M

    2012-06-22

    The Q motif, conserved in a number of RNA and DNA helicases, is proposed to be important for ATP binding based on structural data, but its precise biochemical functions are less certain. FANCJ encodes a Q motif DEAH box DNA helicase implicated in Fanconi anemia and breast cancer. A Q25A mutation of the invariant glutamine in the Q motif abolished its ability to complement cisplatin or telomestatin sensitivity of a fancj null cell line and exerted a dominant negative effect. Biochemical characterization of the purified recombinant FANCJ-Q25A protein showed that the mutation disabled FANCJ helicase activity and the ability to disrupt protein-DNA interactions. FANCJ-Q25A showed impaired DNA binding and ATPase activity but displayed ATP binding and temperature-induced unfolding transition similar to FANCJ-WT. Size exclusion chromatography and sedimentation velocity analyses revealed that FANCJ-WT existed as molecular weight species corresponding to a monomer and a dimer, and the dimeric form displayed a higher specific activity for ATPase and helicase, as well as greater DNA binding. In contrast, FANCJ-Q25A existed only as a monomer, devoid of helicase activity. Thus, the Q motif is essential for FANCJ enzymatic activity in vitro and DNA repair function in vivo. PMID:22582397

  2. Addition of High-Dose Cytarabine to Fludarabine-Based Conditioning for Hematopoietic Stem Cell Transplantation for Treating Fanconi Anemia Patients with Advanced Myeloid Malignancy: A Single-Center Experience and Literature Review.

    PubMed

    Aoki, Takahiro; Koh, Katsuyoshi; Ikeda, Yuhachi; Sekinaka, Yujin; Akiyama, Kosuke; Mori, Makiko; Arakawa, Yuki; Hanada, Ryoji

    2016-09-01

    The complication of Fanconi anemia (FA) with acute leukemia is rare and challenging to treat because of high relapse rates, despite the improved outcome of hematopoietic stem cell transplantation with fludarabine-based conditioning for treating FA patients with hematological abnormalities. We added high-dose cytarabine to fludarabine-based conditioning to promote an enhanced antitumor effect and successfully subjected 4 patients with FA, including 3 with acute leukemia, to hematopoietic stem cell transplantation. All patients remain alive without treatment-related mortality or evidence of disease. Adding high-dose cytarabine to fludarabine-based conditioning may be tolerable and effective for treating FA patients with acute leukemia. PMID:27246371

  3. Novel Function of the Fanconi Anemia Group J or RECQ1 Helicase to Disrupt Protein-DNA Complexes in a Replication Protein A-stimulated Manner*

    PubMed Central

    Sommers, Joshua A.; Banerjee, Taraswi; Hinds, Twila; Wan, Bingbing; Wold, Marc S.; Lei, Ming; Brosh, Robert M.

    2014-01-01

    Understanding how cellular machinery deals with chromosomal genome complexity is an important question because protein bound to DNA may affect various cellular processes of nucleic acid metabolism. DNA helicases are at the forefront of such processes, yet there is only limited knowledge how they remodel protein-DNA complexes and how these mechanisms are regulated. We have determined that representative human RecQ and Fe-S cluster DNA helicases are potently blocked by a protein-DNA interaction. The Fanconi anemia group J (FANCJ) helicase partners with the single-stranded DNA-binding protein replication protein A (RPA) to displace BamHI-E111A bound to duplex DNA in a specific manner. Protein displacement was dependent on the ATPase-driven function of the helicase and unique properties of RPA. Further biochemical studies demonstrated that the shelterin proteins TRF1 and TRF2, which preferentially bind the telomeric repeat found at chromosome ends, effectively block FANCJ from unwinding the forked duplex telomeric substrate. RPA, but not the Escherichia coli single-stranded DNA-binding protein or shelterin factor Pot1, stimulated FANCJ ejection of TRF1 from the telomeric DNA substrate. FANCJ was also able to displace TRF2 from the telomeric substrate in an RPA-dependent manner. The stimulation of helicase-catalyzed protein displacement is also observed with the DNA helicase RECQ1, suggesting a conserved functional interaction of RPA-interacting helicases. These findings suggest that partnerships between RPA and interacting human DNA helicases may greatly enhance their ability to dislodge proteins bound to duplex DNA, an activity that is likely to be highly relevant to their biological roles in DNA metabolism. PMID:24895130

  4. Genetics Home Reference: Fanconi anemia

    MedlinePlus

    ... when the process of making new copies of DNA, called DNA replication , is blocked due to DNA damage. The FA pathway sends certain proteins to the area of damage, which trigger DNA repair so DNA replication can continue. The FA ...

  5. Anemia

    MedlinePlus

    If you have anemia, your blood does not carry enough oxygen to the rest of your body. The most common cause of anemia is not having enough ... rich protein that gives the red color to blood. It carries oxygen from the lungs to the ...

  6. A polymorphism in the leptin gene promoter is associated with anemia in patients with HIV disease

    PubMed Central

    Jeong, Jee-Yeong; Tate, Janet; Bathulapalli, Harini; Anderson, Damon; Steen, Hanno; Fleming, Mark; Mattocks, Kristin; Telenti, Amalio; Fellay, Jacques; Justice, Amy C.; Berliner, Nancy

    2011-01-01

    To study factors associated with anemia and its effect on survival in HIV-infected persons treated with modern combined antiretroviral therapy (cART), we characterized the prevalence of anemia in the Veterans Aging Cohort Study (VACS) and used a candidate gene approach to identify proinflammatory gene single nucleotide polymorphisms (SNPs) associated with anemia in HIV disease. The study comprised 1597 HIV+ and 865 HIV− VACS subjects with DNA, blood, and annotated clinical data available for analysis. Anemia was defined according to World Health Organization criteria (hemoglobin < 13 g/dL and < 12 g/dL in men and women, respectively). The prevalence of anemia in HIV+ and HIV− subjects was 23.1% and 12.9%, respectively. Independent of HIV status, anemia was present in 23.4% and 8% in blacks and whites, respectively. Analysis of our candidate genes revealed that the leptin −2548 G/A SNP was associated with anemia in HIV+, but not HIV−, patients, with the AA and AG genotypes significantly predicting anemia (P < .003 and P < .039, respectively, logistic regression). This association was replicated in an independent cohort of HIV+ women. Our study provides novel insight into the association between genetic variability in the leptin gene and anemia in HIV+ individuals. PMID:21926355

  7. Fanconi-Bickel Syndrome: Two Pakistani Patients Presenting with Hypophosphatemic Rickets.

    PubMed

    Afroze, Bushra; Chen, Margaret

    2016-09-01

    Fanconi-Bickel syndrome is a rare inherited disorder characterized by hepatorenal glycogen accumulation, renal tubular dysfunction, growth failure, and impaired utilization of glucose and galactose. We report the first two children with Fanconi-Bickel syndrome from Pakistan who presented with classical features of Fanconi-Bickel Syndrome. Both patients were found to be homozygous for a single nucleotide deletion in the SLC2A2 gene defined as c.339delC. This mutation was previously described in an Arab patient who was initially presented as permanent neonatal diabetes mellitus before developing classical features of Fanconi-Bickel syndrome. PMID:27617158

  8. Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.

    PubMed

    Bär, Christian; Povedano, Juan Manuel; Serrano, Rosa; Benitez-Buelga, Carlos; Popkes, Miriam; Formentini, Ivan; Bobadilla, Maria; Bosch, Fatima; Blasco, Maria A

    2016-04-01

    Aplastic anemia is a fatal bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of hematopoietic stem and progenitor cells due to very short telomeres as a result of mutations in telomerase and other telomere components. Abnormal telomere shortening is also described in cases of acquired aplastic anemia, most likely secondary to increased turnover of bone marrow stem and progenitor cells. Here, we test the therapeutic efficacy of telomerase activation by using adeno-associated virus (AAV)9 gene therapy vectors carrying the telomeraseTertgene in 2 independent mouse models of aplastic anemia due to short telomeres (Trf1- andTert-deficient mice). We find that a high dose of AAV9-Terttargets the bone marrow compartment, including hematopoietic stem cells. AAV9-Terttreatment after telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. These findings indicate that telomerase gene therapy represents a novel therapeutic strategy to treat aplastic anemia provoked or associated with short telomeres. PMID:26903545

  9. Gene therapy cures the anemia and lethal bone marrow failure in a mouse model of RPS19-deficient Diamond-Blackfan anemia.

    PubMed

    Jaako, Pekka; Debnath, Shubhranshu; Olsson, Karin; Modlich, Ute; Rothe, Michael; Schambach, Axel; Flygare, Johan; Karlsson, Stefan

    2014-12-01

    Diamond-Blackfan anemia is a congenital erythroid hypoplasia caused by functional haploinsufficiency of genes encoding ribosomal proteins. Mutations involving the ribosomal protein S19 gene are detected in 25% of patients. Enforced expression of ribosomal protein S19 improves the overall proliferative capacity, erythroid colony-forming potential and erythroid differentiation of hematopoietic progenitors from ribosomal protein S19-deficient patients in vitro and in vivo following xenotransplantation. However, studies using animal models are needed to assess the therapeutic efficacy and safety of the viral vectors. In the present study we have validated the therapeutic potential of gene therapy using mouse models of ribosomal protein S19-deficient Diamond-Blackfan anemia. Using lentiviral gene transfer we demonstrated that enforced expression of ribosomal protein S19 cures the anemia and lethal bone marrow failure in recipients transplanted with ribosomal protein S19-deficient cells. Furthermore, gene-corrected ribosomal protein S19-deficient cells showed an increased pan-hematopoietic contribution over time compared to untransduced cells without signs of vector-mediated toxicity. Our study provides a proof of principle for the development of clinical gene therapy to cure ribosomal protein 19-deficient Diamond-Blackfan anemia. PMID:25216681

  10. Somatic, hematologic phenotype, long-term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Association of Pediatric Hematology-Oncology).

    PubMed

    Svahn, Johanna; Bagnasco, Francesca; Cappelli, Enrico; Onofrillo, Daniela; Caruso, Silvia; Corsolini, Fabio; De Rocco, Daniela; Savoia, Anna; Longoni, Daniela; Pillon, Marta; Marra, Nicoletta; Ramenghi, Ugo; Farruggia, Piero; Locasciulli, Anna; Addari, Carmen; Cerri, Carla; Mastrodicasa, Elena; Casazza, Gabriella; Verzegnassi, Federico; Riccardi, Francesca; Haupt, Riccardo; Barone, Angelica; Cesaro, Simone; Cugno, Chiara; Dufour, Carlo

    2016-07-01

    We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy-two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow-up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow-up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666-671, 2016. © 2016 Wiley Periodicals, Inc. PMID:27013026

  11. Deletion of a Malaria Invasion Gene Reduces Death and Anemia, in Model Hosts

    PubMed Central

    Gómez, Noé D.; Safeukui, Innocent; Adelani, Aanuoluwa A.; Tewari, Rita; Reddy, Janardan K.; Rao, Sam; Holder, Anthony; Buffet, Pierre; Mohandas, Narla; Haldar, Kasturi

    2011-01-01

    Malaria parasites induce complex cellular and clinical phenotypes, including anemia, cerebral malaria and death in a wide range of mammalian hosts. Host genes and parasite ‘toxins’ have been implicated in malarial disease, but the contribution of parasite genes remains to be fully defined. Here we assess disease in BALB/c mice and Wistar rats infected by the rodent malaria parasite Plasmodium berghei with a gene knock out for merozoite surface protein (MSP) 7. MSP7 is not essential for infection but in P. falciparum, it enhances erythrocyte invasion by 20%. In vivo, as compared to wild type, the P. berghei Δmsp7 mutant is associated with an abrogation of death and a decrease from 3% to 2% in peak, circulating parasitemia. The Δmsp7 mutant is also associated with less anemia and modest increase in the size of follicles in the spleen. Together these data show that deletion of a single parasite invasion ligand modulates blood stage disease, as measured by death and anemia. This work is the first to assess the contribution of a gene present in all plasmodial species in severe disease. PMID:21980474

  12. p53 downregulates the Fanconi anaemia DNA repair pathway

    PubMed Central

    Jaber, Sara; Toufektchan, Eléonore; Lejour, Vincent; Bardot, Boris; Toledo, Franck

    2016-01-01

    Germline mutations affecting telomere maintenance or DNA repair may, respectively, cause dyskeratosis congenita or Fanconi anaemia, two clinically related bone marrow failure syndromes. Mice expressing p53Δ31, a mutant p53 lacking the C terminus, model dyskeratosis congenita. Accordingly, the increased p53 activity in p53Δ31/Δ31 fibroblasts correlated with a decreased expression of 4 genes implicated in telomere syndromes. Here we show that these cells exhibit decreased mRNA levels for additional genes contributing to telomere metabolism, but also, surprisingly, for 12 genes mutated in Fanconi anaemia. Furthermore, p53Δ31/Δ31 fibroblasts exhibit a reduced capacity to repair DNA interstrand crosslinks, a typical feature of Fanconi anaemia cells. Importantly, the p53-dependent downregulation of Fanc genes is largely conserved in human cells. Defective DNA repair is known to activate p53, but our results indicate that, conversely, an increased p53 activity may attenuate the Fanconi anaemia DNA repair pathway, defining a positive regulatory feedback loop. PMID:27033104

  13. Long-term reversal of chronic anemia using a hypoxia-regulated erythropoietin gene therapy.

    PubMed

    Binley, Katie; Askham, Zoe; Iqball, Sharifah; Spearman, Hayley; Martin, Leigh; de Alwis, Mahesh; Thrasher, Adrian J; Ali, Robin R; Maxwell, Patrick H; Kingsman, Susan; Naylor, Stuart

    2002-10-01

    Anemia is a common clinical problem, and there is much interest in its role in promoting left ventricular hypertrophy through increasing cardiac workload. Normally, red blood cell production is adjusted through the regulation of erythropoietin (Epo) production by the kidney. One important cause of anemia is relative deficiency of Epo, which occurs in most types of renal disease. Clinically, this can be corrected by supplementation with recombinant Epo. Here we describe an oxygen-regulated gene therapy approach to treating homozygous erythropoietin-SV40 T antigen (Epo-TAg(h)) mice with relative erythropoietin deficiency. We used vectors in which murine Epo expression was directed by an Oxford Biomedica hypoxia response element (OBHRE) or a constitutive cytomegalovirus (CMV) promoter. Both corrected anemia, but CMV-Epo-treated mice acquired fatal polycythemia. In contrast, OBHRE-Epo corrected the hematocrit level in anemic mice to a normal physiologic level that stabilized without resulting in polycythemia. Importantly, the OBHRE-Epo vector had no significant effect on the hematocrit of control mice. Homozygous Epo-TAg(h) mice display cardiac hypertrophy, a common adaptive response in patients with chronic anemia. In the OBHRE-Epo-treated Epo-TAg(h) mice, we observed a significant reversal of cardiac hypertrophy. We conclude that the OBHRE promoter gives rise to physiologically regulated Epo secretion such that the hematocrit level is corrected to healthy in anemic Epo-TAg(h) mice. This establishes that a hypoxia regulatory mechanism similar to the natural mechanism can be achieved, and it makes EPO gene therapy more attractive and safer in clinical settings. We envisage that this control system will allow regulated delivery of therapeutic gene products in other ischemic settings. PMID:12239150

  14. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation.

    PubMed

    Nicolas, Gaël; Chauvet, Caroline; Viatte, Lydie; Danan, Jean Louis; Bigard, Xavier; Devaux, Isabelle; Beaumont, Carole; Kahn, Axel; Vaulont, Sophie

    2002-10-01

    The present study was aimed at determining whether hepcidin, a recently identified peptide involved in iron metabolism, plays a role in conditions associated with both iron overload and iron deficiency. Hepcidin mRNA levels were assessed in two models of anemia, acute hemolysis provoked by phenylhydrazine and bleeding provoked by repeated phlebotomies. Hepcidin response to hypoxia was also studied, both ex vivo, in human hepatoma cells, and in vivo. Anemia and hypoxia were associated with a dramatic decrease in liver hepcidin gene expression, which may account for the increase in iron release from reticuloendothelial cells and increase in iron absorption frequently observed in these situations. A single injection of turpentine for 16 hours induced a sixfold increase in liver hepcidin mRNA levels and a twofold decrease in serum iron. The hyposideremic effect of turpentine was completely blunted in hepcidin-deficient mice, revealing hepcidin participation in anemia of inflammatory states. These modifications of hepcidin gene expression further suggest a key role for hepcidin in iron homeostasis under various pathophysiological conditions, which may support the pharmaceutical use of hepcidin agonists and antagonists in various iron homeostasis disorders. PMID:12370282

  15. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation

    PubMed Central

    Nicolas, Gaël; Chauvet, Caroline; Viatte, Lydie; Danan, Jean Louis; Bigard, Xavier; Devaux, Isabelle; Beaumont, Carole; Kahn, Axel; Vaulont, Sophie

    2002-01-01

    The present study was aimed at determining whether hepcidin, a recently identified peptide involved in iron metabolism, plays a role in conditions associated with both iron overload and iron deficiency. Hepcidin mRNA levels were assessed in two models of anemia, acute hemolysis provoked by phenylhydrazine and bleeding provoked by repeated phlebotomies. Hepcidin response to hypoxia was also studied, both ex vivo, in human hepatoma cells, and in vivo. Anemia and hypoxia were associated with a dramatic decrease in liver hepcidin gene expression, which may account for the increase in iron release from reticuloendothelial cells and increase in iron absorption frequently observed in these situations. A single injection of turpentine for 16 hours induced a sixfold increase in liver hepcidin mRNA levels and a twofold decrease in serum iron. The hyposideremic effect of turpentine was completely blunted in hepcidin-deficient mice, revealing hepcidin participation in anemia of inflammatory states. These modifications of hepcidin gene expression further suggest a key role for hepcidin in iron homeostasis under various pathophysiological conditions, which may support the pharmaceutical use of hepcidin agonists and antagonists in various iron homeostasis disorders. PMID:12370282

  16. Exploiting pre-rRNA processing in Diamond Blackfan anemia gene discovery and diagnosis.

    PubMed

    Farrar, Jason E; Quarello, Paola; Fisher, Ross; O'Brien, Kelly A; Aspesi, Anna; Parrella, Sara; Henson, Adrianna L; Seidel, Nancy E; Atsidaftos, Eva; Prakash, Supraja; Bari, Shahla; Garelli, Emanuela; Arceci, Robert J; Dianzani, Irma; Ramenghi, Ugo; Vlachos, Adrianna; Lipton, Jeffrey M; Bodine, David M; Ellis, Steven R

    2014-10-01

    Diamond Blackfan anemia (DBA), a syndrome primarily characterized by anemia and physical abnormalities, is one among a group of related inherited bone marrow failure syndromes (IBMFS) which share overlapping clinical features. Heterozygous mutations or single-copy deletions have been identified in 12 ribosomal protein genes in approximately 60% of DBA cases, with the genetic etiology unexplained in most remaining patients. Unlike many IBMFS, for which functional screening assays complement clinical and genetic findings, suspected DBA in the absence of typical alterations of the known genes must frequently be diagnosed after exclusion of other IBMFS. We report here a novel deletion in a child that presented such a diagnostic challenge and prompted development of a novel functional assay that can assist in the diagnosis of a significant fraction of patients with DBA. The ribosomal proteins affected in DBA are required for pre-rRNA processing, a process which can be interrogated to monitor steps in the maturation of 40S and 60S ribosomal subunits. In contrast to prior methods used to assess pre-rRNA processing, the assay reported here, based on capillary electrophoresis measurement of the maturation of rRNA in pre-60S ribosomal subunits, would be readily amenable to use in diagnostic laboratories. In addition to utility as a diagnostic tool, we applied this technique to gene discovery in DBA, resulting in the identification of RPL31 as a novel DBA gene. PMID:25042156

  17. PIEZO1 gene mutation in a Japanese family with hereditary high phosphatidylcholine hemolytic anemia and hemochromatosis-induced diabetes mellitus.

    PubMed

    Imashuku, Shinsaku; Muramatsu, Hideki; Sugihara, Takashi; Okuno, Yusuke; Wang, Xinan; Yoshida, Kenichi; Kato, Ayako; Kato, Koichi; Tatsumi, Yasuaki; Hattori, Ai; Kita, Shinya; Oe, Keishi; Sueyoshi, Atsushi; Usui, Takeshi; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Ogawa, Seishi; Kojima, Seiji; Kanno, Hitoshi

    2016-07-01

    Hereditary xerocytosis (HX) or dehydrated hereditary stomatocytosis (DHS) [OMIM 194380], in which PIEZO1 gene mutation has recently been identified, is difficult to diagnose. We report here the discovery of a PIEZO1 gene mutation in a Japanese family (father, daughter, and son) who were previously diagnosed with hereditary high phosphatidylcholine hemolytic anemia (HPCHA). All of the affected family members had non-spherocytic hemolytic anemia associated with severe hemochromatosis-related diabetes mellitus. Although the causative correlation between HPCHA and PIEZO1-gene mutated HX/DHS remains to be clarified, our findings raise an important question as to whether any of the HPCHA cases previously diagnosed in Japan may have in fact been the form of hemolytic anemia known as HX/DHS with PIEZO1 gene mutation. PMID:26971963

  18. Pernicious anemia

    MedlinePlus

    ... achylic anemia; Congenital pernicious anemia; Juvenile pernicious anemia; Vitamin B12 deficiency (malabsorption) ... Pernicious anemia is a type of vitamin B12 anemia. The body needs ... cells. You get this vitamin from eating foods such as meat, ...

  19. Deregulation of genes related to iron and mitochondrial metabolism in refractory anemia with ring sideroblasts.

    PubMed

    del Rey, Mónica; Benito, Rocío; Fontanillo, Celia; Campos-Laborie, Francisco J; Janusz, Kamila; Velasco-Hernández, Talía; Abáigar, María; Hernández, María; Cuello, Rebeca; Borrego, Daniel; Martín-Zanca, Dionisio; De Las Rivas, Javier; Mills, Ken I; Hernández-Rivas, Jesús M

    2015-01-01

    The presence of SF3B1 gene mutations is a hallmark of refractory anemia with ring sideroblasts (RARS). However, the mechanisms responsible for iron accumulation that characterize the Myelodysplastic Syndrome with ring sideroblasts (MDS-RS) are not completely understood. In order to gain insight in the molecular basis of MDS-RS, an integrative study of the expression and mutational status of genes related to iron and mitochondrial metabolism was carried out. A total of 231 low-risk MDS patients and 81 controls were studied. Gene expression analysis revealed that iron metabolism and mitochondrial function had the highest number of genes deregulated in RARS patients compared to controls and the refractory cytopenias with unilineage dysplasia (RCUD). Thus mitochondrial transporters SLC25 (SLC25A37 and SLC25A38) and ALAD genes were over-expressed in RARS. Moreover, significant differences were observed between patients with SF3B1 mutations and patients without the mutations. The deregulation of genes involved in iron and mitochondrial metabolism provides new insights in our knowledge of MDS-RS. New variants that could be involved in the pathogenesis of these diseases have been identified. PMID:25955609

  20. Deregulation of Genes Related to Iron and Mitochondrial Metabolism in Refractory Anemia with Ring Sideroblasts

    PubMed Central

    del Rey, Mónica; Benito, Rocío; Fontanillo, Celia; Campos-Laborie, Francisco J.; Janusz, Kamila; Velasco-Hernández, Talía; Abáigar, María; Hernández, María; Cuello, Rebeca; Borrego, Daniel; Martín-Zanca, Dionisio; De Las Rivas, Javier; Mills, Ken I.; Hernández-Rivas, Jesús M.

    2015-01-01

    The presence of SF3B1 gene mutations is a hallmark of refractory anemia with ring sideroblasts (RARS). However, the mechanisms responsible for iron accumulation that characterize the Myelodysplastic Syndrome with ring sideroblasts (MDS-RS) are not completely understood. In order to gain insight in the molecular basis of MDS-RS, an integrative study of the expression and mutational status of genes related to iron and mitochondrial metabolism was carried out. A total of 231 low-risk MDS patients and 81 controls were studied. Gene expression analysis revealed that iron metabolism and mitochondrial function had the highest number of genes deregulated in RARS patients compared to controls and the refractory cytopenias with unilineage dysplasia (RCUD). Thus mitochondrial transporters SLC25 (SLC25A37 and SLC25A38) and ALAD genes were over-expressed in RARS. Moreover, significant differences were observed between patients with SF3B1 mutations and patients without the mutations. The deregulation of genes involved in iron and mitochondrial metabolism provides new insights in our knowledge of MDS-RS. New variants that could be involved in the pathogenesis of these diseases have been identified. PMID:25955609

  1. Chromosomal location of three spectrin genes: relationship to the inherited hemolytic anemias of mouse and man.

    PubMed Central

    Birkenmeier, C S; McFarland-Starr, E C; Barker, J E

    1988-01-01

    Three genetic loci in the mouse affect the synthesis and assembly of the erythrocyte membrane skeleton. The spherocytosis and jaundiced loci affect the membrane skeletal protein known as spectrin. The normoblastosis locus affects the spectrin binding protein called ankyrin. We have obtained genetic data that define the linkage relationships among three spectrin genes and the spherocytosis and jaundiced loci. The erythroid alpha-spectrin gene is tightly linked to the spherocytosis locus on chromosome 1 and the jaundiced locus is on chromosome 12, tightly linked to the erythroid beta-spectrin gene. The brain alpha-spectrin (alpha-fodrin) gene is located on the centromeric end of chromosome 2 and is not closely linked to any previously mapped erythroid or neurological mutation. These results are consistent with the hypothesis that defects in the alpha- and beta-spectrin genes cause the spherocytosis and jaundiced hemolytic anemias in mice. All five loci studied are located within chromosomal segments that are conserved between mouse and man. Analysis of the data from the chromosome 12 study defines a new order for the genes on that chromosome and delineates the largest mouse/human conserved chromosomal segment yet known. Images PMID:3186715

  2. CD34+ gene expression profiling of individual children with very severe aplastic anemia indicates a pathogenic role of integrin receptors and the proapoptotic death ligand TRAIL

    PubMed Central

    Fischer, Ute; Ruckert, Christian; Hubner, Bernd; Eckermann, Olaf; Binder, Vera; Bakchoul, Tamam; Schuster, Friedhelm R.; Merk, Sylvia; Klein, Hans-Ulrich; Führer, Monika; Dugas, Martin; Borkhardt, Arndt

    2012-01-01

    Background Very severe aplastic anemia is characterized by a hypoplastic bone marrow due to destruction of CD34+ stem cells by autoreactive T cells. Investigation of the pathomechanism by patient-specific gene expression analysis of the attacked stem cells has previously been impractical because of the scarcity of these cells at diagnosis. Design and Methods Employing unbiased RNA amplification, patient-specific gene expression profiling was carried out for CD34+ cells from patients newly diagnosed with very severe aplastic anemia (n=13), refractory anemia (n=8) and healthy controls (n=10). These data were compared to profiles of myelodysplastic disease (n=55), including refractory anemia (n=18). To identify possible targets of autoimmune attack, presence of autoreactive antibodies was tested in pre-therapeutic sera of patients with very severe aplastic anemia (n=19). Results CD34+ gene expression profiling distinguished between healthy controls, children with aplastic or refractory anemia and clonal disease. Interferon stimulated genes such as the apoptosis inducing death ligand TRAIL were strongly up-regulated in CD34+ cells of patients with aplastic anemia, in particular in patients responding to immunosuppressive treatment. In contrast, mRNA expression of integrin GPVI and the integrin complexes GPIa/IIa, GPIIb/IIIa, GPIB/GPIX/GPV was significantly down-regulated and corresponding antibodies were detected in 7 of 11 profiled patients and in 11 of 19 aplastic anemia patients. Conclusions As a potential diagnostic tool, patient-specific gene expression profiling of CD34+ stem cells made it possible to make the difficult differential diagnosis of most patients with aplastic and refractory anemia. Profiling indicated a prognostic correlation of TRAIL expression and patient benefit from immunosuppressive therapy. Downregulation of integrin expression and concurrent presence of autoreactive anti-integrin-antibodies suggested a previously unrecognized pathological

  3. Gene disruption of dematin causes precipitous loss of erythrocyte membrane stability and severe hemolytic anemia.

    PubMed

    Lu, Yunzhe; Hanada, Toshihiko; Fujiwara, Yuko; Nwankwo, Jennifer O; Wieschhaus, Adam J; Hartwig, John; Huang, Sha; Han, Jongyoon; Chishti, Athar H

    2016-07-01

    Dematin is a relatively low abundance actin binding and bundling protein associated with the spectrin-actin junctions of mature erythrocytes. Primary structure of dematin includes a loosely folded core domain and a compact headpiece domain that was originally identified in villin. Dematin's actin binding properties are regulated by phosphorylation of its headpiece domain by cyclic adenosine monophosphate-dependent protein kinase. Here, we used a novel gene disruption strategy to generate the whole body dematin gene knockout mouse model (FLKO). FLKO mice, while born at a normal Mendelian ratio, developed severe anemia and exhibited profound aberrations of erythrocyte morphology and membrane stability. Having no apparent effect on primitive erythropoiesis, FLKO mice show significant enhancement of erythroblast enucleation during definitive erythropoiesis. Using membrane protein analysis, domain mapping, electron microscopy, and dynamic deformability measurements, we investigated the mechanism of membrane instability in FLKO erythrocytes. Although many membrane and cytoskeletal proteins remained at their normal levels, the major peripheral membrane proteins spectrin, adducin, and actin were greatly reduced in FLKO erythrocytes. Our results demonstrate that dematin plays a critical role in maintaining the fundamental properties of the membrane cytoskeleton complex. PMID:27073223

  4. Hemolytic anemia

    MedlinePlus

    Anemia - hemolytic ... bones that helps form all blood cells. Hemolytic anemia occurs when the bone marrow isn't making ... destroyed. There are several possible causes of hemolytic anemia. Red blood cells may be destroyed due to: ...

  5. Pernicious Anemia

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Pernicious Anemia? Pernicious anemia (per-NISH-us uh-NEE-me-uh) is ... nervous system working properly. People who have pernicious anemia can't absorb enough vitamin B12 from food. ...

  6. Hemolytic Anemia

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Hemolytic Anemia? Hemolytic anemia (HEE-moh-lit-ick uh-NEE-me-uh) ... blood cells to replace them. However, in hemolytic anemia, the bone marrow can't make red blood ...

  7. Hemolytic anemia

    MedlinePlus

    Anemia - hemolytic ... Hemolytic anemia occurs when the bone marrow is unable to replace the red blood cells that are being destroyed. Immune hemolytic anemia occurs when the immune system mistakenly sees your ...

  8. New Codanin-1 Gene Mutations in a Italian Patient with Congenital Dyserythropoietic Anemia Type I and Heterozygous Beta-Thalassemia.

    PubMed

    D'Alcamo, Elena; Agrigento, V; Pitrolo, L; Sclafani, S; Barone, R; Calvaruso, G; Buffa, V; Maggio, A

    2016-06-01

    Congenital dyserythropoietic anemia type I is an autosomal recessive disorder associated with macrocytic anemia, ineffective erythropoiesis, iron overloading and characterized by abnormal chromatin ultrastructure in erythroblasts such as internuclear chromatin bridges, spongy heterochromatin and invagination of the nuclear membrane. A 58-year-old Causasian man with chronic hemolytic anemia, heterozygous for β (+) -globin IVS1, nt110 G>A mutation (causing abnormal alpha:beta globin chain ratio) showed clinical, laboratory and hematological features suggesting diagnosis of CDA1. Sequence analysis of CDA-related genes revealed compound heterozygosity for two novel mutations in the CDAN1 gene: a frameshift mutation 3367 del 4 (TTAG) in exon 25 and a missense mutation c.1811 G>T in exon 11 causing an aminoacid change from glycine to valine at codon 565 (G565V). One of the propositus' brothers showed the same gene mutations. As the CDA1 can mimic thalassemia, a frequent misdiagnosis is possible especially in countries where the prevalence of thalassemia is high. A strong clinical suspicion in patients who do not reveal a clear genetic basis for presumed thalassemia may help clinch the correct diagnosis. PMID:27408412

  9. Sickle Cell Anemia

    MedlinePlus

    Sickle cell anemia is a disease in which your body produces abnormally shaped red blood cells. The cells are shaped like a crescent or sickle. They don' ... problem causes sickle cell anemia. People with the disease are born with two sickle cell genes, one ...

  10. Haptoglobin gene polymorphisms and interleukin-6 and -8 levels in patients with sickle cell anemia

    PubMed Central

    Pierrot-Gallo, Bruna Spinella; Vicari, Perla; Matsuda, Sandra Satiko; Adegoke, Samuel Ademola; Mecabo, Grazielle; Figueiredo, Maria Stella

    2015-01-01

    Background Haptoglobin genotypes, and interleukin-6 and -8 participate in the pathophysiology of sickle cell anemia. The expression of cytokines is regulated by genetic mechanisms however the effect of haptoglobin polymorphisms on these cytokines is not fully understood. This study aimed to compare the frequency of haptoglobin genotypes and the interleukin-6 and -8 concentrations in sickle cell anemia patients and controls to investigate the association between haptoglobin genotypes and cytokine levels. Methods Sixty sickle cell anemia patients and 74 healthy individuals were analyzed. Haptoglobin genotypes were determined by multiplex polymerase chain reaction, and the interleukin-6 and -8 levels by enzyme linked immunosorbent assay. The association between haptoglobin genotypes and cytokines was investigated by statistical tests. Results Hp2-1 was the most common genotype in both the cases and controls while Hp1-1 was less frequent among sickle cell anemia patients. Interleukin-6 and -8 levels were higher in patients than controls (p-value <0.0001). There was no significant difference in interleukin-6 and -8 concentrations between the genotypes (p-value >0.05). A similar trend was observed among the controls. Conclusion Although, levels of interleukin-6 and -8 were higher in the sickle cell anemia patients, they appeared not to be related to the haptoglobin genotypes. Further investigations are necessary to identify factors responsible for increased secretion of the interleukin-6 and -8 pro-inflammatory cytokines in patients with sickle cell anemia. PMID:26408368

  11. Inborn anemias in mice

    SciTech Connect

    Bernstein, S.E.; Barker, J.E.; Russell, E.S.

    1981-06-01

    hereditary anemias of mice have been the chief objects of investigation. At present under study are four macrocytic anemias, five hemolytic anemias, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, an ..cap alpha..-thalassemia, and a new target-cell anemia. Each of these blood dyscrasias is caused by the action of a unique mutant gene, which determines the structure of different intracellular molecules, and thus controls a different metabolic process. Thus our wide range of different hereditary anemias has considerable potential for uncovering many different aspects of hemopoietic homeostatic mechanisms in the mouse. Each anemia is studied through: (a) characterization of peripheral blood values, (b) determinations of radiosensitivity under a variety of conditions, (c) measurements of iron metabolism and heme synthesis, (d) histological and biochemical study of blood-forming tissue, (e) functional tests of the stem cell component, (f) examination of responses to erythroid stimuli, and (g) transplantation of tissue between individuals of differently affected genotypes.

  12. Post-irradiation phosphorylation of structural maintenance chromosome 1 (SMC1) is independent of the Fanconi protein pathway

    SciTech Connect

    Nahas, Shareef A.; Lai, C.-H.; Gatti, Richard A. . E-mail: rgatti@mednet.ucla.edu

    2005-03-15

    Purpose: To confirm the sensitivity of cells from patients with Fanconi anemia (FA) to ionizing radiation, and to determine whether the phosphorylation of structural maintenance chromosome 1 (SMC1) was associated with radiosensitivity, as it is in other DNA repair disorders. Methods and materials: Using lymphoblastoid cell lines from FA patients before and after exposure to ionizing radiation, the colony survival assay, radioresistant DNA synthesis, and SMC1 phosphorylation were measured. FA lymphoblastoid cell lines that had been transfected with the wild-type FANC gene were used as controls. Results: Cells from FA patients of six complementation groups were radiosensitive. Despite this, SMC1 phosphorylation was normal in each case; radioresistant DNA synthesis, a measure of S phase checkpoint integrity, was defective in FANCD2 lymphoblastoid cell lines and was corrected in FANCD2 + D2 cells. Conclusions: The data indicate that the FANC pathway proteins play a major role in the cellular responses to ionizing radiation, but not in SMC1 phosphorylation or in the S phase checkpoint of FANCD2-deficient cells. Thus, SMC1 activation is not a common denominator of radiosensitivity, as has been suggested by radiation responses of cells from ataxia-telangiectasia, Nijmegen breakage syndrome, or Mre11 deficiency patients.

  13. Aplastic Anemia

    MedlinePlus

    Aplastic anemia is a rare but serious blood disorder. If you have it, your bone marrow doesn't make ... infections and bleeding. Your doctor will diagnose aplastic anemia based on your medical and family histories, a ...

  14. Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28.

    PubMed

    Gripp, Karen W; Curry, Cynthia; Olney, Ann Haskins; Sandoval, Claudio; Fisher, Jamie; Chong, Jessica Xiao-Ling; Pilchman, Lisa; Sahraoui, Rebecca; Stabley, Deborah L; Sol-Church, Katia

    2014-09-01

    Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or mandibulofacial dysostosis (MFD) and macrocytic anemia diagnostic of Diamond-Blackfan anemia (DBA) have been reported. Disease-causing genes have been identified for TCS and other MFDs. Mutations in several ribosomal protein genes and the transcription factor GATA1 result in DBA. However, no disease-causing mutation had been identified in the reported patients with the combination of TCS/MFD and DBA phenotype, and we hypothesized that pathogenic mutations in a single gene could be identified using whole exome analysis. We studied probands from six unrelated families. Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families. Two mutations in unrelated families were seen in RPS26, the known DBA10 gene. One variant was predicted to affect mRNA splicing, and the other to lead to protein truncation. In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26. De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene. We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous. Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth. The phenotype combining TCS/MFD and DBA is highly variable, overlaps with DBA and lies within the phenotypic spectrum of ribosomopathies. © 2014 Wiley Periodicals, Inc. PMID:24942156

  15. Diamond-Blackfan Anemia with Mandibulofacial Dystostosis is Heterogeneous, Including the Novel DBA Genes TSR2 and RPS28

    PubMed Central

    Gripp, Karen W.; Curry, Cynthia; Olney, Ann Haskins; Sandoval, Claudio; Fisher, Jamie; Chong, Jessica Xiao-Ling; Pilchman, Lisa; Sahraoui, Rebecca; Stabley, Deborah L.; Sol-Church, Katia

    2014-01-01

    Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or mandibulofacial dystosis (MFD) and macrocytic anemia diagnostic of Diamond Blackfan anemia (DBA) have been reported. Disease causing genes have been identified for TCS and other MFDs. Mutations in several ribosomal protein genes and the transcription factor GATA1 result in DBA. However, no disease causing mutation had been identified in the reported patients with the combination of TCS/MFD and DBA phenotype, and we hypothesized that pathogenic mutations in a single gene could be identified using whole exome analysis. We studied probands from 6 unrelated families. Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families. Two mutations in unrelated families were seen in RPS26, the known DBA10 gene. One variant was predicted to affect mRNA splicing, and the other to lead to protein truncation. In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26. De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene. We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous. Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth. The phenotype combining TCS/MFD and DBA is highly variable, overlaps with DBA and lies within the phenotypic spectrum of ribosomopathies. PMID:24942156

  16. Self-catalytic DNA depurination underlies human β-globin gene mutations at codon 6 that cause anemias and thalassemias.

    PubMed

    Alvarez-Dominguez, Juan R; Amosova, Olga; Fresco, Jacques R

    2013-04-19

    The human β-globin gene contains an 18-nucleotide coding strand sequence centered at codon 6 and capable of forming a stem-loop structure that can self-catalyze depurination of the 5'G residue of that codon. The resultant apurinic lesion is subject to error-prone repair, consistent with the occurrence about this codon of mutations responsible for 6 anemias and β-thalassemias and additional substitutions without clinical consequences. The 4-residue loop of this stem-loop-forming sequence shows the highest incidence of mutation across the gene. The loop and first stem base pair-forming residues appeared early in the mammalian clade. The other stem-forming segments evolved more recently among primates, thereby conferring self-depurination capacity at codon 6. These observations indicate a conserved molecular mechanism leading to β-globin variants underlying phenotypic diversity and disease. PMID:23457306

  17. Identification of a novel erythroid-specific enhancer for the ALAS2 gene and its loss-of-function mutation which is associated with congenital sideroblastic anemia

    PubMed Central

    Kaneko, Kiriko; Furuyama, Kazumichi; Fujiwara, Tohru; Kobayashi, Ryoji; Ishida, Hiroyuki; Harigae, Hideo; Shibahara, Shigeki

    2014-01-01

    Erythroid-specific 5-aminolevulinate synthase (ALAS2) is the rate-limiting enzyme for heme biosynthesis in erythroid cells, and a missense mutation of the ALAS2 gene is associated with congenital sideroblastic anemia. However, the gene responsible for this form of anemia remains unclear in about 40% of patients. Here, we identify a novel erythroid-specific enhancer of 130 base pairs in the first intron of the ALAS2 gene. The newly identified enhancer contains a cis-acting element that is bound by the erythroid-specific transcription factor GATA1, as confirmed by chromatin immunoprecipitation analysis in vivo and by electrophoretic mobility shift assay in vitro. A promoter activity assay in K562 human erythroleukemia cells revealed that the presence of this 130-base pair region increased the promoter activity of the ALAS2 gene by 10–15-fold. Importantly, two mutations, each of which disrupts the GATA-binding site in the enhancer, were identified in unrelated male patients with congenital sideroblastic anemia, and the lower expression level of ALAS2 mRNA in bone marrow erythroblasts was confirmed in one of these patients. Moreover, GATA1 failed to bind to each mutant sequence at the GATA-binding site, and each mutation abolished the enhancer function on ALAS2 promoter activity in K562 cells. Thus, a mutation at the GATA-binding site in this enhancer may cause congenital sideroblastic anemia. These results suggest that the newly identified intronic enhancer is essential for the expression of the ALAS2 gene in erythroid cells. We propose that the 130-base pair enhancer region located in the first intron of the ALAS2 gene should be examined in patients with congenital sideroblastic anemia in whom the gene responsible is unknown. PMID:23935018

  18. Sequence analysis of the fusion protein gene from infectious salmon anemia virus isolates: evidence of recombination and reassortment.

    PubMed

    Devold, M; Karlsen, M; Nylund, A

    2006-07-01

    Studies of infectious salmon anemia virus (ISAV; genus Isavirus, family Orthomyxoviridae) haemagglutinin-esterase (HE) gene sequences have shown that this gene provides a tool for genotyping and, hence, a tool to follow the dissemination of ISAV. The problem with using only the HE gene is that ISAV has a segmented genome and one segment may not tell the whole story about the origin and history of ISAV from outbreaks. To achieve a better genotyping system, the present study has focused on segment 5, the fusion (F) protein gene, which contains sequence variation at about the same level as the HE gene. The substitution rates of the HE and F gene sequences, based on 54 Norwegian ISAV isolates, are 6.1(+/-0.3)x10(-6) and 8.6(+/-5.0)x10(-5) nt per site per year, respectively. The results of phylogenetic analysis of the two gene segments have been compared and, with the exception of a few cases of reassortment, they tell the same story about the ISAV isolates. A combination of the two segments is recommended as a tool for future genotyping of ISAV. Inserts (INs) of 8-11 aa may occur close to the cleavage site of the precursor F(0) protein in some ISAV isolates. The nucleotide sequence of two of these INs shows 100% sequence identity to parts of the 5' end of the F protein gene, whilst the third IN is identical to a part of the nucleoprotein gene. This shows that recombination is one of the evolutionary mechanisms shaping the genome of ISAV. The possible importance of the INs with respect to virulence remains uncertain. PMID:16760406

  19. Variant at position 10,055 in mitochondrial tRNA(Gly) gene has a negative association with aplastic anemia.

    PubMed

    Jiang, Zhongxing; Wu, Xinai; Zhu, Yanan

    2016-09-01

    Recently, a growing number of reports had shown the association between mitochondrial DNA (mtDNA) sequence variants and aplastic anemia (AA). Owing to its high mutation rate, mtDNA variant had become biomarker for clinical and molecular diagnosis for AA. However, the relationship between mtDNA variant and AA was largely unknown. In this study, we reanalyzed the possible association between a "pathogenic" mutation A10055G in mt-tRNA(Gly) gene and AA, through the application of bioinformatics tool, we found that this mutation did not alter the secondary structure of tRNA(Gly), the pathogenicity scoring system indicated that the score of this mutation was only two points and belonged to a "neutral polymorphism", suggested that the role of A10055G mutation in clinical expression in AA needed to be further experimentally addressed. PMID:25629498

  20. The surface envelope protein gene region of equine infectious anemia virus is not an important determinant of tropism in vitro.

    PubMed Central

    Perry, S T; Flaherty, M T; Kelley, M J; Clabough, D L; Tronick, S R; Coggins, L; Whetter, L; Lengel, C R; Fuller, F

    1992-01-01

    Virulent, wild-type equine infectious anemia virus (EIAV) is restricted in one or more early steps in replication in equine skin fibroblast cells compared with cell culture-adapted virus, which is fully competent for replication in this cell type. We compared the sequences of wild-type EIAV and a full-length infectious proviral clone of the cell culture-adapted EIAV and found that the genomes were relatively well conserved with the exception of the envelope gene region, which showed extensive sequence differences. We therefore constructed several wild-type and cell culture-adapted virus chimeras to examine the role of the envelope gene in replication in different cell types in vitro. Unlike wild-type virus, which is restricted by an early event(s) for replication in equine dermis cells, the wild-type outer envelope gene chimeras are replication competent in this cell type. We conclude that even though there are extensive sequence differences between wild-type and cell culture-adapted viruses in the surface envelope gene region, this domain is not a determinant of the differing in vitro cell tropisms. Images PMID:1318398

  1. Pregnancy Complications: Anemia

    MedlinePlus

    ... Close X Home > Complications & Loss > Pregnancy complications > Anemia Anemia E-mail to a friend Please fill in ... anemia at a prenatal care visit . What causes anemia? Usually, a woman becomes anemic (has anemia) because ...

  2. The Fanconi anaemia pathway: new players and new functions.

    PubMed

    Ceccaldi, Raphael; Sarangi, Prabha; D'Andrea, Alan D

    2016-06-01

    The Fanconi anaemia pathway repairs DNA interstrand crosslinks (ICLs) in the genome. Our understanding of this complex pathway is still evolving, as new components continue to be identified and new biochemical systems are used to elucidate the molecular steps of repair. The Fanconi anaemia pathway uses components of other known DNA repair processes to achieve proper repair of ICLs. Moreover, Fanconi anaemia proteins have functions in genome maintenance beyond their canonical roles of repairing ICLs. Such functions include the stabilization of replication forks and the regulation of cytokinesis. Thus, Fanconi anaemia proteins are emerging as master regulators of genomic integrity that coordinate several repair processes. Here, we summarize our current understanding of the functions of the Fanconi anaemia pathway in ICL repair, together with an overview of its connections with other repair pathways and its emerging roles in genome maintenance. PMID:27145721

  3. p53 mediated apoptosis in osteosarcoma MG-63 cells by inhibition of FANCD2 gene expression

    PubMed Central

    Xia, Peng; Sun, Yifu; Zheng, Changjun; Hou, Tingting; Kang, Mingyang; Yang, Xiaoyu

    2015-01-01

    Purpose: The aim of this study was to investigate the association between osteosarcoma (OS) and Fanconi anemia (FA) related pathways and the molecular mechanisms. Methods: siRNA for Fanconi anemia complementation group D2 (FANCD2) was constructed and transfected into the osteosarcoma cell line MG-63 cells. Expression of TP53INP1, p53, p21, caspase-9, and caspase-3 mRNA in MG-63 cells were examined by real-time fluorescence quantitative PCR, and the protein levels were also determined by western blot. Results: After silence of the FANCD2 gene in MG-63 cells, cell proliferation was inhibited, cell cycle was arrested and cell apoptosis was induced. The apoptosis was mediated by the p53 signaling pathway. After FANCD2 expression was inhibited, TP53INP1 gene expression was up-regulated, phosphorylation of p53 was promoted and the p21 protein was activated, leading to cell cycle arrested in G1, finally resulted in caspase-dependent cell apoptosis. Conclusions: Inhibition of FANCD2 gene expression can induce apoptosis of osteosarcoma cells, which indicated that FANCD2 played an important role in the development of osteosarcoma and it might be a potential target for treatment of osteosarcoma. PMID:26379910

  4. Aplastic anemia

    MedlinePlus

    ... cells. But the disease may return (relapse). A bone marrow transplant with an unrelated donor may be tried if ... Untreated, severe aplastic anemia leads to rapid death. Bone marrow transplant can be very successful in young people. Transplant ...

  5. Aplastic anemia

    MedlinePlus

    ... over time as the disease progresses. Low red cell count (anemia) can cause: Fatigue Pallor (paleness) Rapid heart ... with exercise Weakness Lightheadedness upon standing Low white cell count (leukopenia) causes an increased risk for infection. Low ...

  6. What Causes Anemia?

    MedlinePlus

    ... page from the NHLBI on Twitter. What Causes Anemia? The three main causes of anemia are: Blood ... the blood and can lead to anemia. Aplastic Anemia Some infants are born without the ability to ...

  7. Types of Hemolytic Anemia

    MedlinePlus

    ... from the NHLBI on Twitter. Types of Hemolytic Anemia There are many types of hemolytic anemia. The ... the condition, but you develop it. Inherited Hemolytic Anemias With inherited hemolytic anemias, one or more of ...

  8. What Is Aplastic Anemia?

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Aplastic Anemia? Aplastic anemia (a-PLAS-tik uh-NEE-me-uh) is ... heart, heart failure , infections, and bleeding. Severe aplastic anemia can even cause death. Overview Aplastic anemia is ...

  9. About Anemia (For Kids)

    MedlinePlus

    ... Homework? Here's Help White House Lunch Recipes About Anemia KidsHealth > For Kids > About Anemia Print A A ... to every cell in your body. What Is Anemia? Anemia occurs when a person doesn't have ...

  10. Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping.

    PubMed Central

    Neufeld, E J; Mandel, H; Raz, T; Szargel, R; Yandava, C N; Stagg, A; Fauré, S; Barrett, T; Buist, N; Cohen, N

    1997-01-01

    Thiamine-responsive megaloblastic anemia, also known as "TRMA" or "Rogers syndrome," is an early-onset autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural deafness, responding in varying degrees to thiamine treatment. On the basis of a linkage analysis of affected families of Alaskan and of Italian origin, we found, using homozygosity mapping, that the TRMA-syndrome gene maps to a region on chromosome 1q23.2-23.3 (maximum LOD score of 3.7 for D1S1679). By use of additional consanguineous kindreds of Israeli-Arab origin, the putative disease-gene interval also has been confirmed and narrowed, suggesting genetic homogeneity. Linkage analysis generated the highest combined LOD-score value, 8.1 at a recombination fraction of 0, with marker D1S2799. Haplotype analysis and recombination events narrowed the TRMA locus to a 16-cM region between markers D1S194 and D1S2786. Several heterozygote parents had diabetes mellitus, deafness, or megaloblastic anemia, which raised the possibility that mutations at this locus predispose carriers in general to these manifestations. Characterization of the metabolic defect of TRMA may shed light on the role of thiamine deficiency in such common diseases. PMID:9399900

  11. A population study of severe aplastic anemia in children. Incidence, etiology and course.

    PubMed

    Clausen, N

    1986-01-01

    The total number of registered cases of severe aplastic anemia in Denmark was 39 among children aged 0-14 years in 1967 to 1982 giving an annual incidence of 2.2 cases per 1 million children in a well defined and stable population. A probable cause of the aplastic anemia was found in 21 cases (54%). Exposure of the population to known etiological factors of aplastic anemia such as chloramphenicol, pesticides and hepatitis was constant in the study period, and accounted for 2, 5, and 2 cases, respectively. Other infections caused 6 cases, other drugs 2 cases, and organic diluents one case. Three children with constitutional aplasia developed severe aplastic anemia among a total of 6 Fanconi's anemias, 3 probable Fanconi's anemias, and 10 cases of erythrogenesis imperfecta diagnosed during the same 16 years. Thirteen patients (33%) died within 3 months after the diagnosis while on supportive treatment and low dose prednisolone supplemented with androgen treatment. Long term survival occurred in 10 patients (26%), of which 5 patients were in complete and 5 in partial remission. PMID:3953278

  12. Hypocholesterolemia in chronic anemias with increased erythropoietic activity.

    PubMed

    Shalev, Hanna; Kapelushnik, Joseph; Moser, Asher; Knobler, Hilla; Tamary, Hannah

    2007-03-01

    Hypocholesterolemia of unknown etiology has been previously described in various chronic anemias. Few small studies also suggested that those patients have a lower incidence of atherosclerotic events. The aim of our study was to determine the extent of hypocholesterolemia in various types of anemias. We studied 59 patients with chronic anemias associated with high-erythropoietic activity (thalassemia intermedia, congenital dyserythropoietic anemia type I, congenital spherocytosis), 8 patients with low-erythropoietic activity anemias (acquired aplastic anemia, Fanconi anemia, and Diamond Blackfan anemia), and 20 healthy controls. Mean serum cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, hemoglobin, serum ferritin, soluble transferrin receptor (STR), and serum erythropoietin levels were determined in each patient. All patients with chronic anemia and increased erythropoietic activity had hypocholesterolemia, whereas none of those with low erythropoietic activity was hypocholesterolemic. Mean serum cholesterol, HDL cholesterol, and LDL cholesterol levels were found to be significantly lower in the high-erythropoietic activity group (80+/-19 mg/dl; 31+/-10 mg/dl; 35+/-14 mg/dl, respectively) compared with the control group (P<0.001; 0.001; 0.001, respectively) and the low-erythropoietic activity group (P<0.001; 0.001; 0.01, respectively). Significant inverse correlation (R2=0.507) was observed between serum cholesterol and STR levels, which in the absence of iron deficiency reflect bone marrow activity. Taken together, our results imply that hypocholesterolemia accompanies anemias with high-erythropoietic activity. We suggest that the high-erythropoitic activity-associated hypocholesterolemia is due to increased cholesterol requirements by the proliferating erythoid cells. Further studies are needed to elucidate the exact mechanism and the possible clinical consequences of this phenomenon. PMID

  13. Virtual screening of gene expression regulatory sites in non-coding regions of the infectious salmon anemia virus

    PubMed Central

    2014-01-01

    Background Members of the Orthomyxoviridae family, which contains an important fish pathogen called the infectious salmon anemia virus (ISAV), have a genome consisting of eight segments of single-stranded RNA that encode different viral proteins. Each of these segments is flanked by non-coding regions (NCRs). In other Orthomyxoviruses, sequences have been shown within these NCRs that regulate gene expression and virulence; however, only the sequences of these regions are known in ISAV, and a biological role has not yet been attributed to these regions. This study aims to determine possible functions of the NCRs of ISAV. Results The results suggested an association between the molecular architecture of NCR regions and their role in the viral life cycle. The available NCR sequences from ISAV isolates were compiled, alignments were performed to obtain a consensus sequence, and conserved regions were identified in this consensus sequence. To determine the molecular structure adopted by these NCRs, various bioinformatics tools, including RNAfold, RNAstructure, Sfold, and Mfold, were used. This hypothetical structure, together with a comparison with influenza, yielded reliable secondary structure models that lead to the identification of conserved nucleotide positions on an intergenus level. These models determined which nucleotide positions are involved in the recognition of the vRNA/cRNA by RNA-dependent RNA polymerase (RdRp) or mRNA by the ribosome. Conclusions The information obtained in this work allowed the proposal of previously unknown sites that are involved in the regulation of different stages of the viral cycle, leading to the identification of new viral targets that may assist future antiviral strategies. PMID:25069483

  14. Comparative analysis of LTR and structural genes in an equine infectious anemia virus strain isolated from a feral horse in Japan.

    PubMed

    Dong, Jianbao; Cook, Frank R; Haga, Takeshi; Horii, Yoichiro; Norimine, Junzo; Misawa, Naoaki; Goto, Yoshitaka; Zhu, Wei

    2014-12-01

    Although equine infectious anemia virus (EIAV) poses a major threat to the equine industry worldwide, the molecular epidemiology of this virus is poorly understood. Recently, an EIAV strain (EIAVMiyazaki2011-A) representing a new monophyletic group was discovered in feral horses in southern Japan. In the present study, the EIAVMiyazaki2011-A proviral genome is compared with evolutionarily divergent EIAV isolates to investigate conservation of functional elements or motifs within the long terminal repeats (LTRs) and structural genes. This analysis represents a significant step forward in increasing understanding of the molecular conservation and variation between geographically distinct strains of this equine lentivirus. PMID:25149072

  15. Living with Anemia

    MedlinePlus

    ... page from the NHLBI on Twitter. Living With Anemia Often, you can treat and control anemia. If ... by an inherited or chronic disease or trauma. Anemia and Children/Teens Infants and young children have ...

  16. Folate-deficiency anemia

    MedlinePlus

    ... medlineplus.gov/ency/article/000551.htm Folate-deficiency anemia To use the sharing features on this page, please enable JavaScript. Folate-deficiency anemia is a decrease in red blood cells (anemia) ...

  17. Sickle cell anemia - resources

    MedlinePlus

    Resources - sickle cell anemia ... The following organizations are good resources for information on sickle cell anemia : American Sickle Cell Anemia Association -- www.ascaa.org National Heart, Blood, and Lung Institute -- www. ...

  18. Folate-deficiency anemia

    MedlinePlus

    Folate-deficiency anemia is a decrease in red blood cells (anemia) due to a lack of folate. Folate is a type ... B vitamin. It is also called folic acid. Anemia is a condition in which the body does ...

  19. Anemia of chronic disease

    MedlinePlus

    Anemia of inflammation; AOCD; ACD ... Anemia is a lower-than-normal number of red blood cells in the blood. Some conditions can lead to anemia of chronic disease include: Autoimmune disorders , such as ...

  20. Incomplete synthesis of N-glycans in congenital dyserythropoietic anemia type II caused by a defect in the gene encoding. alpha. -mannosidase II

    SciTech Connect

    Fukuda, M.N.; Masri, K.A. ); Dell, A. ); Luzzatto, L. ); Moremen, K.W. )

    1990-10-01

    Congenital dyserythropoietic anemia type II, or hereditary erythroblastic multinuclearity with a positive acidified-serum-lysis test (HEMPAS), is a genetic anemia in humans inherited by an autosomally recessive mode. The enzyme defect in most HEMPAS patients has previously been proposed as a lowered activity of N-acetylglucosaminyltransferase II, resulting in a lack of polylactosamine on proteins and leading to the accumulation of polylactosaminyl lipids. A recent HEMPAS case, G.C., has now been analyzed by cell-surface labeling, fast-atom-bombardment mass spectrometry of glycopeptides, and activity assay of glycosylation enzymes. Significantly decreased glycosylation of polylactosaminoglycan proteins and incompletely processed asparagine-linked oligosaccharides were detected in the erythrocyte membranes of G.C. These results suggest that G.C. cells contain a mutation in {alpha}-ManII-encoding gene that results in inefficient expression of {alpha}-ManII mRNA, either through reduced transcription or message instability. This report demonstrates that HEMPAS is caused by a defective gene encoding an enzyme necessary for the synthesis of asparagine-linked oligosaccharides.

  1. Novel nonsense mutation (p.Ile411Metfs*12) in the SLC19A2 gene causing Thiamine Responsive Megaloblastic Anemia in an Indian patient.

    PubMed

    Manimaran, Paramasivam; Subramanian, Veedamali S; Karthi, Sellamuthu; Gandhimathi, Krishnan; Varalakshmi, Perumal; Ganesh, Ramasamy; Rathinavel, Andiappan; Said, Hamid M; Ashokkumar, Balasubramaniem

    2016-01-15

    Thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive disorder, is caused by mutations in SLC19A2 gene encodes a high affinity thiamine transporter (THTR-1). The occurrence of TRMA is diagnosed by megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Here, we report a female TRMA patient of Indian descent born to 4th degree consanguineous parents presented with retinitis pigmentosa and vision impairment, who had a novel homozygous mutation (c.1232delT/ter422; p.Ile411Metfs*12) in 5th exon of SLC19A2 gene that causes premature termination of hTHTR-1. PROSITE analysis predicted to abrogate GPCRs family-1 signature motif in the variant by this mutation c.1232delT/ter422, suggesting uncharacteristic rhodopsin function leading to cause RP clinically. Thiamine transport activity by the clinical variant was severely inhibited than wild-type THTR-1. Confocal imaging had shown that the variant p.I411Mfs*12 is targeted to the cell membrane and showed no discrepancy in membrane expression than wild-type. Our findings are the first report, to the best of our knowledge, on this novel nonsense mutation of hTHTR-1 causing TRMA in an Indian patient through functionally impaired thiamine transporter activity. PMID:26549656

  2. Iron refractory iron deficiency anemia

    PubMed Central

    De Falco, Luigia; Sanchez, Mayka; Silvestri, Laura; Kannengiesser, Caroline; Muckenthaler, Martina U.; Iolascon, Achille; Gouya, Laurent; Camaschella, Clara; Beaumont, Carole

    2013-01-01

    Iron refractory iron deficiency anemia is a hereditary recessive anemia due to a defect in the TMPRSS6 gene encoding Matriptase-2. This protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values. The anemia appears in the post-natal period, although in some cases it is only diagnosed in adulthood. The disease is refractory to oral iron treatment but shows a slow response to intravenous iron injections and partial correction of the anemia. To date, 40 different Matriptase-2 mutations have been reported, affecting all the functional domains of the large ectodomain of the protein. In vitro experiments on transfected cells suggest that Matriptase-2 cleaves Hemojuvelin, a major regulator of hepcidin expression and that this function is altered in this genetic form of anemia. In contrast to the low/undetectable hepcidin levels observed in acquired iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin is inappropriately high for the low iron status and accounts for the absent/delayed response to oral iron treatment. A challenge for the clinicians and pediatricians is the recognition of the disorder among iron deficiency and other microcytic anemias commonly found in pediatric patients. The current treatment of iron refractory iron deficiency anemia is based on parenteral iron administration; in the future, manipulation of the hepcidin pathway with the aim of suppressing it might become an alternative therapeutic approach. PMID:23729726

  3. The Fanconi Anaemia Components UBE2T and FANCM Are Functionally Linked to Nucleotide Excision Repair

    PubMed Central

    Kelsall, Ian R.; Langenick, Judith; MacKay, Craig; Patel, Ketan J.; Alpi, Arno F.

    2012-01-01

    The many proteins that function in the Fanconi anaemia (FA) monoubiquitylation pathway initiate replicative DNA crosslink repair. However, it is not clear whether individual FA genes participate in DNA repair pathways other than homologous recombination and translesion bypass. Here we show that avian DT40 cell knockouts of two integral FA genes – UBE2T and FANCM are unexpectedly sensitive to UV-induced DNA damage. Comprehensive genetic dissection experiments indicate that both of these FA genes collaborate to promote nucleotide excision repair rather than translesion bypass to protect cells form UV genotoxicity. Furthermore, UBE2T deficiency impacts on the efficient removal of the UV-induced photolesion cyclobutane pyrimidine dimer. Therefore, this work reveals that the FA pathway shares two components with nucleotide excision repair, intimating not only crosstalk between the two major repair pathways, but also potentially identifying a UBE2T-mediated ubiquitin-signalling response pathway that contributes to nucleotide excision repair. PMID:22615860

  4. Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families.

    PubMed

    Mirabello, Lisa; Macari, Elizabeth R; Jessop, Lea; Ellis, Steven R; Myers, Timothy; Giri, Neelam; Taylor, Alison M; McGrath, Katherine E; Humphries, Jessica M; Ballew, Bari J; Yeager, Meredith; Boland, Joseph F; He, Ji; Hicks, Belynda D; Burdett, Laurie; Alter, Blanche P; Zon, Leonard; Savage, Sharon A

    2014-07-01

    Diamond-Blackfan anemia (DBA) is a cancer-prone inherited bone marrow failure syndrome. Approximately half of DBA patients have a germ-line mutation in a ribosomal protein gene. We used whole-exome sequencing to identify disease-causing genes in 2 large DBA families. After filtering, 1 nonsynonymous mutation (p.I31F) in the ribosomal protein S29 (RPS29[AUQ1]) gene was present in all 5 DBA-affected individuals and the obligate carrier, and absent from the unaffected noncarrier parent in 1 DBA family. A second DBA family was found to have a different nonsynonymous mutation (p.I50T) in RPS29. Both mutations are amino acid substitutions in exon 2 predicted to be deleterious and resulted in haploinsufficiency of RPS29 expression compared with wild-type RPS29 expression from an unaffected control. The DBA proband with the p.I31F RPS29 mutation had a pre-ribosomal RNA (rRNA) processing defect compared with the healthy control. We demonstrated that both RPS29 mutations failed to rescue the defective erythropoiesis in the rps29(-/-) mutant zebra fish DBA model. RPS29 is a component of the small 40S ribosomal subunit and essential for rRNA processing and ribosome biogenesis. We uncovered a novel DBA causative gene, RPS29, and showed that germ-line mutations in RPS29 can cause a defective erythropoiesis phenotype using a zebra fish model. PMID:24829207

  5. Endothelial Nitric Oxide Synthase (-786T>C) and Endothelin-1 (5665G>T) Gene Polymorphisms as Vascular Dysfunction Risk Factors in Sickle Cell Anemia.

    PubMed

    Vilas-Boas, Wendell; Figueiredo, Camylla V B; Pitanga, Thassila N; Carvalho, Magda O S; Santiago, Rayra P; Santana, Sânzio S; Guarda, Caroline C; Zanette, Angela M D; Cerqueira, Bruno A V; Gonçalves, Marilda S

    2016-01-01

    Sickle cell anemia (SCA) patients have vascular complications, and polymorphisms in endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) genes were associated with ET-1 and nitric oxide disturbance. We investigate the association of ET-1 5665G>T and eNOS -786T>C polymorphisms with soluble adhesion molecules (sVCAM-1 and sICAM-1), biochemical markers, and medical history. We studied 101 SCA patients; carriers of eNOS minor allele (C) had the highest levels of sVCAM-1, and carriers of ET-1 minor allele had more occurrence of acute chest syndrome (ACS). The multivariate analysis suggested the influence of the ET-1 gene on ACS outcome and an association of the eNOS gene with upper respiratory tract infection. We suggest that eNOS and ET-1 gene polymorphisms can influence SCA pathophysiology and that eNOS variant in SCA patients might be important to nitric oxide activity and vascular alteration. We found an association of the ET-1 minor allele in ACS, showing the importance of genetic screening in SCA. PMID:27486304

  6. Endothelial Nitric Oxide Synthase (−786T>C) and Endothelin-1 (5665G>T) Gene Polymorphisms as Vascular Dysfunction Risk Factors in Sickle Cell Anemia

    PubMed Central

    Vilas-Boas, Wendell; Figueiredo, Camylla V. B.; Pitanga, Thassila N.; Carvalho, Magda O. S.; Santiago, Rayra P.; Santana, Sânzio S.; Guarda, Caroline C.; Zanette, Angela M. D.; Cerqueira, Bruno A. V.; Gonçalves, Marilda S.

    2016-01-01

    Sickle cell anemia (SCA) patients have vascular complications, and polymorphisms in endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) genes were associated with ET-1 and nitric oxide disturbance. We investigate the association of ET-1 5665G>T and eNOS −786T>C polymorphisms with soluble adhesion molecules (sVCAM-1 and sICAM-1), biochemical markers, and medical history. We studied 101 SCA patients; carriers of eNOS minor allele (C) had the highest levels of sVCAM-1, and carriers of ET-1 minor allele had more occurrence of acute chest syndrome (ACS). The multivariate analysis suggested the influence of the ET-1 gene on ACS outcome and an association of the eNOS gene with upper respiratory tract infection. We suggest that eNOS and ET-1 gene polymorphisms can influence SCA pathophysiology and that eNOS variant in SCA patients might be important to nitric oxide activity and vascular alteration. We found an association of the ET-1 minor allele in ACS, showing the importance of genetic screening in SCA. PMID:27486304

  7. Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice

    PubMed Central

    Burns, Monika; Muthupalani, Sureshkumar; Ge, Zhongming; Wang, Timothy C.; Bakthavatchalu, Vasudevan; Cunningham, Catriona; Ennis, Kathleen; Georgieff, Michael; Fox, James G.

    2015-01-01

    Iron deficiency anemia (IDA) affects > 500 million people worldwide, and is linked to impaired cognitive development and function in children. Helicobacter pylori, a class 1 carcinogen, infects about half of the world’s population, thus creating a high likelihood of overlapping risk. This study determined the effect of H. pylori infection on iron homeostasis in INS-GAS mice. Two replicates of INS-GAS/FVB male mice (n = 9-12/group) were dosed with H. pylori (Hp) strain SS1 or sham dosed at 6–9 weeks of age, and were necropsied at 27–29 weeks of age. Hematologic and serum iron parameters were evaluated, as was gene expression in gastric and brain tissues. Serum ferritin was lower in Hp SS1-infected mice than uninfected mice (p < 0.0001). Infected mice had a lower red blood cell count (p<0.0001), hematocrit (p < 0.001), and hemoglobin concentration (p <0.0001) than uninfected mice. Relative expression of gastric hepcidin antimicrobial peptide (Hamp) was downregulated in mice infected with Hp SS1 compared to sham-dosed controls (p<0.001). Expression of bone morphogenic protein 4 (Bmp4), a growth factor upstream of hepcidin, was downregulated in gastric tissue of Hp SS1-infected mice (p<0.001). Hp SS1-infected mice had downregulated brain expression of tyrosine hydroxylase (Th) (p = 0.02). Expression of iron-responsive genes involved in myelination (myelin basic protein (Mbp) and proteolipid protein 2 (Plp2)) was downregulated in infected mice (p = 0.001 and p = 0.02). Expression of synaptic plasticity markers (brain derived neurotrophic factor 3 (Bdnf3), Psd95 (a membrane associated guanylate kinase), and insulin-like growth factor 1 (Igf1)) was also downregulated in Hp SS1-infected mice (p = 0.09, p = 0.04, p = 0.02 respectively). Infection of male INS-GAS mice with Hp SS1, without concurrent dietary iron deficiency, depleted serum ferritin, deregulated gastric and hepatic expression of iron regulatory genes, and altered iron-dependent neural processes. The use

  8. How Is Anemia Treated?

    MedlinePlus

    ... blood cells. Chelation (ke-LAY-shun) therapy for lead poisoning. Chelation therapy is used mainly in children. This ... iron-deficiency anemia are at increased risk of lead poisoning. Procedures If your anemia is severe, your doctor ...

  9. Anemia in the Newborn

    MedlinePlus

    ... Video) Meconium Aspiration Syndrome Additional Content Medical News Anemia in the Newborn By Arthur E. Kopelman, MD ... Prematurity (ROP) Necrotizing Enterocolitis (NEC) Jaundice in Newborns Anemia in the Newborn Polycythemia in the Newborn Thyroid ...

  10. Sickle cell anemia

    MedlinePlus

    Anemia - sickle cell; Hemoglobin SS disease (Hb SS); Sickle cell disease ... Sickle cell anemia is caused by an abnormal type of hemoglobin called hemoglobin S. Hemoglobin is a protein inside red blood cells ...

  11. The Anemias of Athletes.

    ERIC Educational Resources Information Center

    Eichner, Edward R.

    1986-01-01

    Diagnosing anemia in athletes is complicated because athletes normally have a pseudoanemia that needs no treatment. Athletes, however, can develop anemia from iron deficiency or footstrike hemolysis, which require diagnosis and treatment. (Author/MT)

  12. Congenital spherocytic anemia

    MedlinePlus

    ... spheres, and premature breakdown of red blood cells ( hemolytic anemia ). ... Schwartz RS. Autoimmune and intravascular hemolytic anemias In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 24th ed. Philadelphia, PA: Saunders Elsevier; 2011:chap 163.

  13. Association of ITPA gene polymorphisms and the risk of ribavirin-induced anemia in HIV/hepatitis C virus (HCV)-coinfected patients receiving HCV combination therapy.

    PubMed

    Domingo, Pere; Guardiola, Josep M; Salazar, Juliana; Torres, Ferran; Mateo, M Gracia; Pacho, Cristina; Del Mar Gutierrez, M; Lamarca, Karuna; Fontanet, Angels; Martin, Jordi; Muñoz, Jessica; Vidal, Francesc; Baiget, Montserrat

    2012-06-01

    Polymorphisms of the ITPA gene have been associated with anemia during combination therapy in hepatitis C virus (HCV)-monoinfected patients. Our aim was to confirm this association in HIV/HCV-coinfected patients. In this prospective, observational study, 73 HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin (RBV) were enrolled. Two single nucleotide polymorphisms within or adjacent to the ITPA gene (rs1127354 and rs7270101) were genotyped. The associations between the ITPA genotype and anemia or treatment outcome were examined. Fifty-nine patients (80.8%) had CC at rs1127354, whereas 14 (19.2%) had a CA/AA ITPA genotype. Percent decreases from baseline hemoglobin level were significantly greater in patients with the CC genotype than in those with the CA/AA genotype at week 4 (P = 0.0003), week 12 (P < 0.0001), and week 36 (P = 0.0102) but not at the end of treatment. RBV dose reduction was more often needed in patients with the CC genotype than in those with the CA/AA genotype (odds ratio [OR] = 11.81; 95% confidence interval [CI] = 1.45 to 256.17; P = 0.0039), as was erythropoietin therapy (OR = 8.28; 95% CI = 1.04 to 371.12; P = 0.0057). Risk factors independently associated with percent hemoglobin nadir decrease were RBV dose reduction (OR = 11.72; 95% CI = 6.82 to 16.63; P < 0.001), baseline hemoglobin (OR = 1.69; 95% CI = 0.23 to 3.15; P = 0.024), and body mass index (OR = -0.7; 95% CI = -1.43 to 0.03; P = 0.061). ITPA polymorphism was not an independent predictor of sustained virological response. Polymorphisms at rs1127354 in the ITPA gene influence hemoglobin levels during combination HCV therapy and the need for RBV dose reduction and erythropoietin use in HIV/HCV-coinfected patients. PMID:22430973

  14. Association of ITPA Gene Polymorphisms and the Risk of Ribavirin-Induced Anemia in HIV/Hepatitis C Virus (HCV)-Coinfected Patients Receiving HCV Combination Therapy

    PubMed Central

    Guardiola, Josep M.; Salazar, Juliana; Torres, Ferran; Mateo, M. Gracia; Pacho, Cristina; del Mar Gutierrez, M.; Lamarca, Karuna; Fontanet, Angels; Martin, Jordi; Muñoz, Jessica; Vidal, Francesc; Baiget, Montserrat

    2012-01-01

    Polymorphisms of the ITPA gene have been associated with anemia during combination therapy in hepatitis C virus (HCV)-monoinfected patients. Our aim was to confirm this association in HIV/HCV-coinfected patients. In this prospective, observational study, 73 HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin (RBV) were enrolled. Two single nucleotide polymorphisms within or adjacent to the ITPA gene (rs1127354 and rs7270101) were genotyped. The associations between the ITPA genotype and anemia or treatment outcome were examined. Fifty-nine patients (80.8%) had CC at rs1127354, whereas 14 (19.2%) had a CA/AA ITPA genotype. Percent decreases from baseline hemoglobin level were significantly greater in patients with the CC genotype than in those with the CA/AA genotype at week 4 (P = 0.0003), week 12 (P < 0.0001), and week 36 (P = 0.0102) but not at the end of treatment. RBV dose reduction was more often needed in patients with the CC genotype than in those with the CA/AA genotype (odds ratio [OR] = 11.81; 95% confidence interval [CI] = 1.45 to 256.17; P = 0.0039), as was erythropoietin therapy (OR = 8.28; 95% CI = 1.04 to 371.12; P = 0.0057). Risk factors independently associated with percent hemoglobin nadir decrease were RBV dose reduction (OR = 11.72; 95% CI = 6.82 to 16.63; P < 0.001), baseline hemoglobin (OR = 1.69; 95% CI = 0.23 to 3.15; P = 0.024), and body mass index (OR = −0.7; 95% CI = −1.43 to 0.03; P = 0.061). ITPA polymorphism was not an independent predictor of sustained virological response. Polymorphisms at rs1127354 in the ITPA gene influence hemoglobin levels during combination HCV therapy and the need for RBV dose reduction and erythropoietin use in HIV/HCV-coinfected patients. PMID:22430973

  15. Iron deficiency anemia

    MedlinePlus

    Anemia - iron deficiency ... iron from old red blood cells. Iron deficiency anemia develops when your body's iron stores run low. ... You may have no symptoms if the anemia is mild. Most of the time, ... slowly. Symptoms may include: Feeling weak or tired more often ...

  16. Anemia: Progress in molecular mechanisms and therapy

    PubMed Central

    Sankaran, Vijay G.; Weiss, Mitchell J.

    2015-01-01

    Anemia is a major source of morbidity and mortality worldwide. Here we review recent insights into how red blood cells (RBCs) are produced, the pathogenic mechanisms underlying various forms of anemia, and novel therapies derived from these findings. It is likely that these new insights, mainly arising from basic scientific studies, will contribute immensely to understanding frequently debilitating forms of anemia and the ability to treat affected patients. Major worldwide diseases that may stand to benefit from the new advances include the hemoglobinopathies (β-thalassemia and sickle cell disease), rare genetic disorders of red blood cell production, and anemias associated with chronic kidney disease, inflammation, and cancer. Promising new treatment approaches include drugs that target recently defined pathways in red blood cell production, iron metabolism, and fetal globin gene expression, as well as gene therapies using improved viral vectors and newly developed genome editing technologies. PMID:25742458

  17. Mitochondrial Myopathy, Lactic Acidosis, and Sideroblastic Anemia (MLASA) Plus Associated with a novel De Novo Mutation (m.8969G>A) in the Mitochondrial Encoded ATP6 gene

    PubMed Central

    Burrage, Lindsay C.; Tang, Sha; Wang, Jing; Donti, Taraka R.; Walkiewicz, Magdalena; Luchak, J. Michael; Chen, Li-Chieh; Schmitt, Eric S.; Niu, Zhiyv; Erana, Rodrigo; Hunter, Jill V.; Graham, Brett H.; Wong, Lee-Jun; Scaglia, Fernando

    2014-01-01

    Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) is a rare mitochondrial disorder that has previously been associated with mutations in PUS1 and YARS2. In the present report, we describe a 6 year old male with an MLASA plus phenotype. This patient had features of MLASA in the setting of developmental delay, sensorineural hearing loss, epilepsy, agenesis of the corpus callosum, failure to thrive, and stroke-like episodes. Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N). Whole exome sequencing did not identify mutations or variants in PUS1 or YARS2 or any known nuclear genes that could affect mitochondrial function and explain this phenotype. Studies of fibroblasts derived from the patient revealed a decrease in oligomycin-sensitive respiration, a finding which is consistent with a complex V defect. Thus, this mutation in MT-ATP6 may represent the first mtDNA point mutation associated with the MLASA phenotype. PMID:25037980

  18. Nephropathic Cystinosis Presenting as Renal Fanconi Syndrome without Glycosuria

    PubMed Central

    Kanthila, Jayashree; Dsa, Smitha

    2015-01-01

    Renal Fanconi syndrome is diagnosed by its cardinal features of glycosuria without diabetes, aminoaciduria, phosphaturia, and renal tubular acidosis. It is often associated with hypokalaemia, hypophosphatemia and rickets. We report a seven-year-old boy with nephropathic cystinosis who presented with all the cardinal features of renal Fanconi syndrome associated with rickets, pathological fractures, stage IV chronic kidney disease (CKD) and hypothyroidism. Slit-lamp examination of the cornea confirmed the diagnosis. However glycosuria was conspicuously absent. Whenever there are features of rickets with failure to thrive and recurrent vomiting renal rickets should be ruled out. Cystinosis is one such disorder and we report this case due its rarity and interesting clinical presentation. PMID:25954677

  19. Endocrine studies in Fanconi's anaemia. Report of 4 cases.

    PubMed Central

    Aynsley-Green, A; Zachmann, M; Werder, E A; Illig, R; Prader, A

    1978-01-01

    Four boys with Fanconi's anaemia and growth hormone (GH) deficiency are reported. Case 1 had isolated GH deficiency and responded to HGH and to oxandrolone treatment. Case 2, his brother, had milder haematological and dysmorphic manifestations and maintained a low-normal growth rate without treatment in spite of laboratory evidence of GH deficiency. Case 3 had multiple hypothalamopituitary defects, including deficiencies of GH, ACTH, and gonadotrophins. Case 4 had isolated GH deficiency and responded moderately well to HGH treatment. 3 of the 4 patients had bilateral cryptorchidism, 2 with increased plasma gonadotrophins, indicating primary testicular failure. We conclude that GH deficiency, isolated or combined with other hypothalamopituitary defects, and primary testicular failure with cryptorchidism are frequent but not constant features of Fanconi's anaemia. PMID:25628

  20. Malaria and anemia.

    PubMed

    Ekvall, Håkan

    2003-03-01

    Anemia due to infection is a major health problem in endemic areas for young children and pregnant women. The anemia is caused by excess removal of nonparasitized erythrocytes in addition to immune destruction of parasitized red cells, and impaired compensation for this loss by bone marrow dysfunction. The pathogenesis is complex, and a predominant mechanism has not been identified. Certain parasite and host characteristics may modify the anemia. Concomitant infections and nutritional deficiencies also contribute to anemia and may interact with the malarial infection. Few preventive strategies exist, and the management of severe malarial anemia with blood transfusion carries a risk of HIV transmission. The current increase in malaria-specific childhood mortality in sub-Saharan Africa attributed to drug-resistant infection is likely partly related to an increase in severe anemia. This review summarizes recent findings on the pathogenesis and epidemiology of malarial anemia. PMID:12579035

  1. Laboratory Evaluation of Anemia

    PubMed Central

    Wallerstein, Ralph O.

    1987-01-01

    The laboratory evaluation of anemia begins with a complete blood count and reticulocyte count. The anemia is then categorized as microcytic, macrocytic or normocytic, with or without reticulocytosis. Examination of the peripheral smear and a small number of specific tests confirm the diagnosis. The serum iron level, total iron-binding capacity, serum ferritin level and hemoglobin electrophoresis generally separate the microcytic anemias. The erythrocyte size-distribution width may be particularly helpful in distinguishing iron deficiency from thalassemia minor. Significant changes have occurred in the laboratory evaluation of macrocytic anemia, and a new syndrome of nitrous oxide-induced megaloblastosis and neurologic dysfunction has been recognized. A suggested approach to the hemolytic anemias includes using the micro-Coombs' test and ektacytometry. Finally, a number of causes have been identified for normocytic anemia without reticulocytosis, including normocytic megaloblastic anemia and the acquired immunodeficiency syndrome. PMID:3577135

  2. Born for a Noble Cause?--A Case Study on Fanconi Anemia

    ERIC Educational Resources Information Center

    Elwess, Nancy L.; Butterfield, Savanna R.; Charles, Amanda; DeVeaugh, Maxine C.; Lu, Gloria J.; Shafqat, Hira; Watts, Andrew

    2005-01-01

    The fictional case study presented here is not based on one case, but is actually based on several cases. College students enrolled in a bioethics course for non-majors wrote it. The case entails the thought processes and decision-making involved in order to save one child suffering from a genetic disorder by producing another child, a "designer…

  3. Thinking of VACTERL-H? Rule out Fanconi Anemia according to PHENOS.

    PubMed

    Alter, Blanche P; Giri, Neelam

    2016-06-01

    VACTERL-H association includes three of eight features: vertebral anomalies, anal atresia, congenital heart disease, tracheo-esophageal fistula, esophageal atresia, renal, limb anomalies, and hydrocephalus. The VACTERL-H phenotype among cases with FA is considered to be about 5%; the frequency of FA among patients with VACTERL-H is unknown. We examined 54 patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome Cohort for features of VACTERL-H, including imaging studies (radiology and ultrasound). Eighteen of the fifty-four patients had three or more VACTERL-H features. The presence of VACTERL-H association in 33% of those with FA is much higher than the previous estimate of 5% (P < 0.0001). We created the acronym PHENOS (Pigmentation, small Head, small Eyes, central Nervous system (not hydrocephalus), Otology, and Short stature) which includes all major phenotypic features of FA that are not in VACTERL-H; these findings were more frequent in the patients with FA who had VACTERL-H. Identification of any components of the VACTERL-H association should lead to imaging studies, and to consideration of the diagnosis of FA, particularly if the patient has radial ray and renal anomalies, as well as many features of PHENOS. There was no association of the presence or absence of VACTERL-H with development of cancer, stem cell transplant, or survival. Early diagnosis will lead to genetic counseling and early surveillance and management of complications of FA. © 2016 Wiley Periodicals, Inc. PMID:27028275

  4. Bilineal Acute Leukemia Associated With Fanconi Syndrome: The First Case Report.

    PubMed

    Miri-Aliabad, Ghasem; Sadat-Hosseini, Maryam; Dorgalaleh, Akbar

    2016-06-01

    Fanconi syndrome is a metabolic disorder involving dysfunction of the renal proximal tubules, resulting in excessive urinary excretion of several metabolites. Various factors may lead to Fanconi syndrome, as it may be a genetic disease with primary or secondary etiologies, or may be acquired. In this study, we report a unique case of Fanconi syndrome with development of a relatively rare acute leukemia, a condition that has not been reported before. The case was an 8-year-old boy with familial occurrence of Fanconi syndrome, presenting with pallor, asthenia, recurrent infections, growth failure, and a variety of biochemical and hematological abnormalities. After physical examination, radiographic studies, and comprehensive laboratory analyses, Fanconi syndrome associated with bilineal acute leukemia, of myeloid and T-lymphoid lineages, was diagnosed. PMID:27617066

  5. Epigenetic Alterations in Fanconi Anaemia: Role in Pathophysiology and Therapeutic Potential

    PubMed Central

    Belo, Hélio; Silva, Gabriela; Cardoso, Bruno A.; Porto, Beatriz; Minguillon, Jordi; Barbot, José; Coutinho, Jorge; Casado, Jose A.; Benedito, Manuela; Saturnino, Hema; Costa, Emília; Bueren, Juan A.; Surralles, Jordi; Almeida, Antonio

    2015-01-01

    Fanconi anaemia (FA) is an inherited disorder characterized by chromosomal instability. The phenotype is variable, which raises the possibility that it may be affected by other factors, such as epigenetic modifications. These play an important role in oncogenesis and may be pharmacologically manipulated. Our aim was to explore whether the epigenetic profiles in FA differ from non-FA individuals and whether these could be manipulated to alter the disease phenotype. We compared expression of epigenetic genes and DNA methylation profile of tumour suppressor genes between FA and normal samples. FA samples exhibited decreased expression levels of genes involved in epigenetic regulation and hypomethylation in the promoter regions of tumour suppressor genes. Treatment of FA cells with histone deacetylase inhibitor Vorinostat increased the expression of DNM3Tβ and reduced the levels of CIITA and HDAC9, PAK1, USP16, all involved in different aspects of epigenetic and immune regulation. Given the ability of Vorinostat to modulate epigenetic genes in FA patients, we investigated its functional effects on the FA phenotype. This was assessed by incubating FA cells with Vorinostat and quantifying chromosomal breaks induced by DNA cross-linking agents. Treatment of FA cells with Vorinostat resulted in a significant reduction of aberrant cells (81% on average). Our results suggest that epigenetic mechanisms may play a role in oncogenesis in FA. Epigenetic agents may be helpful in improving the phenotype of FA patients, potentially reducing tumour incidence in this population. PMID:26466379

  6. Downregulation of oxidative and nitrosative apoptotic signaling by L-carnitine in Ifosfamide-induced Fanconi syndrome rat model.

    PubMed

    Sayed-Ahmed, Mohamed M; Hafez, Mohamed M; Aldelemy, Meshan Lafi; Aleisa, Abdulaziz M; Al-Rejaie, Salem S; Al-Hosaini, Khaled A; Al-Harbi, Naif O; Al-Harbi, Mohamed M; Al-Shabanah, Othman A

    2012-01-01

    It is well documented that ifosfamide (IFO) therapy is associated with sever nephropathy in the form of Fanconi syndrome. Although oxidative stress has been reported as a major player in IFO-induced Fanconi syndrome, no mechanism for this effect has been ascertained. Therefore, this study has been initiated to investigate, on gene expression level, the mechanism of IFO-induce nephrotoxicity and those whereby carnitine supplementation attenuates this serious side effect of IFO. To achieve the ultimate goals of this study, adult male rats were assigned to one of four treatment groups, namely, control, L-carnitine, IFO, and IFO plus L-carnitine. Administration of IFO for 5 days significantly increased serum creatinine, blood urea nitrogen (BUN), and total nitrate/nitrite (NOx) production in kidney tissues. In addition, IFO significantly increased mRNA expression of inducible nitric oxide synthase (iNOS), caspase-9, and caspase-3 and significantly decreased expression of glutathione peroxides (GPx), catalase (CAT), and Bcl2 in kidney tissues. Administration of L-carnitine to IFO-treated rats resulted in a complete reversal of the all biochemical and gene expression changes, induced by IFO, to the control values. Data from this study suggest that L-carnitine prevents the development of IFO-induced nephrotoxicity via downregulation of oxidative and nitrosative apoptotic signaling in kidney tissues. PMID:23213347

  7. Iron deficiency anemia

    PubMed Central

    Naigamwalla, Dinaz Z.; Webb, Jinelle A.; Giger, Urs

    2012-01-01

    Iron is essential to virtually all living organisms and is integral to multiple metabolic functions. The most important function is oxygen transport in hemoglobin. Iron deficiency anemia in dogs and cats is usually caused by chronic blood loss and can be discovered incidentally as animals may have adapted to the anemia. Severe iron deficiency is characterized by a microcytic, hypochromic, potentially severe anemia with a variable regenerative response. Iron metabolism and homeostasis will be reviewed, followed by a discussion of diagnostic testing and therapeutic recommendations for dogs and cats with iron deficiency anemia. PMID:22942439

  8. Evaluation of Anemia.

    PubMed

    Kujovich, Jody L

    2016-06-01

    Anemia is a common problem in primary care. Classification based on mean cell volume narrows the differential diagnosis and directs testing. A marked macrocytosis is characteristic of vitamin B12 and folate deficiencies, certain medications, and primary bone marrow disorders. The three most common causes of microcytic anemia are iron deficiency, thalassemia trait, and anemia of inflammation. Additional laboratory testing is required for diagnosis. Determination of the rate of development of anemia and examination of a blood smear may provide diagnostic clues to guide more specialized testing. Diagnosis of iron, vitamin B12, or folate deficiency mandates determination of the underlying cause. PMID:27212091

  9. Sickle Cell Anemia (For Teens)

    MedlinePlus

    ... Can You Do to Stay Well? en español Anemia falciforme What Is Sickle Cell Disease? Sickle cell ... about 10 to 20 days. This usually causes anemia . Anemia is what happens when the body's number ...

  10. How Is Pernicious Anemia Treated?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Pernicious Anemia Treated? Doctors treat pernicious anemia by replacing the missing vitamin B12 in the body. People who have pernicious anemia may need lifelong treatment. The goals of treating ...

  11. Hypokalemic paralysis secondary to tenofovir induced fanconi syndrome.

    PubMed

    Ramteke, Vishal V; Deshpande, Rushi V; Srivastava, Om; Wagh, Adinath

    2015-01-01

    Tenofovir induced fanconi syndrome (FS) presenting as hypokalemic paralysis is an extremely rare complication in patients on anti-retroviral therapy. We report a 50-year-old male with acquired immunodeficiency syndrome on tenofovir-based anti-retroviral therapy who presented with acute onset quadriparesis. On evaluation, he was found to have hypokalemia with hypophosphatemia, glucosuria and proteinuria suggesting FS. He regained normal power in limbs over next 12 h following correction of hypokalemia. Ours would be the second reported case in India. PMID:26692618

  12. Tenofovir induced Fanconi syndrome: A rare cause of hypokalemic paralysis.

    PubMed

    Venkatesan, E P; Pranesh, M B; Gnanashanmugam, G; Balasubramaniam, J

    2014-03-01

    We report a 55-year-old female who presented to the emergency department with acute onset quadriparesis. She was diagnosed to have acquired immunodeficiency syndrome 7 years ago and was on tenofovir based anti-retroviral therapy for past 10 months. As the patient also had hypophosphatemia, glucosuria and proteinuria Fanconi syndrome (FS) was suspected. She improved dramatically over next 12 h to regain normal power and also her renal functions improved over next few days. Tenofovir induced FS presenting as hypokalemic paralysis is very rare complication and is the first case reported from India. PMID:24701043

  13. Recurrent aphthous ulcers in Fanconi's anaemia: a case report.

    PubMed

    Otan, Feyza; Açikgöz, Gokhan; Sakallioglu, Umur; Ozkan, Burcu

    2004-05-01

    Fanconi's anaemia (FA) is an autosomal recessive disorder that is clinically characterized by aplastic anaemia, congenital malformations of the renal, cardiac, skeletal and skin structures, and an increased predisposition to malignancies. Patients with FA often present with bleeding and infection, which are symptoms related to thrombocytopenia and neutropenia. There are few reports of the oral manifestations of FA. We describe oral aphthous ulcerations in two siblings with FA. There was a rapid improvement and healing of ulcers after blood transfusions and increased haemoglobin levels. This may support the role of severe anaemia in oral ulcerations. PMID:15139958

  14. Hypokalemic paralysis secondary to tenofovir induced fanconi syndrome

    PubMed Central

    Ramteke, Vishal V.; Deshpande, Rushi V.; Srivastava, Om; Wagh, Adinath

    2015-01-01

    Tenofovir induced fanconi syndrome (FS) presenting as hypokalemic paralysis is an extremely rare complication in patients on anti-retroviral therapy. We report a 50-year-old male with acquired immunodeficiency syndrome on tenofovir-based anti-retroviral therapy who presented with acute onset quadriparesis. On evaluation, he was found to have hypokalemia with hypophosphatemia, glucosuria and proteinuria suggesting FS. He regained normal power in limbs over next 12 h following correction of hypokalemia. Ours would be the second reported case in India. PMID:26692618

  15. Hematologic Disorders: Anemia.

    PubMed

    Baltierra, David; Harper, Tiffany; Jones, Matthew Page; Nau, Konrad C

    2015-06-01

    Anemia occurs in up to 25% of the US population. Normal hemoglobin levels vary by race, sex, and age. Classification of anemia by mean corpuscular volume guides the differential diagnosis and evaluation. Iron studies, reticulocyte count, the red blood cell distribution width index, and blood test results are used to make the diagnosis. Iron deficiency anemia is the most common microcytic anemia and is managed with iron therapy. Parenteral iron is available when the oral route cannot be used. Patients who do not benefit from therapy should be evaluated for adherence, malabsorption, occult bleeding, systemic disease, or less common inherited disorders. A source of gastrointestinal bleeding is found in 60% to 70% of patients with iron deficiency anemia who are referred for endoscopy. Normocytic anemia has a broad differential, including nutritional deficiencies, blood loss, renal disease, malignancy (solid tumors or hematologic cancer), rheumatologic disorders, endocrine disorders, and other systemic diseases. Macrocytic anemias are seen with vitamin B12 and folate deficiency, alcohol use, thyroid disease, hydroxyurea, antiretroviral drugs, myelodysplastic syndromes, and myeloma. Oral vitamin B12 is underused, and can be as effective as intramuscular vitamin B12 in managing anemia due to vitamin B12 deficiency. PMID:26080453

  16. Fifth Cooley's anemia symposium

    SciTech Connect

    Bank, A.; Anderson, W.F.; Zaino, E.C.

    1985-01-01

    This book discusses the topics presented at the symposium on the subject of 'Thalassemia'. Sickle cell anemia is also briefly discussed. The aspects discussed are chromosomal defects of anemias particularly globin synthesis, and the role of messenger RNA and other chromosomes.

  17. Sickle Cell Anemia

    MedlinePlus

    Sickle cell anemia is a disease in which your body produces abnormally shaped red blood cells. The cells are shaped like a crescent or sickle. They ... last as long as normal, round red blood cells. This leads to anemia. The sickle cells also ...

  18. Anemia in Chronic Kidney Disease

    MedlinePlus

    ... 345 KB)​​​​​ Alternate Language URL Anemia in Chronic Kidney Disease Page Content On this page: What is anemia? ... should. [ Top ] How is anemia related to chronic kidney disease? Anemia commonly occurs in people with chronic kidney ...

  19. A Japanese family with X-linked sideroblastic anemia affecting females and manifesting as macrocytic anemia.

    PubMed

    Katsurada, Tatsuya; Kawabata, Hiroshi; Kawabata, Daiki; Kawahara, Masahiro; Nakabo, Yukiharu; Takaori-Kondo, Akifumi; Yoshida, Yataro

    2016-06-01

    X-linked sideroblastic anemia (XLSA) is a rare hereditary disorder that typically manifests in males as microcytic anemia. Here, we report a family with XLSA that affects females and manifests as macrocytic anemia. The proband was a Japanese woman harboring a heterozygous mutation c.679C>T in the ALAS2 gene. This mutation causes the amino acid substitution R227C, which disrupts the enzymatic activity of erythroid-specific δ-aminolevulinic acid synthase. The mutation was not detected in the ALAS2 complementary DNA from peripheral blood red blood cells of the proband, indicating that the cells were mostly derived from erythroblasts expressing wild-type ALAS2. The proband's mother, who had been diagnosed with myelodysplastic syndrome, also had XLSA with the same mutation. Clinicians should be aware that XLSA can occur not only in males but also in females, in whom it manifests as macrocytic anemia. PMID:26862056

  20. [Acquired aplastic anemia].

    PubMed

    Yamazaki, Hirohito

    2016-02-01

    Idiopathic aplastic anemia (AA) is an autoimmune disease caused by T cells. An increase in the percentage of glycosylphosphatidylinositol-anchored protein-deficient cells and the presence of HLA allele-lacking leukocytes due to 6pUPD provide indirect evidence that T cells contribute to the pathophysiology of AA. Recent studies have revealed the presence of somatic mutations in MDS and/or AML candidate genes in one third of AA patients. Current treatment topics include the efficacy of eltrombopag for AA found to be refractory to immunosuppressive therapy as well as for newly diagnosed AA when administered in combination with ATG and cyclosporine. Furthermore, improved outcomes of allogeneic bone marrow transplantation from unrelated donors using reduced-intensity conditioning regimens have been obtained with eltrombopag. Fludarabine-based regimens are now the mainstream approach for preconditioning and have lowered the transplant-related mortality rate. However, new problems such as mixed chimerism and secondary graft failure have arisen. Attempts to prevent GVHD more efficiently by including ATG and alemtuzumab in the preconditioning regimen are being investigated. PMID:26935624

  1. Anemia of Central Origin.

    PubMed

    Ishii, Kazusa; Young, Neal S

    2015-10-01

    Hypoproliferative anemia results from the inability of bone marrow to produce adequate numbers of red blood cells. The list of conditions that cause hypoproliferative anemia is long, starting from common etiologies as iron deficiency to rarer diagnoses of constitutional bone marrow failure syndromes. There is no perfect diagnostic algorithm, and clinical data may not always clearly distinguish "normal" from "abnormal", yet it is important for practicing clinicians to recognize each condition so that treatment can be initiated promptly. This review describes diagnostic approaches to hypoproliferative anemia, with particular emphasis on bone marrow failure syndromes. PMID:26404444

  2. Evaluation of Macrocytic Anemias.

    PubMed

    Green, Ralph; Dwyre, Denis M

    2015-10-01

    Macrocytic anemia, defined as a mean cell volume (MCV) ≥100 fL in adults, has a narrow differential diagnosis that requires evaluation of the peripheral blood smear as well as additional laboratory testing taken in conjunction with clinical information that includes patient history and physical examination findings. This review is an update on the approach to a patient with macrocytic anemia with attention paid to the differentiation of megaloblastic and non-megaloblastic macrocytic anemias. Critical to the determination of the diagnosis is the judicious use of laboratory testing and the evaluation of those findings in conjunction with the patient medical, surgical, and medication history. PMID:26404440

  3. [Cytogenetic study of a case of Fanconi's syndrome with a familial pericentric inversion].

    PubMed

    Crippa, L; Ferrier, S

    1975-03-01

    The cytogenetic study of a case of Fanconi syndrome in a 16-year-old boy revealed besides chromosomal breakages, quadriradials and dicentric chromosomes, a pericentric inversion of chromosome No. 1. An uncle and an aunt on the paternal side presented likewise this pericentric inversion, however without breakages or clinical signs of Fanconi syndrome. Another paternal aunt showed short thumbs, but without chromosomal anomalies. The authors point to possible genetic repercussions of this familial pericentric inversion. PMID:1165481

  4. A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51.

    PubMed

    Ameziane, Najim; May, Patrick; Haitjema, Anneke; van de Vrugt, Henri J; van Rossum-Fikkert, Sari E; Ristic, Dejan; Williams, Gareth J; Balk, Jesper; Rockx, Davy; Li, Hong; Rooimans, Martin A; Oostra, Anneke B; Velleuer, Eunike; Dietrich, Ralf; Bleijerveld, Onno B; Maarten Altelaar, A F; Meijers-Heijboer, Hanne; Joenje, Hans; Glusman, Gustavo; Roach, Jared; Hood, Leroy; Galas, David; Wyman, Claire; Balling, Rudi; den Dunnen, Johan; de Winter, Johan P; Kanaar, Roland; Gelinas, Richard; Dorsman, Josephine C

    2015-01-01

    Fanconi anaemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and a strong predisposition to cancer. A total of 17 FA disease genes have been reported, all of which act in a recessive mode of inheritance. Here we report on a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in one allele of the homologous recombination DNA repair gene RAD51 in an FA-like patient. This heterozygous mutation causes a novel FA subtype, 'FA-R', which appears to be the first subtype of FA caused by a dominant-negative mutation. The patient, who features microcephaly and mental retardation, has reached adulthood without the typical bone marrow failure and paediatric cancers. Together with the recent reports on RAD51-associated congenital mirror movement disorders, our results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and cancer susceptibility. PMID:26681308

  5. A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51

    PubMed Central

    Ameziane, Najim; May, Patrick; Haitjema, Anneke; van de Vrugt, Henri J.; van Rossum-Fikkert, Sari E.; Ristic, Dejan; Williams, Gareth J.; Balk, Jesper; Rockx, Davy; Li, Hong; Rooimans, Martin A.; Oostra, Anneke B.; Velleuer, Eunike; Dietrich, Ralf; Bleijerveld, Onno B.; Maarten Altelaar, A. F.; Meijers-Heijboer, Hanne; Joenje, Hans; Glusman, Gustavo; Roach, Jared; Hood, Leroy; Galas, David; Wyman, Claire; Balling, Rudi; den Dunnen, Johan; de Winter, Johan P.; Kanaar, Roland; Gelinas, Richard; Dorsman, Josephine C.

    2015-01-01

    Fanconi anaemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and a strong predisposition to cancer. A total of 17 FA disease genes have been reported, all of which act in a recessive mode of inheritance. Here we report on a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in one allele of the homologous recombination DNA repair gene RAD51 in an FA-like patient. This heterozygous mutation causes a novel FA subtype, ‘FA-R', which appears to be the first subtype of FA caused by a dominant-negative mutation. The patient, who features microcephaly and mental retardation, has reached adulthood without the typical bone marrow failure and paediatric cancers. Together with the recent reports on RAD51-associated congenital mirror movement disorders, our results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and cancer susceptibility. PMID:26681308

  6. Inborn anemias in mice. Progress report, 1 August 1979-15 July 1980

    SciTech Connect

    Bernstein, S.E.; Russell, E.S.

    1980-08-01

    Four macrocytic anemias, four hemolytic anemias, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, an ..cap alpha..-thalassemia, and a new target-cell anemia are under investigation in mice. Each of these blood dyscrasias is caused by the action of a unique mutant gene, which determines the structure of different intracellular molecules, and thus controls a different metabolic process. Thus the wide range of different hereditary anemias has considerable potential for uncovering many different aspects of hemopoietic homeostatic mechanisms in the mouse. Each anemia is studied through: (a) characterization of peripheral blood values; (b) determinations of radiosensitivity under a variety of conditions; (c) measurements of iron metabolism and heme synthesis; (d) histological and biochemical study of blood-forming tissue; (e) functional tests of the stem cell component; (f) examination of responses to erythroid stimuli; and (g) transplantation of tissue between individuals of differently affected genotypes.

  7. Genetic modulation of sickle cell anemia

    SciTech Connect

    Steinberg, M.H.

    1995-05-01

    Sickle cell anemia, a common disorder associated with reduced life span of the red blood cell and vasoocclusive events, is caused by a mutation in the {Beta}-hemoglobin gene. Yet, despite this genetic homogeneity, the phenotype of the disease is heterogeneous. This suggests the modulating influence of associated inherited traits. Some of these may influence the accumulation of fetal hemoglobin, a hemoglobin type that interferes with the polymerization of sickle hemoglobin. Another inherited trait determines the accumulation of {alpha}-globin chains. This review focuses on potential genetic regulators of the phenotype of sickle cell anemia. 125 refs., 6 figs., 3 tabs.

  8. Your Guide to Anemia

    MedlinePlus

    ... lymphoma, and multiple myeloma) l Toxins (e.g., pesticides) l Diamond-Blackfan anemia l Amegakaryocytic thrombocytopenia l ... are stopped. n Environmental toxins. Substances such as pesticides, arsenic, and benzene can damage your bone marrow, ...

  9. Anemia (For Parents)

    MedlinePlus

    ... the body. About 1 out of every 500 African-American children is born with this form of anemia. Thalassemia , which usually affects people of Mediterranean, African, and Southeast Asian descent, is ...

  10. Iron-Deficiency Anemia

    MedlinePlus Videos and Cool Tools

    ... a lower than normal number of red blood cells. Red blood cells carry oxygen and remove carbon dioxide (a waste ... Anemia also can occur if your red blood cells don't contain enough hemoglobin (HEE-muh-glow- ...

  11. Iron-refractory iron deficiency anemia.

    PubMed

    Yılmaz Keskin, Ebru; Yenicesu, İdil

    2015-03-01

    Iron is essential for life because it is indispensable for several biological reactions, such as oxygen transport, DNA synthesis, and cell proliferation. Over the past few years, our understanding of iron metabolism and its regulation has changed dramatically. New disorders of iron metabolism have emerged, and the role of iron as a cofactor in other disorders has begun to be recognized. The study of genetic conditions such as hemochromatosis and iron-refractory iron deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited to improve treatment of both genetic and acquired iron disorders. IRIDA is caused by mutations in TMPRSS6, the gene encoding matriptase-2, which downregulates hepcidin expression under conditions of iron deficiency. The typical features of this disorder are hypochromic, microcytic anemia with a very low mean corpuscular volume of erythrocytes, low transferrin saturation, no (or inadequate) response to oral iron, and only a partial response to parenteral iron. In contrast to classic iron deficiency anemia, serum ferritin levels are usually low-normal, and serum or urinary hepcidin levels are inappropriately high for the degree of anemia. Although the number of cases reported thus far in the literature does not exceed 100, this disorder is considered the most common of the "atypical" microcytic anemias. The aim of this review is to share the current knowledge on IRIDA and increase awareness in this field. PMID:25805669

  12. Frequency and origin of haplotypes associated with the beta-globin gene cluster in individuals with trait and sickle cell anemia in the Atlantic and Pacific coastal regions of Colombia.

    PubMed

    Fong, Cristian; Lizarralde-Iragorri, María Alejandra; Rojas-Gallardo, Diana; Barreto, Guillermo

    2013-12-01

    Sickle cell anemia is a genetic disease with high prevalence in people of African descent. There are five typical haplotypes associated with this disease and the haplotypes associated with the beta-globin gene cluster have been used to establish the origin of African-descendant people in America. In this work, we determined the frequency and the origin of haplotypes associated with hemoglobin S in a sample of individuals with sickle cell anemia (HbSS) and sickle cell hemoglobin trait (HbAS) in coastal regions of Colombia. Blood samples from 71 HbAS and 79 HbSS individuals were obtained. Haplotypes were determined based on the presence of variable restriction sites within the β-globin gene cluster. On the Pacific coast of Colombia the most frequent haplotype was Benin, while on the Atlantic coast Bantu was marginally higher than Benin. Eight atypical haplotypes were observed on both coasts, being more diverse in the Atlantic than in the Pacific region. These results suggest a differential settlement of the coasts, dependent on where slaves were brought from, either from the Gulf of Guinea or from Angola, where the haplotype distributions are similar. Atypical haplotypes probably originated from point mutations that lost or gained a restriction site and/or by recombination events. PMID:24385850

  13. Who Is at Risk for Anemia?

    MedlinePlus

    ... Trials Links Related Topics Aplastic Anemia Hemolytic Anemia Iron-Deficiency Anemia Pernicious Anemia Sickle Cell Disease Send ... develop during pregnancy due to low levels of iron and folic acid (folate) and changes in the ...

  14. The ERCC1 and ERCC4 (XPF) genes and gene products.

    PubMed

    Manandhar, Mandira; Boulware, Karen S; Wood, Richard D

    2015-09-15

    The ERCC1 and ERCC4 genes encode the two subunits of the ERCC1-XPF nuclease. This enzyme plays an important role in repair of DNA damage and in maintaining genomic stability. ERCC1-XPF nuclease nicks DNA specifically at junctions between double-stranded and single-stranded DNA, when the single-strand is oriented 5' to 3' away from a junction. ERCC1-XPF is a core component of nucleotide excision repair and also plays a role in interstrand crosslink repair, some pathways of double-strand break repair by homologous recombination and end-joining, as a backup enzyme in base excision repair, and in telomere length regulation. In many of these activities, ERCC1-XPF complex cleaves the 3' tails of DNA intermediates in preparation for further processing. ERCC1-XPF interacts with other proteins including XPA, RPA, SLX4 and TRF2 to perform its functions. Disruption of these interactions or direct targeting of ERCC1-XPF to decrease its DNA repair function might be a useful strategy to increase the sensitivity of cancer cells to some DNA damaging agents. Complete deletion of either ERCC1 or ERCC4 is not compatible with viability in mice or humans. However, mutations in the ERCC1 or ERCC4 genes cause a remarkable array of rare inherited human disorders. These include specific forms of xeroderma pigmentosum, Cockayne syndrome, Fanconi anemia, XFE progeria and cerebro-oculo-facio-skeletal syndrome. PMID:26074087

  15. Blood Group Discrepancy-First Sign of Autoimmune Hemolytic Anemia after Hematopoietic Stem Cell Transplantation in a Child.

    PubMed

    Datta, Suvro Sankha; Reddy, Mahua; Basu, Sabita; Krishnan, Shekhar

    2016-06-01

    A 12-year-old male child was presented in the emergency with features of anemia and mild icterus on day+67 of HSCT. The child was suffering from Fanconi anemia and undergone HSCT from ABO-matched, fully HLA matched sibling donor. The diagnosis of mixed type AIHA due to cytomegalovirus reactivation was made in the immunohematology laboratory and blood group discrepancy was the first sign of AIHA in this patient. Though the cold agglutinin titer was not significant but the clinical symptoms and laboratory evidences were suggestive of significant hemolysis due to underlying IgG autoantibody. In addition the high complement avidity of IgM autoantibody might also be a contributing factor for clinically significant hemolysis in this case. The patient was successfully treated with phenotype matched blood transfusion, rituximab and oral steroid therapy. PMID:27408394

  16. How Is Hemolytic Anemia Treated?

    MedlinePlus

    ... medicines rituximab and cyclosporine. If you have severe sickle cell anemia , your doctor may recommend a medicine called hydroxyurea. ... hemoglobin that newborns have. In people who have sickle cell anemia, fetal hemoglobin helps prevent red blood cells from ...

  17. [Autoimmune hemolytic anemia in children].

    PubMed

    Becheur, M; Bouslama, B; Slama, H; Toumi, N E H

    2015-01-01

    Autoimmune hemolytic anemia is a rare condition in children which differs from the adult form. It is defined by immune-mediated destruction of red blood cells caused by autoantibodies. Characteristics of the autoantibodies are responsible for the various clinical entities. Classifications of autoimmune hemolytic anemia include warm autoimmune hemolytic anemia, cold autoimmune hemolytic anemia, and paroxysmal cold hemoglobinuria. For each classification, this review discusses the epidemiology, etiology, clinical presentation, laboratory evaluation, and treatment options. PMID:26575109

  18. Anemia in Chronic Kidney Disease

    MedlinePlus

    ... Disease Organizations​​ . (PDF, 345 KB)​​​​​ Alternate Language URL Anemia in CKD Page Content On this page: What ... Nutrition Points to Remember Clinical Trials What is anemia? Anemia is a condition in which the body ...

  19. Anemia in People with Cancer

    MedlinePlus

    ... My ACS » Your Local Offices Close + - Text Size Anemia in People With Cancer What is anemia? When you don’t have enough healthy red ... the symptoms that bother people most. What causes anemia? There are many different reasons a person with ...

  20. How Is Aplastic Anemia Diagnosed?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Aplastic Anemia Diagnosed? Your doctor will diagnose aplastic anemia based on your medical and family histories, a ... your primary care doctor thinks you have aplastic anemia, he or she may refer you to a ...

  1. Anemia and Oxygen Delivery.

    PubMed

    Bliss, Stuart

    2015-09-01

    Clinical assessment of tissue oxygenation is challenging. Anemia reflects a decreased oxygen carrying capacity of the blood and its significance in the perioperative setting relates largely to the associated risk of insufficient oxygen delivery and cellular hypoxia. Until meaningful clinical measures of tissue oxygenation are available in veterinary practice, clinicians must rely on evaluation of a patient's hemodynamic and ventilatory performance, along with biochemical and hemogasometric measurements. Blood transfusion is used commonly for treatment of perioperative anemia, and may improve tissue oxygenation by normalizing the rheologic properties of blood and enhancing perfusion, independent of increases in oxygen carrying capacity. PMID:26033442

  2. "Untangling Sickle-Cell Anemia and the Teaching of Heterozygote Protection"

    ERIC Educational Resources Information Center

    Howe, Eric Michael

    2007-01-01

    Introductory biology textbooks often use the example of sickle-cell anemia to illustrate the concept of heterozygote protection. Ordinarily scientists expect the frequency of a gene associated with a debilitating illness would be low owing to its continual elimination by natural selection. The gene that causes sickle-cell anemia, however, has a…

  3. How Is Anemia Diagnosed?

    MedlinePlus

    ... parts of your blood. The test checks your hemoglobin and hematocrit (hee-MAT-oh-crit) levels. Hemoglobin is the iron-rich protein in red blood ... up in your blood. A low level of hemoglobin or hematocrit is a sign of anemia. The ...

  4. Sickle Cell Anemia Bibliography.

    ERIC Educational Resources Information Center

    Christy, Steven C.

    Presents sources for the acquisition of medical, social, psychological, educational, and practical knowledge of sickle cell anemia. The materials listed are designed to help parents, educators, and public service workers. Materials include journal articles, films, brochures, slides, and fact sheets. The usual bibliographic information is given.…

  5. Anemia and School Participation

    ERIC Educational Resources Information Center

    Bobonis, Gustavo J.; Miguel, Edward; Puri-Sharma, Charu

    2006-01-01

    Anemia is among the most widespread health problems for children in developing countries. This paper evaluates the impact of a randomized health intervention delivering iron supplementation and deworming drugs to Indian preschool children. At baseline, 69 percent were anemic and 30 percent had intestinal worm infections. Weight increased among…

  6. Hepcidin and sports anemia

    PubMed Central

    2014-01-01

    Iron is an important mineral element used by the body in a variety of metabolic and physiologic processes. These processes are highly active when the body is undergoing physical exercises. Prevalence of exercise-induced iron deficiency anemia (also known as sports anemia) is notably high in athletic populations, particularly those with heavy training loads. The pathogenesis of sports anemia is closely related to disorders of iron metabolism, and a more comprehensive understanding of the mechanism of iron metabolism in the course of physical exercises could expand ways of treatment and prevention of sports anemia. In recent years, there have been remarkable research advances regarding the molecular mechanisms underlying changes of iron metabolism in response to physical exercises. This review has covered these advances, including effects of exercise on duodenum iron absorption, serum iron status, iron distribution in organs, erythropoiesis, and hepcidin’s function and its regulation. New methods for the treatment of exercise-induced iron deficiency are also discussed. PMID:24731443

  7. Characterization of the Mus308 Gene in Drosophila Melanogaster

    PubMed Central

    Leonhardt, E. A.; Henderson, D. S.; Rinehart, J. E.; Boyd, J. B.

    1993-01-01

    Among the available mutagen-sensitive mutations in Drosophila, those at the mus308 locus are unique in conferring hypersensitivity to DNA cross-linking agents but not to monofunctional agents. Those mutations are also associated with an elevated frequency of chromosomal aberrations, altered DNA metabolism and the modification of a deoxyribonuclease. This spectrum of phenotypes is shared with selected mammalian mutations including Fanconi anemia in humans. In anticipation of the molecular characterization of the mus308 gene, it has been localized cytogenetically to 87C9-87D1,2 on the right arm of chromosome three. Nine new mutant alleles of the gene have been generated by X-ray mutagenesis and one was recovered following hybrid dysgenesis. Characterization of these new alleles has uncovered additional phenotypes of mutations at this locus. Homozygous mus308 flies that have survived moderate mutagen treatment exhibit an altered wing position that is correlated with reduced flight ability and an altered mitochondrial morphology. In addition, observations of elevated embryo mortality are potentially explained by an aberrant distribution of nuclear material in early embryos which is similar to that seen in the mutant giant nuclei. PMID:8417992

  8. Characterization of the mus308 gene in Drosophila melanogaster

    SciTech Connect

    Leonhardt, E.A.; Henderson, D.S.; Rinehart, J.E.; Boyd, J.B. )

    1993-01-01

    Among the available mutagen-sensitive mutations in Drosophila, those at the mus3O8 locus are unique in conferring hypersensitivity to DNA cross-linking agents but not to monofunctional agents. Those mutations are also associated with an elevated frequency of chromosomal aberrations, altered DNA metabolism and the modification of a deoxyribonuclease. This spectrum of phenotypes is shared with selected mammalian mutations including Fanconi anemia in humans. In anticipation of the molecular characterization of the mus3O8 gene, it has been localized cytogenetically to 87C9-87D1,2 on the right arm of chromosome three. Nine new mutant alleles of the gene have been generated by X-ray mutagenesis and one was recovered following hybrid dysgenesis. Characterization of these new alleles has uncovered additional phenotypes of mutations at this locus. Homozygous mus3O8 flies that have survived moderate mutagen treatment exhibit an altered wing position that is correlated with reduced flight ability and an altered mitochondrial morphology. In addition, observations of elevated embryo mortality are potentially explained by an aberrant distribution of nuclear material in early embryos which is similar to that seen in the mutant giant nuclei.

  9. Fanconi syndrome induced by tenofovir: A case report.

    PubMed

    Lify, Bouchra; Dabo, G; Nascimento, O; Iraqui, S; Elkhayat, S; Zamd, M; Medkouri, G; Benghanem, M; Ramdani, B; Sodqi, M M; Marih, L; Chakib, A; El FilaliMarhoum, K

    2016-01-01

    Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor discovered in the USA in 2001. It is currently the treatment of choice for patients co-infected with human immunodeficiency virus (HIV) and hepatitis B virus. Its antiretroviral efficacy and good tolerance are responsible for the higher frequency of prescriptions compared with other nucleoside analogs. However, it can induce acute renal toxicity causing impairment of the proximal tubular function of the kidney. This is highly dependent on factors such as associated co-prescription didanosine or a protease inhibitor "boosted" with ritonavir, preexisting renal insufficiency, low body weight, or presence of associated diabetes. In contrast, long-term renal toxicity remains highly debated. Some studies describe a decrease in estimated glomerular filtration rate during prolonged treatment with TDF. Others reported renal safety even during prolonged use. The differences between patients enrolled in the different studies, the measured parameters and their interpretation could explain these discrepancies. We describe a case of a patient infected with HIV, who presented with Fanconi syndrome with acute renal failure six months after starting antiretroviral treatment including tenofovir. PMID:27424704

  10. Fanconi Syndrome: A Rare Initial Presentation of Acute Lymphoblastic Leukemia.

    PubMed

    Sahu, Kamal Kant; Law, Arjun Datt; Jain, Nidhi; Khadwal, Alka; Suri, Vikas; Malhotra, Pankaj; Varma, Subhash Chander

    2016-06-01

    A-14-year old boy, presented with a short history of excessive thirst and increased urine output. Clinical examination showed pallor, generalized lymphadenopathy and hepatosplenomegaly. For evaluation of his polyuric state he underwent routine laboratory investigations, including renal function test, acid-base studies, urine analysis. Blood tests suggested hypokalemia, hypouricemia, hypocalcemia and hyperchloremia with normal liver and kidney function tests. The arterial blood gas analysis was suggestive of normal anion gap metabolic acidosis. Urine analysis was suggestive of hyperuricosuria, hypercalciuria and glycosuria with a positive urine anion gap. His hemogram showed pancytopenia with differential count showing 88% blasts. Bone marrow examination and flowcytometry confirmed the diagnosis of B cell acute lymphoblastic leukemia. Hence this case was atypical and very interesting in the sense that the Fanconi syndrome is very rare to be an initial presenting feature of acute lymphoblastic leukemia. The patient was started on oral as well intravenous supplementation with potassium, bicarbonate, calcium and phosphorus. Simultaneously, as per the modified BFM -90 protocol (four drug based regimen-Prednisolone, vincristine, daunorubicin, cyclophosphamide along with l-asparaginase), he was started on induction protocol. By the end of 3rd week of induction therapy, his urine output started normalizing and finally settled at the end of induction therapy. At present he is in the maintenance phase of chemotherapy. PMID:27408343

  11. Two Novel Missense Mutations and a 5bp Deletion in the Erythroid-Specific Promoter of the PKLR Gene in Two Unrelated Patients With Pyruvate Kinase Deficient Transfusion-Dependent Chronic Nonspherocytic Hemolytic Anemia.

    PubMed

    Kager, Leo; Minkov, Milen; Zeitlhofer, Petra; Fahrner, Bernhard; Ratzinger, Franz; Boztug, Kaan; Dossenbach-Glaninger, Astrid; Haas, Oskar A

    2016-05-01

    We report two children with severe chronic hemolytic anemia, the cause of which was difficult to establish because of transfusion dependency. Reduced erythrocyte pyruvate kinase activity in their asymptomatic parents provided the diagnostic clues for mutation screening of the PKLR gene and revealed that one child was a compound heterozygote of a novel paternally derived 5-bp deletion in the promoter region (c.-88_-84delTCTCT) and a maternally derived missense mutation in exon nine (c.1174G>A; p.Ala392Thr). The second child was a compound heterozygote of two novel missense mutations, namely a paternally derived exon ten c.1381G>A (p.Glu461Lys) and a maternally derived exon seven c.907-908delCC (p.Pro303GlyfsX12) variant. PMID:26728349

  12. Discovering the hidden sub-network component in a ranked list of genes or proteins derived from genomic experiments.

    PubMed

    García-Alonso, Luz; Alonso, Roberto; Vidal, Enrique; Amadoz, Alicia; de María, Alejandro; Minguez, Pablo; Medina, Ignacio; Dopazo, Joaquín

    2012-11-01

    Genomic experiments (e.g. differential gene expression, single-nucleotide polymorphism association) typically produce ranked list of genes. We present a simple but powerful approach which uses protein-protein interaction data to detect sub-networks within such ranked lists of genes or proteins. We performed an exhaustive study of network parameters that allowed us concluding that the average number of components and the average number of nodes per component are the parameters that best discriminate between real and random networks. A novel aspect that increases the efficiency of this strategy in finding sub-networks is that, in addition to direct connections, also connections mediated by intermediate nodes are considered to build up the sub-networks. The possibility of using of such intermediate nodes makes this approach more robust to noise. It also overcomes some limitations intrinsic to experimental designs based on differential expression, in which some nodes are invariant across conditions. The proposed approach can also be used for candidate disease-gene prioritization. Here, we demonstrate the usefulness of the approach by means of several case examples that include a differential expression analysis in Fanconi Anemia, a genome-wide association study of bipolar disorder and a genome-scale study of essentiality in cancer genes. An efficient and easy-to-use web interface (available at http://www.babelomics.org) based on HTML5 technologies is also provided to run the algorithm and represent the network. PMID:22844098

  13. Unraveling the Fanconi anaemia-DNA repair connection through DNA helicase and translocase activities

    SciTech Connect

    Thompson, L H

    2005-08-16

    How the Fanconi anaemia (FA) chromosome stability pathway functions to cope with interstrand crosslinks and other DNA lesions has been elusive, even after FANCD1 proved to be BRCA2, a partner of Rad51 in homologous recombination. The identification and characterization of two new Fanconi proteins having helicase motifs, FANCM and FANCJ/BRIP1/BACH1, implicates the FANC nuclear core complex as a participant in recognizing or processing damaged DNA, and the BRIP1 helicase as acting independently of this complex.

  14. TNF-alpha and IL-8: serum levels and gene polymorphisms (-308G>A and -251A>T) are associated with classical biomarkers and medical history in children with sickle cell anemia.

    PubMed

    Cajado, C; Cerqueira, B A V; Couto, F D; Moura-Neto, J P; Vilas-Boas, W; Dorea, M J; Lyra, I M; Barbosa, C G; Reis, M G; Goncalves, M S

    2011-11-01

    Sickle cell anemia (SCA) is a disorder characterized by a heterogeneous clinical outcome. In the present study, we investigated the associations between Tumor Necrosis Factor-alpha (TNF-alpha) -308G>A and Interleukin 8 (IL-8) -251A>T gene polymorphisms, medical history and classical biomarkers in children with steady-state SCA. In total, 210 SCA patients aged 2-21 years and 200 healthy controls were studied. Gene polymorphisms, betaS-globin haplotypes and a 3.7-kb deletion in alpha2-thalassemia (α2-thal3.7 kb) were investigated by PCR/RFLP analysis, and cytokine levels were determined by ELISA. Splenomegaly (p=.032) was more prevalent among children younger than 5 years of age. The A allele of the TNF-alpha -308G>A gene polymorphism and the presence of α2-thal3.7 kb were associated with an increase risk of splenic sequestration events (p=.001; p=.046), while the T allele of the IL-8 -251A>T gene polymorphism was considered to be a protective factor for splenomegaly events (p=.032). Moreover, the A allele of the TNF-alpha -308G>A gene polymorphism was associated with high TNF-alpha levels (p=.021), and the hemoglobin F and hemoglobin S haplotypes were correlated with serum levels of IL-8. The logistic regression analysis showed significant effects of the TNF-alpha and IL-8 gene polymorphisms, beta(S)-globin gene haplotypes and α2-thal3.7 kb on the occurrence of splenic sequestration events. Our study emphasizes that the identification of new genetic and immunological biomarkers and their associations with classical markers is an important strategy to elucidate the underlying causes of different SCA phenotypes and their effects on patient outcome. PMID:21802960

  15. Nutritional anemia and its control.

    PubMed

    Kapur, Deeksha; Agarwal, Kailash Nath; Agarwal, Dev Kumari

    2002-07-01

    Available studies on prevalence of nutritional anemia in India show that 65% infant and toddlers, 60% 1-6 years of age, 88% adolescent girls (3.3% had hemoglobin < 7.0 g/dl; severe anemia) and 85% pregnant women (9.9% having severe anemia) were anemic. The prevalence of anemia was marginally higher in lactating women as compared to pregnancy. The commonest is iron deficiency anemia. National programmes to control and prevent anemia have not been successful. Experiences from other countries in controlling moderately-severe anemia guide to adopt long-term measures i.e. fortification of food items like milk, cereal, sugar, salt with iron. Use of iron utensils in boiling milk, cooking vegetables etc may contribute significant amount of dietary iron. Nutrition education to improve dietary intakes in family for receiving needed macro/micro nutrients as protein, iron and vitamins like folic acid, B12, A and C etc. for hemoglobin synthesis is important. As an immediate measure medicinal iron is necessary to control anemia. Addition of folate with iron controls anemia and is neuroprotective. Evidence in early childhood suggests vitamin B12 deficiency anemia; thus it may also be given along with iron and folate. PMID:12173702

  16. Conserved Overlapping Gene Arrangement, Restricted Expression, and Biochemical Activities of DNA Polymerase ν (POLN)*

    PubMed Central

    Takata, Kei-ichi; Tomida, Junya; Reh, Shelley; Swanhart, Lisa M.; Takata, Minoru; Hukriede, Neil A.; Wood, Richard D.

    2015-01-01

    DNA polymerase ν (POLN) is one of 16 DNA polymerases encoded in vertebrate genomes. It is important to determine its gene expression patterns, biological roles, and biochemical activities. By quantitative analysis of mRNA expression, we found that POLN from the zebrafish Danio rerio is expressed predominantly in testis. POLN is not detectably expressed in zebrafish embryos or in mouse embryonic stem cells. Consistent with this, injection of POLN-specific morpholino antisense oligonucleotides did not interfere with zebrafish embryonic development. Analysis of transcripts revealed that vertebrate POLN has an unusual gene expression arrangement, sharing a first exon with HAUS3, the gene encoding augmin-like complex subunit 3. HAUS3 is broadly expressed in embryonic and adult tissues, in contrast to POLN. Differential expression of POLN and HAUS3 appears to arise by alternate splicing of transcripts in mammalian cells and zebrafish. When POLN was ectopically overexpressed in human cells, it specifically coimmunoprecipitated with the homologous recombination factors BRCA1 and FANCJ, but not with previously suggested interaction partners (HELQ and members of the Fanconi anemia core complex). Purified zebrafish POLN protein is capable of thymine glycol bypass and strand displacement, with activity dependent on a basic amino acid residue known to stabilize the primer-template. These properties are conserved with the human enzyme. Although the physiological function of pol ν remains to be clarified, this study uncovers distinctive aspects of its expression control and evolutionarily conserved properties of this DNA polymerase. PMID:26269593

  17. Fanconi Syndrome and Antiretrovirals: It Is Never Too Late.

    PubMed

    Luni, Faraz Khan; Khan, Abdur Rahman; Prashar, Rohini; Vetteth, Sandeep; Duggan, Joan M

    2016-01-01

    Antiretroviral medications such as tenofovir have been associated with Fanconi syndrome (FS) usually identified within the first 1-29 months after exposure to the medication. We present a case of life-threatening FS which developed in a 37-year-old woman with HIV after 8 years of asymptomatic tenofovir use. The patient was diagnosed with HIV in 1996 at 20 years of age, hepatitis C 10 years later, and Staphylococcus aureus sepsis with secondary osteomyelitis of the spine 3 years before admission for FS. She developed nausea, vomiting, diarrhea, and generalized weakness over a 2-week time period and presented to the hospital. In the emergency department, her serum potassium was 1.5 mEq/L, bicarbonate was 12 mEq/L, chloride was 111 mEq/L, phosphorus was 1.8 mg/dL, and creatinine was 1.95 mg/dL (baseline, 1.4). Arterial blood gas revealed a non-anion gap (hyperchloremic) metabolic acidosis. Type 2 renal tubular acidosis induced by antiretroviral therapy (ART) was suspected and the ART was discontinued with resolution of the renal abnormalities within 7 days. A non-tenofovir-containing ART regimen consisting of lamivudine/abacavir and efavirenz was begun, and over the next 8 months, the patient was without recurrence of the FS. This case report demonstrates the acute development of FS after prolonged exposure to tenofovir without exposure to additional nephrotoxins such as nonsteroidal medications or aminoglycosides. Tenofovir can cause FS at any time and should be considered in any patient presenting with renal tubular acidosis type 2 while on tenofovir regardless of the duration of drug exposure. PMID:24914503

  18. Anemia in Heart Failure Patients

    PubMed Central

    Alexandrakis, Michael G.; Tsirakis, George

    2012-01-01

    Heart failure is a very common disease, with severe morbidity and mortality, and a frequent reason of hospitalization. Anemia and a concurrent renal impairment are two major risk factors contributing to the severity of the outcome and consist of the cardio renal anemia syndrome. Anemia in heart failure is complex and multifactorial. Hemodilution, absolute or functional iron deficiency, activation of the inflammatory cascade, and impaired erythropoietin production and activity are some pathophysiological mechanisms involved in anemia of the heart failure. Furthermore other concomitant causes of anemia, such as myelodysplastic syndrome and chemotherapy, may worsen the outcome. Based on the pathophysiology of cardiac anemia, there are several therapeutic options that may improve hemoglobin levels, tissues' oxygenation, and probably the outcome. These include administration of iron, erythropoiesis-stimulating agents, and blood transfusions but still the evidence provided for their use remains limited. PMID:22536520

  19. Iron deficiency anemia in pregnancy.

    PubMed

    Di Renzo, Gian Carlo; Spano, Filippo; Giardina, Irene; Brillo, Eleonora; Clerici, Graziano; Roura, Luis Cabero

    2015-11-01

    Anemia is the most frequent derailment of physiology in the world throughout the life of a woman. It is a serious condition in countries that are industrialized and in countries with poor resources. The main purpose of this manuscript is to give the right concern of anemia in pregnancy. The most common causes of anemia are poor nutrition, iron deficiencies, micronutrients deficiencies including folic acid, vitamin A and vitamin B12, diseases like malaria, hookworm infestation and schistosomiasis, HIV infection and genetically inherited hemoglobinopathies such as thalassemia. Depending on the severity and duration of anemia and the stage of gestation, there could be different adverse effects including low birth weight and preterm delivery. Treatment of mild anemia prevents more severe forms of anemia, strictly associated with increased risk of fetal-maternal mortality and morbidity. PMID:26472066

  20. Erythro-megakaryocytic transcription factors associated with hereditary anemia

    PubMed Central

    Weiss, Mitchell J.

    2014-01-01

    Most heritable anemias are caused by mutations in genes encoding globins, red blood cell (RBC) membrane proteins, or enzymes in the glycolytic and hexose monophosphate shunt pathways. A less common class of genetic anemia is caused by mutations that alter the functions of erythroid transcription factors (TFs). Many TF mutations associated with heritable anemia cause truncations or amino acid substitutions, resulting in the production of functionally altered proteins. Characterization of these mutant proteins has provided insights into mechanisms of gene expression, hematopoietic development, and human disease. Mutations within promoter or enhancer regions that disrupt TF binding to essential erythroid genes also cause anemia and heritable variations in RBC traits, such as fetal hemoglobin content. Defining the latter may have important clinical implications for de-repressing fetal hemoglobin synthesis to treat sickle cell anemia and β thalassemia. Functionally important alterations in genes encoding TFs or their cognate cis elements are likely to occur more frequently than currently appreciated, a hypothesis that will soon be tested through ongoing genome-wide association studies and the rapidly expanding use of global genome sequencing for human diagnostics. Findings obtained through such studies of RBCs and associated diseases are likely generalizable to many human diseases and quantitative traits. PMID:24652993

  1. Iron-Deficiency Anemia (For Parents)

    MedlinePlus

    ... Things to Know About Zika & Pregnancy Iron-Deficiency Anemia KidsHealth > For Parents > Iron-Deficiency Anemia Print A ... common nutritional deficiency in children. About Iron-Deficiency Anemia Every red blood cell in the body contains ...

  2. Drug-induced immune hemolytic anemia

    MedlinePlus

    Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... Drugs that can cause this type of hemolytic anemia include: Cephalosporins (a class of antibiotics), most common ...

  3. Genetics Home Reference: Diamond-Blackfan anemia

    MedlinePlus

    ... Home Health Conditions Diamond-Blackfan anemia Diamond-Blackfan anemia Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Diamond-Blackfan anemia is a disorder of the bone marrow . The ...

  4. Anemia of Inflammation and Chronic Disease

    MedlinePlus

    ... Disease Organizations (PDF, 270 KB). Alternate Language URL Anemia of Inflammation and Chronic Disease Page Content On ... Nutrition Points to Remember Clinical Trials What is anemia? Anemia is a condition in which a person ...

  5. Special Issues for People with Aplastic Anemia

    MedlinePlus

    ... Menu Donate Special Issues for People with Aplastic Anemia Because you have aplastic anemia , everyday events can ... bleeding, such as contact sports. Pregnancy and Aplastic Anemia Pregnancy is possible for women who have been ...

  6. Avoiding Anemia: Boost Your Red Blood Cells

    MedlinePlus

    ... link, please review our exit disclaimer . Subscribe Avoiding Anemia Boost Your Red Blood Cells If you’re ... and sluggish, you might have a condition called anemia. Anemia is a common blood disorder that many ...

  7. Transient Fanconi syndrome with severe polyuria and polydipsia in a 4-year old Shih Tzu fed chicken jerky treats.

    PubMed

    Major, A; Schweighauser, A; Hinden, S E; Francey, T

    2014-12-01

    Acquired Fanconi syndrome is characterized by inappropriate urinary loss of amino acids, bicarbonate, electrolytes, and water. It has recently been described in dogs fed chicken jerky treats from China, a new differential diagnosis to the classical inciting infectious diseases (e.g. leptospirosis, pyelonephritis) and toxins. A dog fed exclusively chicken jerky treats purchased in Switzerland was presented to our clinic with severe polyuria, polydipsia and profound electrolyte and acid base disturbances. Other inciting causes of Fanconi syndrome were ruled out. The requirement of a very intensive supportive treatment in this dog stands in contrast to treatment of chronic forms of Fanconi syndrome as described in the Basenji. This intensive therapy and the associated monitoring can be a real challenge and a limiting factor for the prognosis of acquired Fanconi syndrome. Veterinarians should be aware of the risk of excessive feeding of chicken jerky treats. PMID:25497565

  8. Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation of DNA around the gamma-delta-beta-globin gene complex.

    PubMed Central

    Charache, S; Dover, G; Smith, K; Talbot, C C; Moyer, M; Boyer, S

    1983-01-01

    Increased production of fetal hemoglobin (HbF) was observed in a patient with sickle cell anemia treated with 5-azacytidine. Each of four courses of therapy resulted in a rapid and prolonged increase in the percentage of HbF containing reticulocytes (F reticulocytes) and HbF containing erythrocytes (F cells). The percentage of HbF in peripheral blood rose from 1.8 to 8.9%. The rise in HbF production was accompanied by an increase in peripheral blood hemoglobin concentration from 8 to 12 g/dl and an increase in mean erythrocyte volume. Treatment with 5-azacytidine resulted in hypomethylation of total genomic and a Y-chromosome-specific DNA fragment isolated from both peripheral blood and bone marrow. Of 15 restriction enzyme sites around the gamma-delta-beta-globin gene complex, only 2 became hypomethylated: one 107 bases 5' to the gamma G and the other 107 bases 5' to the gamma A globin genes. Images PMID:6192443

  9. Sjögren's syndrome complicated with Fanconi syndrome and Hashimoto's thyroiditis: Case report and literature review.

    PubMed

    Shi, Mingmin; Chen, Lei

    2016-06-01

    We report a unique case of Sjögren's syndrome complicated with Fanconi syndrome and Hashimoto's thyroiditis in a 53-year-old Chinese woman, initially found to have proteinuria, fatigue and multiple old costal fractures. Distal tubular dysfunction is the most common renal damage in Sjögren's syndrome, while Fanconi syndrome (which is caused by proximal tubular dysfunction) and Hypothyroidism are rare complications of Sjögren's syndrome. PMID:26966155

  10. Resveratrol improves ifosfamide-induced Fanconi syndrome in rats

    SciTech Connect

    Sehirli, Ozer; Sakarcan, Abdullah; Velioglu-Oguenc, Ayliz; Cetinel, Sule; Gedik, Nursal; Yegen, Berrak C.; Sener, Goeksel . E-mail: gsener@marmara.edu.tr

    2007-07-01

    Regarding the mechanisms of ifosfamide (IFO)-induced urinary toxicity, several hypotheses have been put forward, among which oxidative stress and depletion of glutathione are suggested. This investigation elucidates the role of free radicals in IFO-induced toxicity and the protection by resveratrol, a natural phytoalexin. Wistar albino rats were injected intraperioneally with saline (0.9% NaCl; control), saline + resveratrol (RVT; 10 mg/kg/day), ifosfamide (IFO; 50 mg/kg/day) or IFO + RVT for 5 days. Urine was collected for 24 h during the 5th day, and at the 120th h after the first injections, animals were killed by decapitation and trunk blood was collected. Lactate dehydrogenase (LDH) activity, total antioxidant capacity (AOC) and pro-inflammatory cytokines TNF-{alpha}, IL-{beta} and IL-6 were assayed in plasma samples. Kidney and bladder tissues were obtained for biochemical and histological analysis. Formation of reactive oxygen species in the tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes. The results demonstrated that IFO induced a Fanconi syndrome characterized by increased urinary sodium, phosphate, glucose and protein, along with increased serum creatinine and urea levels. On the other hand, RVT markedly ameliorated the severity of renal dysfunction induced by IFO. Furthermore IFO caused a significant decrease in plasma AOC, which was accompanied with significant increases in the levels of the pro-inflammatory mediators and LDH activity, while RVT treatment reversed all these biochemical indices. In the saline-treated IFO group, glutathione levels were decreased significantly, while the malondialdehyde levels, myeloperoxidase activity and collagen content were increased in both tissues, which were in parallel with the increases in CL values. In the RVT-treated IFO group, all of these oxidant responses were prevented significantly. Our results suggest that IFO causes oxidative damage in the renal

  11. Pharmacogenetics of ribavirin-induced anemia in hepatitis C.

    PubMed

    Ampuero, Javier; Romero-Gómez, Manuel

    2016-09-01

    Pharmacogenetics assesses inherited genetic differences in drug metabolic pathways and its role in medicine is growing. Ribavirin (RBV) and peginterferon were the standard of care therapy in hepatitis C virus infection during 15 years, with the addition of first-generation protease inhibitors at the beginning of 2010s. New direct-acting agents are the new standard of care, but RBV remains important in some scenarios. The main adverse effect of RBV is anemia, which requires dose reduction and even stopping treatment in some patients. Pharmacogenetics has identified ITPA and SLC28/29 genes to be closely related to RBV-induced anemia. The routine evaluation of these genes could help to identify those patients at risk of developing anemia during the hepatitis C virus treatment. PMID:27547881

  12. Early Complication in Sickle Cell Anemia Children due to A(TA)nTAA Polymorphism at the Promoter of UGT1A1 Gene

    PubMed Central

    Chaouch, Leila; Talbi, Emna; Moumni, Imen; Ben Chaabene, Arij; Kalai, Miniar; Chaouachi, Dorra; Mallouli, Fethi; Ghanem, Abderraouf; Abbes, Salem

    2013-01-01

    Aim. To determine the implication of the polymorphism, namely, A(TA)nTAA of UGT1A1 in lithogenesis for the first time in Tunisia among sickle cell anemia (SCA) children patients. Material and Methods. Our study was performed in 2010 and it involved 76 subjects chosen as control group characterized with normal hemoglobin status and presence of cholelithiasis and 102 SCA pediatric patients among whom 52 have cholelithiasis. We analyzed the polymorphism A(TA)nTAA at the UGT1A1 promoter and the relationships between the various A(TA)nTAA genotypes and alleles and bilirubin levels and occurrence of cholelithiasis. Results and Discussion. The repartition of genotypes found according to serum bilirubin level shows a significant association between genotypes carrying variant (TA)7 and hyperbilirubinemia (P < 0.05). We demonstrated the association of two genotypes with gallstones formation among SCA children patients: (TA)7/(TA)7 and (TA)7/(TA)8 with P = 8.1 × 10−8 and P = 0.01, respectively. (TA)7 and (TA)8 allele variants act as a risk factor for early gallstones formation in SCA patients with P = 5.8 × 10−9 and P = 0.01, respectively. As for the control group only the genotype (TA)7/(TA)7 presented a risk factor for gallstones formation. Conclusion. The novelty of this report is that it is the first time that a similar study was made on the Tunisian children sickle cell population and that the results show a clear association of (TA)7 variant in early gallstones formation in Tunisian SCA children. Interestingly our findings highlighted the association of (TA)8 variant as well, which was not found in previous studies. PMID:24167350

  13. Anemia of renal failure. Use of erythropoietin.

    PubMed

    Humphries, J E

    1992-05-01

    Chronic renal failure is almost invariably accompanied by symptomatic anemia. It has been demonstrated that the primary cause of this anemia is inadequate production of erythropoietin by the diseased kidneys. The isolation of erythropoietin, followed by the cloning and expression of the human erythropoietin gene, made possible clinical trials of rHuEPO in uremic patients. rHuEPO produced dramatic increases in the hematocrit in almost all patients treated and also ameliorated many symptoms, such as lethargy, dizziness, and poor appetite, that had long been attributed to the effect of uremic toxins. Adverse effects of treatment with rHuEPO noted in the early clinical trials included hypertension, seizures, arteriovenous fistula or shunt thrombosis, and hyperkalemia. Further study of rHuEPO has shown that many of these side effects may be no more frequent in patients receiving rHuEPO than in other uremic patients not receiving rHuEPO. Reduction of the rHuEPO dosage and subcutaneous administration produce less rapid increases in the hematocrit and may lessen the incidence and severity of these side effects. rHuEPO therapy places great demands on both the body's iron stores and the capacity to rapidly transfer iron from storage sites to the erythroid progenitor cells. Thus, almost all patients treated with rHuEPO become iron deficient and require oral or parenteral iron replacement. Response to rHuEPO in uremic patients is diminished if the anemia is complicated by iron deficiency, inflammatory disorders, aluminum overload, or deficiency of folate or vitamin B12. rHuEPO therapy is safe and effective in the treatment of the anemia of chronic renal failure. The use of rHuEPO leads to enhanced quality of life and eliminates the need for red cell transfusions. In addition to hemodialysis patients, predialysis patients and those on CAPD benefit from and are candidates for rHuEPO therapy. PMID:1578966

  14. Inborn anemias in mice: (Annual report, 1980-1981)

    SciTech Connect

    Bernstein, S.E.

    1981-07-02

    The basic purpose of this study is the delineation and exploitation of inborn anemias of the laboratory mouse, carried out by utilization of genetically homogeneous stocks segregating only for anemia-producing genes; by physiological and histological descriptions of each condition at all stages in the life history; by determination of tissue sites of primary gene action through tissue culture studies, tissue transplantation and parabiosis experiments; by analysis of reactions of normal and anemic mice to a variety of stressful stimuli, including x-irradiation, hypoxia, and toxic chemicals, and by biochemical comparisons between tissues, especially erythrocytes and hemopoietic cells of normal vs each type of anemic mouse. At present 16 single-locus anemias are known in the mouse, plus one with multifactorial inheritance (the autoimmune hemolytic anemia of NZB inbred mice). Of these, six are maintained only by the Jackson Laboratory, and two others have but one additional source. Effects of anemia-producing mutant alleles of these loci (an; f; ja; ha; Hba/sup th/; mk; nb; Sl and Sl/sup d/; sla; sph; and W, W/sup v/, W/sup J/ and 10 other putative W-alleles) are currently under investigation at the Jackson Laboratory. 15 refs.

  15. Pathologic Femoral Neck Fracture Due to Fanconi Syndrome Induced by Adefovir Dipivoxil Therapy for Hepatitis B

    PubMed Central

    Lee, Yoon-Suk; Kim, Byung-Kook; Lee, Ho-Jae

    2016-01-01

    In Fanconi syndrome, hypophosphatemic osteomalacia is caused by proximal renal tubule dysfunction which leads to impaired reabsorption of amino acids, glucose, urate, and phosphate. We present a rare case of a 43-year-old Korean male who was found to have insufficiency stress fracture of the femoral neck secondary to osteomalacia due to Fanconi syndrome. He had been receiving low-dose adefovir dipivoxil (ADV, 10 mg/day) for the treatment of chronic hepatitis B virus infection for 7 years and he subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. The incomplete femoral neck fracture was fixed with multiple cannulated screws to prevent further displacement of the initial fracture. After cessation of ADV and correction of hypophosphatemia with oral phosphorus supplementation, the patient's clinical symptoms, such as bone pain, muscle weakness, and laboratory findings improved. PMID:27247753

  16. Pathologic Femoral Neck Fracture Due to Fanconi Syndrome Induced by Adefovir Dipivoxil Therapy for Hepatitis B.

    PubMed

    Lee, Yoon-Suk; Kim, Byung-Kook; Lee, Ho-Jae; Dan, Jinmyoung

    2016-06-01

    In Fanconi syndrome, hypophosphatemic osteomalacia is caused by proximal renal tubule dysfunction which leads to impaired reabsorption of amino acids, glucose, urate, and phosphate. We present a rare case of a 43-year-old Korean male who was found to have insufficiency stress fracture of the femoral neck secondary to osteomalacia due to Fanconi syndrome. He had been receiving low-dose adefovir dipivoxil (ADV, 10 mg/day) for the treatment of chronic hepatitis B virus infection for 7 years and he subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. The incomplete femoral neck fracture was fixed with multiple cannulated screws to prevent further displacement of the initial fracture. After cessation of ADV and correction of hypophosphatemia with oral phosphorus supplementation, the patient's clinical symptoms, such as bone pain, muscle weakness, and laboratory findings improved. PMID:27247753

  17. Fulminant limb and retroperitoneal necrotizing fasciitis in a 15-year-old girl with Fanconi anaemia.

    PubMed

    O'Regan, Kevin; O'Mahony, Edward; MacEneaney, Peter; Fitzgerald, Edward; Maher, Michael M

    2009-10-01

    Necrotizing fasciitis (NF) is an uncommon soft-tissue infection in children that carries a high mortality rate. We present a 15-year-old girl with chronic pancytopenia secondary to Fanconi anaemia who developed extensive NF of the lower limb, which unfortunately resulted in a fatal outcome. Immunodeficiency is a known risk factor for the development of this condition. The findings in this case demonstrate that patients with Fanconi anaemia may be susceptible to NF and that the clinical course may be more aggressive due to underlying immunosuppression. Prompt diagnosis of NF is vital in order to initiate appropriate treatment and to optimize patient outcome. Radiological investigation demonstrated extensive soft-tissue gas and destruction affecting the entire lower limb, abdominal wall and retroperitoneum, which led to timely definitive diagnosis and management. PMID:19547962

  18. Acquired Fanconi syndrome in a dog exposed to jerky treats in Japan

    PubMed Central

    IGASE, Masaya; BABA, Kenji; SHIMOKAWA MIYAMA, Takako; NOGUCHI, Shunsuke; MIZUNO, Takuya; OKUDA, Masaru

    2015-01-01

    A 6-year-old spayed female Jack Russell Terrier presented with a 1-month history of lethargy, anorexia, vomiting and weight loss. The dog was fed beef and chicken jerky treats daily in addition to a commercial diet. Laboratory tests revealed azotemia, hypokalemia, hyperchloremia, metabolic acidosis and glucosuria with normoglycemia. Urine amino acid analysis showed significant amino acid loss into the urine. Thus, Fanconi syndrome was diagnosed, and based on the case history and extensive diagnostic testing, excessive consumption of jerky treats was strongly suspected as the cause. Glucosuria resolved 7 days after the withdrawal of jerky treats and fluid therapy. Aminoaciduria was substantially, but not completely, improved 3 months after diagnosis. Mild azotemia remained, suggesting chronic renal disease. To the best of our knowledge, this is the first reported case of Fanconi syndrome following the consumption of jerky treats in Japan. PMID:26062568

  19. Complement in hemolytic anemia.

    PubMed

    Brodsky, Robert A

    2015-11-26

    Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD. PMID:26582375

  20. [Autoimmune hemolytic anemia].

    PubMed

    Karasawa, Masamitsu

    2008-03-01

    Diagnosis of autoimmune hemolytic anemia (AIHA) requires both serologic evidence of an autoantibody and hemolysis. Based on the characteristic temperature reactivity of the autoantibody to red cell membranes, AIHA is classified into warm AIHA or cold AIHA (cold agglutinin disease and paroxysmal cold hemoglobinuria). Sensitized RBCs are destructed by intravascular and/or extravascular hemolysis. On the basis of etiology, AIHA are classified as idiopathic or secondary. The common cause of secondary AIHA is lymphoproliferative disorders, autoimmune diseases, and infections. The first line therapy of patients with warm AIHA is glucocorticoids and primary treatment for cold AIHA is avoiding cold exposure. The other standard treatments include splenectomy and immunosuppressive drugs. Recently, rituximab, a monoclonal anti-CD20 antibody, has been used in refractory AIHA with excellent responses. PMID:18326320

  1. Complement in hemolytic anemia.

    PubMed

    Brodsky, Robert A

    2015-01-01

    Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD. PMID:26637747

  2. Autoimmune hemolytic anemia.

    PubMed

    Dacie, J V

    1975-10-01

    Warm-type autoantibodies of autoimmune hemolytic anemia (AIHA) are usually IgG but may be IgM or IgA. They are usual Rh specific. Cold-type antibodies are IgM or IgG (Donath-Landsteiner [DL] antibody). IgM antibodies are usually anit-l (occasionally anti-i) and DL antibodies anti-P. The warm IgG antibodies do not fix complement (C); they cause red blood cell (RBC) destruction predominantly in the spleen as the result of interaction between fixing; they cause RBC destruction either by intravascular lysis (complement sequence completed) or by interaction between C3-coated RBCs and phagocytes in liver and spleen. Gentic factors, immunoglobulin deficiency, somatic mutation, viral infections and drugs, and failure of T-lymphocyte function, all probably play a part in breaking immunological tolerance and the development of AIHA. PMID:1164110

  3. Therapy for aplastic anemia.

    PubMed

    DeZern, Amy E; Guinan, Eva C

    2011-01-01

    A 24-year-old man from Ecuador presents to your clinic with dyspnea on exertion, bruising, and petechiae. He is noted to be pancytopenic with ANC 430, hemoglobin 7.4 g/dL (reticulocyte count 0.9%), and platelets 18 000. His BM biopsy is hypocellular for age. Ultimately, he is diagnosed with severe aplastic anemia. He is the only child of 2 South American parents without any matches in the unrelated donor registry, including cord blood. He is red cell- and platelet transfusion-dependent. He has been recommended therapy with antithymocyte globulin and cyclosporine but declined it. He seeks recommendations about new alternatives to this regimen to improve his chance of response. PMID:22160016

  4. Clinical and biochemical signs in Fleckvieh cattle with genetically confirmed Fanconi-Bickel syndrome (cattle homozygous for Fleckvieh haplotype 2).

    PubMed

    Burgstaller, Johann; Url, Angelika; Pausch, Hubert; Schwarzenbacher, Hermann; Egerbacher, Monika; Wittek, Thomas

    2016-01-01

    Fanconi-Bickel Syndrome (FBS) is an autosomal recessive disorder of the carbohydrate metabolism, which has been reported in human and some animals (OMIA 000366-9913). In Fleckvieh cattle it is caused by mutations in SLC2A2, a gene encoding for glucose transporter protein 2 (GLUT2), which is primarily expressed in liver, kidney, pancreas and intestines. The causal mutation resides in a previously reported Fleckvieh Haplotype 2 (FH-2). FH-2 homozygous individuals are rare, but due to widespread use of heterozygous bulls in artificial insemination, heterozygous animals are likely to be present in a larger number in the cattle population. Two clinical cases of Fleckvieh cattle with a syndrome resembling the phenotypic appearance of FBS are presented in the present study describing the association between the clinical manifestations of FBS and the postulated frameshift mutation in bovine SLC2A2. Clinical examination showed poor growth, retarded development, polyuria, and polydipsia. Laboratory analyses showed an increased plasma glucose but normal insulin concentration and increased renal glucose excretion. Histopathological examination of kidney and liver samples revealed massively increased liver glycogen storage and nephrosis. Sires of both cases were tested positive for being heterozygous carriers for the same frameshift mutation in SLC2A2 as was originally reported in Fleckvieh cattle. DNA of both cases described was analyzed and Sanger sequencing confirmed homozygosity for the frameshift mutation in SLC2A2. PMID:27169150

  5. Rifampin-associated tubulointersititial nephritis and Fanconi syndrome presenting as hypokalemic paralysis

    PubMed Central

    2013-01-01

    Background Rifampin is one of the most important drugs in first-line therapies for tuberculosis. The renal toxicity of rifampin has been reported sporadically and acute tubulointerstitial nephritis (ATIN) is a frequent histological finding. We describe for the first time a case of ATIN and Fanconi syndrome presenting as hypokalemic paralysis, associated with the use of rifampin. Case presentation A 42-year-old man was admitted with sudden-onset lower extremity paralysis and mild renal insufficiency. He had been treated for pulmonary tuberculosis with isoniazid, rifampin, and ethambutol for 2 months. Laboratory tests revealed proteinuria, profound hypokalemia, hyperchloremic metabolic acidosis with a normal anion gap, positive urine anion gap, hypophosphatemia with hyperphosphaturia, hypouricemia with hyperuricosuria, glycosuria with normal serum glucose level, generalized aminoaciduria, and β2-microglobulinuria. A kidney biopsy revealed findings typical of ATIN and focal granular deposits of immunoglubulin A and complement 3 in the glomeruli and tubules. Electron microscopy showed epithelial foot process effacement and electron-dense deposits in the subendothelial and mesangial spaces. Cessation of rifampin resolved the patient’s clinical presentation of Fanconi syndrome, and improved his renal function and proteinuria. Conclusion This case demonstrates that rifampin therapy can be associated with Fanconi syndrome presenting as hypokalemic paralysis, which is a manifestation of ATIN. Kidney function and the markers of proximal tubular injury should be carefully monitored in patients receiving rifampin. PMID:23320835

  6. How Is Aplastic Anemia Treated?

    MedlinePlus

    ... need for blood transfusions. Medicines To Suppress the Immune System Research suggests that aplastic anemia may sometimes occur because the body's immune system attacks its own cells by mistake. For this ...

  7. Managing Chemotherapy Side Effects: Anemia

    MedlinePlus

    ... I told my doctor that I was very tired. My doctor did blood tests to check for ... or faint ● ● Short of breath ● ● Very weak and tired ● ● Your heart beating very fast What is anemia? ...

  8. Sexuality and sickle cell anemia

    PubMed Central

    Côbo, Viviane de Almeida; Chapadeiro, Cibele Alves; Ribeiro, João Batista; Moraes-Souza, Helio; Martins, Paulo Roberto Juliano

    2013-01-01

    Background Sickle cell disease, the most common hereditary blood disease in the world, is the result of an atypical hemoglobin called S (Hb S) which, when homozygous (Hb SS) is the cause of sickle cell anemia. Changes of puberty, correlated with a delayed growth spurt, begin late in both male and female sickle cell anemia individuals with repercussions on sexuality and reproduction. The objectives of this exploratory and descriptive study were to characterize the development of sexuality in adults with sickle cell anemia by investigating the patient's perception of their sex life, as well as the information they had and needed on this subject. Methods Twenty male and female sickle cell anemia patients treated at the Hemocentro Regional de Uberaba (UFTM) with ages between 19 and 47 years old were enrolled. A socioeconomic questionnaire and a semi-structured interview on sexuality, reproduction and genetic counseling were applied. Results This study shows that the sickle cell anemia patients lacked information on sexuality especially about the risks of pregnancy and the possible inheritance of the disease by their children. Moreover, the sexual life of the patients was impaired due to pain as well as discrimination and negative feelings experienced in close relationships. Conclusion The health care of sickle cell anemia patients should take into account not only the clinical aspects of the disease, but also psychosocial aspects by providing counseling on sexuality, reproduction and genetics, in order to give this population the possibility of a better quality of life. PMID:23741184

  9. Microcytic anemia in a pregnant woman: beyond iron deficiency.

    PubMed

    Rollón, Noelia; Fernández-Jiménez, María Cristina; Moreno-Carralero, María Isabel; Murga-Fernández, María José; Morán-Jiménez, María Josefa

    2015-05-01

    Sideroblastic anemias are a heterogeneous group of disorders characterized by anemia of varying severity and the presence of ringed sideroblasts in bone marrow. The most common form of inherited sideroblastic anemia is X-linked sideroblastic anemia (XLSA). In many XLSA patients, anemia responds variably to supplementation with pyridoxine (vitamin B6). We describe the case of a pregnant female with XLSA who had a novel mutation on the ALAS2 gene (c.1218G > T, p.Leu406Phe). Oral chelation therapy was contraindicated and high-dose vitamin B6 would have possible side effects in pregnancy. Serum hepcidin level was very low, indicating increased absorption of iron secondary to ineffective erythropoiesis. Therapy was begun with a low dose of pyridoxine that was increased post-partum. The patient's liver showed moderate iron deposits. During a subsequent 3-month period of pyridoxine supplementation, serum ferritin level and transferrin saturation decreased, hemoglobin content and serum hepcidin level normalized, and morphologic red cell abnormalities improved markedly. The patient responded well to treatment, showing the pyridoxine responsiveness of this novel ALAS2 mutation. The baby girl had the same mutation heterozygously, and although she was neither anemic nor showed abnormalities in a peripheral blood smear, she had a mild increment in RDW and her condition is now being followed. PMID:25547425

  10. Hepcidin-Dependent Regulation of Erythropoiesis during Anemia in a Teleost Fish, Dicentrarchus labrax

    PubMed Central

    Caldas, Carolina; Ramos, Miguel F.; Rodrigues, Pedro N. S.

    2016-01-01

    Anemia is a common disorder, characterized by abnormally low levels of red blood cells or hemoglobin. The mechanisms of anemia development and response have been thoroughly studied in mammals, but little is known in other vertebrates, particularly teleost fish. In this study, different degrees of anemia were induced in healthy European sea bass specimens (Dicentrarchus labrax) and at pre-determined time points hematological parameters, liver iron content and the expression of genes involved in iron homeostasis and hematopoiesis, with particular attention on hepcidins, were evaluated. The experimental anemia prompted a decrease in hamp1 expression in all tested organs, in accordance to an increased need for iron absorption and mobilization, with slight increases in hamp2 in the kidney and intestine. The liver was clearly the major organ involved in iron homeostasis, decreasing its iron content and showing a gene expression profile consistent with an increased iron release and mobilization. Although both the spleen and head kidney are involved in erythropoiesis, the spleen was found to assume a more preponderant role in the recovery of erythrocyte levels. The intestine was also involved in the response to anemia, through the increase of iron transporting genes. Administration of Hamp1 or Hamp2 mature peptides showed that only Hamp1 affects hematological parameters and liver iron content. In conclusion, the molecular mechanisms of response to anemia present in sea bass are similar to the ones described for mammals, with these results indicating that the two hepcidin types from teleosts assume different roles during anemia. PMID:27100629

  11. Genetics Home Reference: iron-refractory iron deficiency anemia

    MedlinePlus

    ... refractory iron deficiency anemia iron-refractory iron deficiency anemia Enable Javascript to view the expand/collapse boxes. ... All Close All Description Iron-refractory iron deficiency anemia is one of many types of anemia , which ...

  12. What Are the Signs and Symptoms of Anemia?

    MedlinePlus

    ... Twitter. What Are the Signs and Symptoms of Anemia? The most common symptom of anemia is fatigue ( ... mild symptoms or none at all. Complications of Anemia Some people who have anemia may have arrhythmias ( ...

  13. Frequency of three polymorphisms of the CCL5 gene (rs2107538, rs2280788 and rs2280789) and their implications for the phenotypic expression of sickle cell anemia in Tunisia.

    PubMed

    Kalai, M; Chaouch, L; Mansour, I B; Hafsia, R; Ghanem, A; Abbes, S

    2013-06-01

    The pro-inflammatory context of sickle cell disease promotes the liberation of cytokines such as CCL5, encoded by a gene located on chromosome 17. Herein, the occurrence of three variations of CCL5 in sickle cell anemia (SCA) and their relations to two major complications - painful crisis and presence of infections - were investigated. 100 SCA Tunisian patients and 100 healthy subjects were included in the case control study. Then the sample of patients was divided into two groups according to the presence or absence of each complication. The polymorphisms, namely g.-403G>A, g.-28C>G and g.In1.+1T>C, were analyzed by PCR/sequencing. Our findings show the presence of eight genotypes, namely GG, GA and AA of g.-403G>A, CC, CG and GG of g.-28C>G, and TT and TC of g.In1.+1T>C. The frequencies of studied single nucleotide polymorphisms (SNPs) and haplotypes in SCA patients do not differ significantly from healthy control group results. There is also no significant association between the analyzed polymorphisms and complications as for painful crisis and presence of infections (p > 0.05). Altogether, our data support the conclusion that the three polymorphisms of CCL5, namely g.-403G>A, g.-28C>G and g.In1.+1T>C, do not seem to be involved in the clinical variability of SCA in Tunisia. PMID:23900864

  14. Classification of anemia for gastroenterologists

    PubMed Central

    Moreno Chulilla, Jose Antonio; Romero Colás, Maria Soledad; Gutiérrez Martín, Martín

    2009-01-01

    Most anemia is related to the digestive system by dietary deficiency, malabsorption, or chronic bleeding. We review the World Health Organization definition of anemia, its morphological classification (microcytic, macrocytic and normocytic) and pathogenic classification (regenerative and hypo regenerative), and integration of these classifications. Interpretation of laboratory tests is included, from the simplest (blood count, routine biochemistry) to the more specific (iron metabolism, vitamin B12, folic acid, reticulocytes, erythropoietin, bone marrow examination and Schilling test). In the text and various algorithms, we propose a hierarchical and logical way to reach a diagnosis as quickly as possible, by properly managing the medical interview, physical examination, appropriate laboratory tests, bone marrow examination, and other complementary tests. The prevalence is emphasized in all sections so that the gastroenterologist can direct the diagnosis to the most common diseases, although the tables also include rare diseases. Digestive diseases potentially causing anemia have been studied in preference, but other causes of anemia have been included in the text and tables. Primitive hematological diseases that cause anemia are only listed, but are not discussed in depth. The last section is dedicated to simplifying all items discussed above, using practical rules to guide diagnosis and medical care with the greatest economy of resources and time. PMID:19787825

  15. Drug-induced immune hemolytic anemia

    MedlinePlus

    Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... In some cases, a drug can cause the immune system to mistake your own red blood cells for foreign substances. The body responds by making ...

  16. Anemia caused by low iron - children

    MedlinePlus

    ... deficiency in children can also be related to lead poisoning . Symptoms Mild anemia may have no symptoms. As ... Saunders; 2011:chap 449. Read More Anemia Hemoglobin Lead poisoning Update Date 2/25/2014 Updated by: Sameer ...

  17. Anemia Boosts Stroke Death Risk, Study Finds

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_160476.html Anemia Boosts Stroke Death Risk, Study Finds Blood condition ... 2016 (HealthDay News) -- Older stroke victims suffering from anemia -- a lack of red blood cells -- may have ...

  18. Genetics Home Reference: congenital dyserythropoietic anemia

    MedlinePlus

    ... Understand Genetics Home Health Conditions CDA congenital dyserythropoietic anemia Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Congenital dyserythropoietic anemia ( CDA ) is an inherited blood disorder that affects ...

  19. Hemolytic anemia caused by chemicals and toxins

    MedlinePlus

    Anemia - hemolytic - caused by chemicals or toxins ... Possible substances that can cause hemolytic anemia include: Anti-malaria drugs (quinine compounds) Arsenic Dapsone Intravenous water infusion (not half-normal saline or normal saline) Metals (chromium/chromates, ...

  20. Anemia - Multiple Languages: MedlinePlus

    MedlinePlus

    ... Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Anemia URL of this page: https://www.nlm.nih.gov/medlineplus/languages/anemia.html Other topics A-Z A B ...

  1. [Algorithm for treating preoperative anemia].

    PubMed

    Bisbe Vives, E; Basora Macaya, M

    2015-06-01

    Hemoglobin optimization and treatment of preoperative anemia in surgery with a moderate to high risk of surgical bleeding reduces the rate of transfusions and improves hemoglobin levels at discharge and can also improve postoperative outcomes. To this end, we need to schedule preoperative visits sufficiently in advance to treat the anemia. The treatment algorithm we propose comes with a simple checklist to determine whether we should refer the patient to a specialist or if we can treat the patient during the same visit. With the blood count test and additional tests for iron metabolism, inflammation parameter and glomerular filtration rate, we can decide whether to start the treatment with intravenous iron alone or erythropoietin with or without iron. With significant anemia, a visit after 15 days might be necessary to observe the response and supplement the treatment if required. The hemoglobin objective will depend on the type of surgery and the patient's characteristics. PMID:26320341

  2. Iron deficiency anemia in children.

    PubMed

    Subramaniam, Girish; Girish, Meenakshi

    2015-06-01

    Iron deficiency is not just anemia; it can be responsible for a long list of other manifestations. This topic is of great importance, especially in infancy and early childhood, for a variety of reasons. Firstly, iron need is maximum in this period. Secondly, diet in infancy is usually deficient in iron. Thirdly and most importantly, iron deficiency at this age can result in neurodevelopmental and cognitive deficits, which may not be reversible. Hypochromia and microcytosis in a complete blood count (CBC) makes iron deficiency anemia (IDA) most likely diagnosis. Absence of response to iron should make us look for other differential diagnosis like β thalassemia trait and anemia of chronic disease. Celiac disease is the most important cause of true IDA not responding to oral iron therapy. While oral ferrous sulphate is the cheapest and most effective therapy for IDA, simple nonpharmacological and pharmacological measures can go a long way in prevention of iron deficiency. PMID:25636824

  3. Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia.

    PubMed

    Fernández-Murray, J Pedro; Prykhozhij, Sergey V; Dufay, J Noelia; Steele, Shelby L; Gaston, Daniel; Nasrallah, Gheyath K; Coombs, Andrew J; Liwski, Robert S; Fernandez, Conrad V; Berman, Jason N; McMaster, Christopher R

    2016-01-01

    Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala) a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia. PMID:26821380

  4. Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia

    PubMed Central

    Dufay, J. Noelia; Steele, Shelby L.; Gaston, Daniel; Nasrallah, Gheyath K.; Coombs, Andrew J.; Liwski, Robert S.; Fernandez, Conrad V.; Berman, Jason N.; McMaster, Christopher R.

    2016-01-01

    Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala) a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia. PMID:26821380

  5. (Inborn anemias of mice): Terminal progress report

    SciTech Connect

    Bernstein, S.E.

    1987-01-01

    Mutations located at 11 different chromosomal locations in the mouse all affecting hemopoiesis have been studied. These include: Hertwig's anemia (an), W-anemias (W, W/sup v/, W/sup 17J/ to W/sup 41J/), Steel anemias (Sl, Sl/sup d/, etc.), Normoblastic anemia (nb), Jaundiced (ja), Spherocytic anemias (sph, sph/sup ha/), sph/sup 2J/, sph/sup 2BC/, Flexed-tail anemia (f), Microcytic anemia (mk), Sex-linked anemia (Sla), Alpha thallasemia (Hba/sup th/), and a hypochromic anemia associated with low transferrin levels (hpx). Our findings indicate that the erythroid defect in W-anemias stem from an intrinsic defect in the erythroid progenitor cells, and that all other erythroid hemostatic mechanisms are fully functional. Hertwig's anemia (an) is affected in a similar fashion. However, in the case of Steel anemias, the erythroid progenitors are repressed, but when transplanted to appropriate recipients were found to be fully functional. 70 refs., 4 tabs.

  6. Thymoma with Autoimmune Hemolytic Anemia

    PubMed Central

    Suzuki, Kensuke; Inomata, Minehiko; Shiraishi, Shiori; Hayashi, Ryuji; Tobe, Kazuyuki

    2014-01-01

    A 38-year-old Japanese male was referred to our hospital with abnormal chest X-ray results and severe Coombs-positive hemolytic anemia. He was diagnosed with a stage IV, WHO type A thymoma and was treated with oral prednisolone (1 mg/kg/day) and subsequent chemotherapy. After chemotherapy, the patient underwent surgical resection of the thymoma. Hemolysis rapidly disappeared and did not return after the discontinuation of oral corticosteroids. Corticosteroid therapy may be preferable to chemotherapy or thymoma surgical resection in the management of autoimmune hemolytic anemia with thymoma. PMID:25722666

  7. Pernicious Anemia with Autoimmune Hemolytic Anemia: A Case Report and Literature Review.

    PubMed

    Yeruva, Sri Lakshmi Hyndavi; Manchandani, Raj Pal; Oneal, Patricia

    2016-01-01

    Pernicious anemia is a common cause of vitamin B12 deficiency. Here, we discuss a case of a young woman who presented with severe anemia along with a history of iron deficiency anemia. After a review of her clinical presentation and laboratory data, we identified an autoimmune hemolytic anemia and a concomitant pernicious anemia. The concurrence of both these hematological diagnoses in a patient is rare. PMID:27559485

  8. Pernicious Anemia with Autoimmune Hemolytic Anemia: A Case Report and Literature Review

    PubMed Central

    Manchandani, Raj Pal; Oneal, Patricia

    2016-01-01

    Pernicious anemia is a common cause of vitamin B12 deficiency. Here, we discuss a case of a young woman who presented with severe anemia along with a history of iron deficiency anemia. After a review of her clinical presentation and laboratory data, we identified an autoimmune hemolytic anemia and a concomitant pernicious anemia. The concurrence of both these hematological diagnoses in a patient is rare. PMID:27559485

  9. What Is Anemia?

    MedlinePlus

    ... in the News December 3, 2015 Link between congenital heart disease and neurodevelopment issues in children found Scientists have ... set of gene mutations in the development of congenital heart disease and simultaneously discovered a link between them and ...

  10. Carnitine deficiency and oxidative stress provoke cardiotoxicity in an ifosfamide-induced Fanconi Syndrome rat model

    PubMed Central

    Darweesh, Amal Q; Fatani, Amal J

    2010-01-01

    In addition to hemorrhagic cystitis, Fanconi Syndrome is a serious clinical side effect during ifosfamide (IFO) therapy. Fanconi syndrome is a generalized dysfunction of the proximal tubule which is characterized by excessive urinary excretion of glucose, phosphate, bicarbonate, amino acids and other solutes excreted by this segment of the nephron including L-carnitine. Carnitine is essential cofactor for β-oxidation of long-chain fatty acids in the myocardium. IFO therapy is associated with increased urinary carnitine excretion with subsequent secondary deficiency of the molecule. Cardiac abnormalities in IFO-treated cancer patients were reported as isolated clinical cases. This study examined whether carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, provoke IFO-induced cardiomyopathy as well as exploring if carnitine supplementation using Propionyl-L-carnitine (PLC) could offer protection against this toxicity. In the current study, an animal model of carnitine deficiency was developed in rats by D-carnitine-mildronate treatment Adult male Wistar albino rats were assigned to one of six treatment groups: the first three groups were injected intraperitoneally with normal saline, D-carnitine (DC, 250 mg/kg/day) combined with mildronate (MD, 200 mg/kg/day) and PLC (250 mg/kg/day), respectively, for 10 successive days. The 4th, 5th and 6th groups were injected with the same doses of normal saline, DC-MD and PLC, respectively for 5 successive days before and 5 days concomitant with IFO (50 mg/kg/day). IFO significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion and clearance, creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), intramitochondrial acetyl-CoA/CoA-SH and thiobarbituric acid reactive substances (TBARS) in cardiac tissues and significantly decreased adenosine triphosphate (ATP) and total carnitine and reduced glutathione (GSH) content in cardiac tissues. In carnitine

  11. Carnitine deficiency and oxidative stress provoke cardiotoxicity in an ifosfamide-induced Fanconi Syndrome rat model.

    PubMed

    Sayed-Ahmed, Mohamed M; Darweesh, Amal Q; Fatani, Amal J

    2010-01-01

    In addition to hemorrhagic cystitis, Fanconi Syndrome is a serious clinical side effect during ifosfamide (IFO) therapy. Fanconi syndrome is a generalized dysfunction of the proximal tubule which is characterized by excessive urinary excretion of glucose, phosphate, bicarbonate, amino acids and other solutes excreted by this segment of the nephron including L-carnitine. Carnitine is essential cofactor for β-oxidation of long-chain fatty acids in the myocardium. IFO therapy is associated with increased urinary carnitine excretion with subsequent secondary deficiency of the molecule. Cardiac abnormalities in IFO-treated cancer patients were reported as isolated clinical cases. This study examined whether carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, provoke IFO-induced cardiomyopathy as well as exploring if carnitine supplementation using Propionyl-L-carnitine (PLC) could offer protection against this toxicity. In the current study, an animal model of carnitine deficiency was developed in rats by D-carnitine-mildronate treatment Adult male Wistar albino rats were assigned to one of six treatment groups: the first three groups were injected intraperitoneally with normal saline, D-carnitine (DC, 250 mg/kg/day) combined with mildronate (MD, 200 mg/kg/day) and PLC (250 mg/kg/day), respectively, for 10 successive days. The 4(th), 5(th) and 6(th) groups were injected with the same doses of normal saline, DC-MD and PLC, respectively for 5 successive days before and 5 days concomitant with IFO (50 mg/kg/day). IFO significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion and clearance, creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), intramitochondrial acetyl-CoA/CoA-SH and thiobarbituric acid reactive substances (TBARS) in cardiac tissues and significantly decreased adenosine triphosphate (ATP) and total carnitine and reduced glutathione (GSH) content in cardiac tissues. In carnitine

  12. Management of Iron Deficiency Anemia

    PubMed Central

    Jimenez, Kristine; Kulnigg-Dabsch, Stefanie

    2015-01-01

    Anemia affects one-fourth of the world’s population, and iron deficiency is the predominant cause. Anemia is associated with chronic fatigue, impaired cognitive function, and diminished well-being. Patients with iron deficiency anemia of unknown etiology are frequently referred to a gastroenterologist because in the majority of cases the condition has a gastrointestinal origin. Proper management improves quality of life, alleviates the symptoms of iron deficiency, and reduces the need for blood transfusions. Treatment options include oral and intravenous iron therapy; however, the efficacy of oral iron is limited in certain gastrointestinal conditions, such as inflammatory bowel disease, celiac disease, and autoimmune gastritis. This article provides a critical summary of the diagnosis and treatment of iron deficiency anemia. In addition, it includes a management algorithm that can help the clinician determine which patients are in need of further gastrointestinal evaluation. This facilitates the identification and treatment of the underlying condition and avoids the unnecessary use of invasive methods and their associated risks. PMID:27099596

  13. Aplastic Anemia and Myelodysplastic Syndromes

    MedlinePlus

    ... Phone: 202–776–0544 Fax: 202–776–0545 Internet: www.hematology.org Aplastic Anemia & MDS International Foundation ... Fax: 301–279–7205 Email: help@aamds.org Internet: www.aamds.org Iron Disorders Institute P.O. ...

  14. Cooley's Anemia: A Psychosocial Directory.

    ERIC Educational Resources Information Center

    National Center for Education in Maternal and Child Health, Washington, DC.

    The directory is intended to aid patients and their families who are coping with the genetic disorder of Cooley's anemia. A brief review of the disease covers background, genetics, symptoms, effect on the patient, treatment, and current research. The next section looks at psychosocial needs at various times (time of diagnosis, infancy and toddler…

  15. An anemia of Alzheimer's disease.

    PubMed

    Faux, N G; Rembach, A; Wiley, J; Ellis, K A; Ames, D; Fowler, C J; Martins, R N; Pertile, K K; Rumble, R L; Trounson, B; Masters, C L; Bush, A I

    2014-11-01

    Lower hemoglobin is associated with cognitive impairment and Alzheimer's disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that individuals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-ɛ4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline. PMID:24419041

  16. [Neuropsychiatric manifestations ushering pernicious anemia].

    PubMed

    Mrabet, S; Ellouze, F; Ellini, S; Mrad, M F

    2015-12-01

    Biermer disease or pernicious anemia is an autoimmune atrophic gastritis characterized by the lack of secretion of gastric intrinsic factor. This leads to an insufficient absorption of vitamin B12 in the ileum. Clinical manifestations are mainly hematologic. Neuropsychiatric manifestations are known but are less frequent especially early in the disease. Inaugural neuropsychiatric arrays are rare and various thus making diagnosis difficult. In this article, we report through two clinical cases different neuropsychiatric manifestations revealing pernicious anemia. Mrs. C.O., aged 56, presented after surgery for gallstones, an acute psychiatric array associated with gait disorders. She had no history of neurological or psychiatric problems. The psychiatric interview revealed delirious syndrome, depressive symptoms and anxiety. Neurological examination noted a flaccid paraplegia with peripheral neuropathic syndrome and myoclonus in the upper limbs. At the full blood count, a macrocytosis (VGM: 112.2fl) without anemia was found. The level of vitamin B12 in the blood was low. Cerebro-spinal MRI was suggestive of a neuro-Biermer and showed hyper signal in the cervical cord on T2-weighted sagittal section. In axial section, hyper signal appears at the posterior columns in the form of V. There were no brain abnormalities. A sensorimotor axonal polyneuropathy was diagnosed. The patient received vitamin B12 intramuscularly for ten days associated with neuroleptic treatment. Mrs. R.M., aged 40, was brought to the psychiatry consultation for acute behavioral disorders progressively worsening over a month. An anxiety syndrome, depressive syndrome and delirious syndrome were identified. Neurological examination showed a posterior cordonal syndrome with quadripyramidal syndrome. Full blood count showed a macrocytic anemia. Serum B12 level was collapsed. Cerebro-spinal MRI was normal. She received vitamin B12 with clinical and biological improvement. Features of pernicious anemia

  17. [Anemia as a surgical risk factor].

    PubMed

    Moral García, Victoria; Ángeles Gil de Bernabé Sala, M; Nadia Diana, Kinast; Pericas, Bartolomé Cantallops; Nebot, Alexia Galindo

    2013-07-01

    Perioperative anemia is common in patients undergoing surgery and is associated with increased morbidity and mortality and a decreased quality of life. The main causes of anemia in the perioperative context are iron deficiency and chronic inflammation. Anemia can be aggravated by blood loss during surgery, and is most commonly treated with allogeneic transfusion. Moreover, blood transfusions are not without risks, once again increasing patient morbidity and mortality. Given these concerns, we propose to review the pathophysiology of anemia in the surgical environment, as well as its treatment through the consumption of iron-rich foods and by oral or intravenous iron therapy (iron sucrose and iron carboxymaltose). In chronic inflammatory anemia, we use erythropoiesis-stimulating agents (erythropoietin alpha) and, in cases of mixed anemia, the combination of both treatments. The objective is always to reduce the need for perioperative transfusions and speed the recovery from postoperative anemia, as well as decrease the patient morbidity and mortality rate. PMID:24314568

  18. [Hemolytic anemias and vitamin B12 deficieny].

    PubMed

    Dietzfelbinger, Hermann; Hubmann, Max

    2015-08-01

    Hemolytic anemias consist of corpuscular, immun-hemolytic and toxic hemolytic anemias. Within the group of corpuscular hemolytic anemias, except for the paroxysmal nocturnal hemoglobinuria (PNH), all symptoms are caused by underlying heredetiary disorders within the red blood cell membran (hereditary spherocytosis), deficiencies of red cell enzymes (G6PDH- and pyrovatkinase deficiency) or disorders in the hemoglobin molecule (thalassaemia and sickle cell disease). Immune-hemolytic anemias are acquired hemolytic anemias and hemolysis is caused by auto- or allo-antibodies which are directed against red blood cell antigens. They are classified as warm, cold, mixed type or drug-induced hemolytic anemia. Therapy consists of glucocorticoids and other immunsuppressive drugs. Pernicious anemia is the most important vitamin B12 deficiency disorder. Diagnosis relies on cobalamin deficiency and antibodies to intrinsic factor. The management should focus on a possibly life-long replacement treatment with cobalamin. PMID:26306021

  19. Inborn anemias in mice: (Annual report, 1982-1983)

    SciTech Connect

    Bernstein, S.E.

    1983-09-09

    The nature of the defects that shorten the effective lifespan of red blood cells in the circulation and which gave rise to anemia, jaundice and to spleen, liver and heart enlargement are studied because they so closely parallel inherited hemolytic anemias in man. In mice, ''hemolytic disease'' initiated by the ja, sph, sph/sup ha/, or the nb genes has been traced to abnormalities in the protein components of their red cell membranes. Polyacrylamide gel electrophoresis of detergent solubilized membranes reveal that in the different genetic types one or more of the major high molecular weight proteins called spectrins is decreased or totally missing. It is one thing to observe a correlation between missing or defective components in selected analytical procedures, and another to establish a causal relationship between the two. To investigate the possible interrelationships, we examined the associations between spectrin or ankyrin content, the severity of the resulting anemia, red cell osmotic fragilities, and the capacity of cells from each genotype to be deformed in a continuous osmotic gradient at constant sheer stress. Our findings indicate that sensitivity to osmotic stress, cell rigidity (inadequate deformability), deficiency of spectrin or ankyrin, and the severity of the anemia, are statistically highly correlated. 11 refs., 3 tabs.

  20. Cystinuria in dogs: comparison of the cystinuric component of the Fanconi syndrome in basenji dogs to isolated cystinuria.

    PubMed

    McNamara, P D; Rea, C T; Bovee, K C; Reynolds, R A; Segal, S

    1989-01-01

    Two animal models for cystinuria have been examined: the Basenji dog with Fanconi syndrome and cystine stone-forming dogs of various breeds. Brush-border membranes were isolated from these animals and uptake of D-glucose and L-cystine was characterized. Experiments with isolated brush-border vesicles from Basenji dogs with cystinuria as a component of the Fanconi syndrome showed diminished sodium-dependent D-glucose uptake but no decrease in L-cystine uptake even though the cystine defect in vivo was as high as 94% (ie, 6% reabsorption). In contrast, brush-border vesicles isolated from the kidney of a cystine stone-forming dog (Welsh Corgi) with a cystine defect of only 16% (ie, 84% reabsorption) had decreased uptake of cystine compared to values found for Beagle and Basenji vesicles. Thus, cystinuria found in Basenji dogs with the Fanconi syndrome differs from that in classic stone-forming cystinuric dogs. The alteration responsible for the cystinuria of Basenji dogs with Fanconi syndrome does not appear to have a membrane locus and may reflect altered energetics for transport, which are not detected in isolated vesicles. The cystine defect in cystinuric stone-forming dogs does appear to be reflected in the isolated membrane. PMID:2909832

  1. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells

    PubMed Central

    Raya, Ángel; Rodríguez-Pizà, Ignasi; Guenechea, Guillermo; Vassena, Rita; Navarro, Susana; Barrero, María José; Consiglio, Antonella; Castellà, Maria; Río, Paula; Sleep, Eduard; González, Federico; Tiscornia, Gustavo; Garreta, Elena; Aasen, Trond; Veiga, Anna; Verma, Inder M.; Surrallés, Jordi; Bueren, Juan; Belmonte, Juan Carlos Izpisúa

    2009-01-01

    The generation of induced pluripotent stem (iPS) cells has enabled the derivation of patient-specific pluripotent cells and provided valuable experimental platforms to model human disease. Patient-specific iPS cells are also thought to hold great therapeutic potential, although direct evidence for this is still lacking. Here we show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals. Most importantly, we show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free. These data offer proof-of-concept that iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications. PMID:19483674

  2. La maladie de Fanconi: à propos d'une nouvelle observation

    PubMed Central

    Es-Seddiki, Anass; Ayyad, Anass; Messouadi, Sahar; Amrani, Rim

    2015-01-01

    La maladie de Fanconi ou l'anémie de Fanconi (AF) est une maladie génétique rare à transmission autosomique récessive. Elle est marquée par une hétérogénéité phénotypique. Certains symptômes et notamment la triade classique faite d'une petite taille, d'un syndrome malformatif varié et parfois discret et d'une insuffisance médullaire d'apparition précoce, doivent faire évoquer le diagnostic. Nous rapportons le cas d'un enfant âgé de sept ans, suivi et traité pour une luxation congénitale des hanches, qui présentait une pancytopénie avec à l'examen clinique on note un faciès dysmorphique triangulaire, une duplication du pouce droit, une surélévation de l’épaule gauche et un retard staturo-pondéral. PMID:26213593

  3. α-Thalassemia frequency and mutations in children with hypochromic microcytic anemias and relation with β-thalassemia, iron deficiency anemia.

    PubMed

    Gulen, Huseyin; Hanimeli, Ozlem; Karaca, Ozlem; Taneli, Fatma

    2012-04-01

    The majority of the anemias during childhood are hypochromic and microcytic. The aim of the present study was to determine the status of α-thalassemia mutations and its association with other etiologies, such as iron deficiency anemia (IDA) and β-thalassemia trait, that are frequently seen hypochromic microcytic anemias in children. Children with hypochromic microcytic anemias were included in the study. Serum iron (SI), total iron-binding capacity (TIBC), ferritin levels, and hemoglobin electrophoresis with high-performance liquid chromatography (HPLC) method were analyzed. Reverse hybridization of biotinylated polymerase chain reaction (PCR) product method was used for detection of α-globin gene mutations. Of the 46 patients involved in the study, 54.3% (n = 25) were boys, and 45.7% (n = 21) were girls. Iron deficiency anemia and β-thalassemia trait were diagnosed in 67.4% (n = 31) and 19.5% (n = 9), respectively. In 17.4% there were α-thalassemia mutations (in 10.9% 3.7 single-gene heterozygote mutation, in 4.3% 20.5-kb double-gene deletion mutation, and in 2.2% α-2 poly-A-1 heterozygote mutation was detected). In 2 patients (4.3%) no etiology was determined. In 2 patients (4.3%) association between iron deficiency anemia and α-thalassemia, in 1 patient (2.2%) association between β and α-thalassemia was detected. In conclusion, α-thalassemia carrier status and its association with other etiologies are frequently seen in Manisa. So, α-thalassemia should be considered in the differential diagnosis of hypochromic microcytic anemias, especially in cases without iron deficiency (ID) and β-thalassemia carrier state. PMID:22475300

  4. Epidemiology of Anemia in Older Adults

    PubMed Central

    Patel, Kushang V.

    2008-01-01

    Anemia is a common, multifactorial condition among older adults. The World Health Organization (WHO) definition of anemia (hemoglobin concentration <12 g/dL in women and <13 g/dL in men) is most often used in epidemiologic studies of older adults. More than 10% of community-dwelling adults age 65 years and older has WHO-defined anemia. After age 50 years, prevalence of anemia increases with advancing age and exceeds 20% in those 85 years and older. In nursing homes, anemia is present in 48–63% of residents. Incidence of anemia in older adults is not well characterized. Among older adults with anemia, approximately one-third have evidence of iron, folate, and/or vitamin B12 deficiency, another third have renal insufficiency and/or chronic inflammation, and the remaining third have anemia that is unexplained. Several studies demonstrate that anemia is associated with poorer survival in older adults. This review details the distribution and consequences of anemia in older adults and identifies future epidemiologic research needs. PMID:18809090

  5. Pearson marrow pancreas syndrome in patients suspected to have Diamond-Blackfan anemia.

    PubMed

    Gagne, Katelyn E; Ghazvinian, Roxanne; Yuan, Daniel; Zon, Rebecca L; Storm, Kelsie; Mazur-Popinska, Magdalena; Andolina, Laura; Bubala, Halina; Golebiowska, Sydonia; Higman, Meghan A; Kalwak, Krzysztof; Kurre, Peter; Matysiak, Michal; Niewiadomska, Edyta; Pels, Salley; Petruzzi, Mary Jane; Pobudejska-Pieniazek, Aneta; Szczepanski, Tomasz; Fleming, Mark D; Gazda, Hanna T; Agarwal, Suneet

    2014-07-17

    Pearson marrow pancreas syndrome (PS) is a multisystem disorder caused by mitochondrial DNA (mtDNA) deletions. Diamond-Blackfan anemia (DBA) is a congenital hypoproliferative anemia in which mutations in ribosomal protein genes and GATA1 have been implicated. Both syndromes share several features including early onset of severe anemia, variable nonhematologic manifestations, sporadic genetic occurrence, and occasional spontaneous hematologic improvement. Because of the overlapping features and relative rarity of PS, we hypothesized that some patients in whom the leading clinical diagnosis is DBA actually have PS. Here, we evaluated patient DNA samples submitted for DBA genetic studies and found that 8 (4.6%) of 173 genetically uncharacterized patients contained large mtDNA deletions. Only 2 (25%) of the patients had been diagnosed with PS on clinical grounds subsequent to sample submission. We conclude that PS can be overlooked, and that mtDNA deletion testing should be performed in the diagnostic evaluation of patients with congenital anemia. PMID:24735966

  6. Pagophagia in iron deficiency anemia.

    PubMed

    Uchida, Tatsumi; Kawati, Yasunori

    2014-04-01

    The relationship between pagophagia (ice pica) and iron deficiency anemia was studied. All 81 patients with iron deficiency anemia defined as hemoglobin <12.0 g/dl and ferritin level <12 ng/ml were interviewed about their habits of eating ice or other non-food substances. Pagophagia was defined as compulsive and repeated ingestion of at least one tray of ice or ice eating which was relieved after iron administration. Pagophagia was present in 13 patients (16.0%). All patients who received oral iron were periodically assessed employing a questionnaire on pagophagia and laboratory data. Iron therapy can cure the pagophagia earlier than hemoglobin recovery and repair of tissue iron deficiency. Although the pathogenesis of pagophagia is unclear, a biochemical approach involving the central nervous system might elucidate the mechanism underlying these abnormal behaviors. PMID:24850454

  7. [Anemia in chronic heart failure].

    PubMed

    Grau-Amorós, J; Formiga, F; Urrutia, A

    2011-01-01

    Anemia is one of the most common comorbidities in patients with decompensated chronic heart failure admitted to the Internal Medicine Ward. However, although there is evidence supporting its treatment to improve the functional capacity of the patients and to reduce the new admissions rate, the clinical practice guidelines do not provide any directives regarding its approach. This is an ideal clinical problem for the internist due to its multifactorial origin and the comprehensive point of view needed to approach the group of syndromes that occur in these patients (anemia, heart failure, geriatric syndromes, diabetes, etc.) The choice of treatment strategy, if such treatment is decided, should always begin after correcting the congestive signs in the outpatient with optimal treatment of heart failure. PMID:21620391

  8. Colonic lymphangiomatosis associated with anemia

    PubMed Central

    Chung, Woo Chul; Kim, Hye-Kang; Yoo, Jin Young; Lee, Jeong Rok; Lee, Kang-Moon; Paik, Chang Nyol; Jang, U-Im; Yang, Jin Mo

    2008-01-01

    Lymphangioma is an uncommon malformation of lymphatic system. Multiple colonic lymphangioma named as lymphangiomatosis is considered an extremely rare disease. Although lymphangioma is a benign tumor and most colonic lymphangiomas do not cause symptoms and do not require treatment, resection of lymphangioma is necessary in the presence of symptoms such as abdominal pain, bleeding, intussusceptions. We report a case of colonic lymphangiomatosis in a man who presented with abdominal discomfort and anemia, which was diagnosed and treated with endoscopic snare polypectomy. PMID:18837097

  9. George Minot and Pernicious Anemia.

    PubMed

    Dhungat, J V Pai

    2015-08-01

    George Minot (1885-1950) was born in Boston, Massachusetts. He was great grandson of James Jackson, co-founder of Massachusetts General Hospital in 1821. Graduating from Harvard College he enrolled at Harvard Medical School and obtained his MD in 1912. As a house pupil (intern) at the hospital he became interested in diseases of the blood and began taking meticulous histories of dietary habits of patients with anemia. PMID:27604448

  10. Musculoskeletal manifestations of chronic anemias.

    PubMed

    Martinoli, Carlo; Bacigalupo, Lorenzo; Forni, Gian Luca; Balocco, Manuela; Garlaschi, Giacomo; Tagliafico, Alberto

    2011-07-01

    This article provides an overview of the current use of diagnostic imaging modalities in the evaluation of a heterogeneous group of disorders causing chronic anemias by impaired blood cell production (inherited bone marrow failure syndromes of childhood, aplastic anemia and myelodysplastic syndromes, β-thalassemia) or increased blood cell destruction (sickle cell disease). During the course of these disorders, various musculoskeletal abnormalities can be encountered, including marrow hyperplasia, reversion of yellow marrow to red marrow, growth disturbances, and, occasionally, extramedullary hematopoiesis. Diagnostic imaging may help the clinician to identify specific complications related to either the disease (e.g., bone infarction and acute osteomyelitis in sickle cell disease) or transfusion (e.g., iron overload due to increased hemolysis) and iron chelation (e.g., desferrioxamine-related dysplastic bone changes and deferiprone-related degenerative arthritis) treatments. In this field, magnetic resonance imaging plays a pivotal role because of its high tissue contrast that enables early assessment of bone marrow changes before they become apparent on plain films or computed tomography or metabolic changes occur on bone scintigraphy or positron emission tomography scan. Overall, familiarity with the range of radiological appearances in chronic anemias is important to diagnose complications and establish appropriate therapy. PMID:21644200

  11. Pathophysiology of anemia and erythrocytosis.

    PubMed

    Hodges, Vivien M; Rainey, Susan; Lappin, Terence R; Maxwell, A Peter

    2007-11-01

    An increasing understanding of the process of erythropoiesis raises some interesting questions about the pathophysiology, diagnosis and treatment of anemia and erythrocytosis. The mechanisms underlying the development of many of the erythrocytoses, previously characterised as idiopathic, have been elucidated leading to an increased understanding of oxygen homeostasis. Characterisation of anemia and erythrocytosis in relation to serum erythropoietin levels can be a useful addition to clinical diagnostic criteria and provide a rationale for treatment with erythropoiesis stimulating agents (ESAs). Recombinant human erythropoietin as well as other ESAs are now widely used to treat anemias associated with a range of conditions, including chronic kidney disease, chronic inflammatory disorders and cancer. There is also heightened awareness of the potential abuse of ESAs to boost athletic performance in competitive sport. The discovery of erythropoietin receptors outside of the erythropoietic compartment may herald future applications for ESAs in the management of neurological and cardiac diseases. The current controversy concerning optimal hemoglobin levels in chronic kidney disease patients treated with ESAs and the potential negative clinical outcomes of ESA treatment in cancer reinforces the need for cautious evaluation of the pleiotropic effects of ESAs in non-erythroid tissues. PMID:17656101

  12. Diamond-Blackfan anemia and nutritional deficiency-induced anemia in children.

    PubMed

    Gelbart, David

    2014-04-01

    Diamond-Blackfan anemia is a rare, inherited disease that characteristically presents as a chronic, normochromic macrocytosis due to red cell lineage bone marrow failure. Although studies are elaborating on the genetic basis for its associated comorbidities, little has been published comparing this anemia to other chronic anemias that have similar laboratory results in children. This article offers a global perspective of the disease and compares it with anemia due to vitamin B12 and folate deficiency in children. PMID:24662257

  13. Anemia and iron deficiency in heart failure.

    PubMed

    Gil, Victor M; Ferreira, Jorge S

    2014-01-01

    Heart failure is a common problem and a major cause of mortality, morbidity and impaired quality of life. Anemia is a frequent comorbidity in heart failure and further worsens prognosis and disability. Regardless of anemia status, iron deficiency is a common and usually unidentified problem in patients with heart failure. This article reviews the mechanisms, impact on outcomes and treatment of anemia and iron deficiency in patients with heart failure. PMID:24216080

  14. Phytomedicines and nutraceuticals: alternative therapeutics for sickle cell anemia.

    PubMed

    Imaga, Ngozi Awa

    2013-01-01

    Sickle cell anemia is a genetically inherited disease in which the "SS" individual possesses an abnormal beta globin gene. A single base substitution in the gene encoding the human β -globin subunit results in replacement of β 6 glutamic acid by valine, leading to the devastating clinical manifestations of sickle cell disease. This substitution causes drastic reduction in the solubility of sickle cell hemoglobin (HbS) when deoxygenated. Under these conditions, the HbS molecules polymerize to form long crystalline intracellular mass of fibers which are responsible for the deformation of the biconcave disc shaped erythrocyte into a sickle shape. First-line clinical management of sickle cell anemia include, use of hydroxyurea, folic acid, amino acids supplementation, penicillinprophylaxis, and antimalarial prophylaxis to manage the condition and blood transfusions to stabilize the patient's hemoglobin level. These are quite expensive and have attendant risk factors. However, a bright ray of hope involving research into antisickling properties of medicinal plants has been rewarding. This alternative therapy using phytomedicines has proven to not only reduce crisis but also reverse sickling (in vitro). The immense benefits of phytomedicines and nutraceuticals used in the management of sickle cell anemia are discussed in this paper. PMID:23476125

  15. Phytomedicines and Nutraceuticals: Alternative Therapeutics for Sickle Cell Anemia

    PubMed Central

    Imaga, Ngozi Awa

    2013-01-01

    Sickle cell anemia is a genetically inherited disease in which the “SS” individual possesses an abnormal beta globin gene. A single base substitution in the gene encoding the human β-globin subunit results in replacement of β6 glutamic acid by valine, leading to the devastating clinical manifestations of sickle cell disease. This substitution causes drastic reduction in the solubility of sickle cell hemoglobin (HbS) when deoxygenated. Under these conditions, the HbS molecules polymerize to form long crystalline intracellular mass of fibers which are responsible for the deformation of the biconcave disc shaped erythrocyte into a sickle shape. First-line clinical management of sickle cell anemia include, use of hydroxyurea, folic acid, amino acids supplementation, penicillinprophylaxis, and antimalarial prophylaxis to manage the condition and blood transfusions to stabilize the patient's hemoglobin level. These are quite expensive and have attendant risk factors. However, a bright ray of hope involving research into antisickling properties of medicinal plants has been rewarding. This alternative therapy using phytomedicines has proven to not only reduce crisis but also reverse sickling (in vitro). The immense benefits of phytomedicines and nutraceuticals used in the management of sickle cell anemia are discussed in this paper. PMID:23476125

  16. Anemia in the frail, elderly patient

    PubMed Central

    Röhrig, Gabriele

    2016-01-01

    Anemia and frailty are two common findings in geriatric patients and have been shown to be associated with poor outcomes in this patient group. Recent studies have contributed to the growing evidence of a possible association with the age-related chronic inflammatory status known as “inflammaging”. These findings do not only give a better insight into the pathogenesis of anemia in frailty, but also offer new treatment options. The present article focuses on this assumed association between anemia, frailty, and inflammaging and summarizes current management options for anemia in frail patients. PMID:27051279

  17. Severe Aplastic Anemia Associated With Eosinophilic Fasciitis

    PubMed Central

    de Masson, Adèle; de Latour, Régis Peffault; Benhamou, Ygal; Moluçon-Chabrot, Cécile; Bay, Jacques-Olivier; Laquerrière, Annie; Picquenot, Jean-Michel; Michonneau, David; Leguy-Seguin, Vanessa; Rybojad, Michel; Bonnotte, Bernard; Jardin, Fabrice; Lévesque, Hervé; Bagot, Martine; Socié, Gérard

    2013-01-01

    Abstract Diffuse eosinophilic fasciitis (Shulman disease) is a rare sclerodermiform syndrome that, in most cases, resolves spontaneously or after corticosteroid therapy. It has been associated with hematologic disorders, such as aplastic anemia. The clinical features and long-term outcomes of patients with eosinophilic fasciitis and associated aplastic anemia have been poorly described. We report the cases of 4 patients with eosinophilic fasciitis and associated severe aplastic anemia. For 3 of these patients, aplastic anemia was refractory to conventional immunosuppressive therapy with antithymocyte globulin and cyclosporine. One of the patients received rituximab as a second-line therapy with significant efficacy for both the skin and hematologic symptoms. To our knowledge, this report is the first to describe rituximab used to treat eosinophilic fasciitis with associated aplastic anemia. In a literature review, we identified 19 additional cases of eosinophilic fasciitis and aplastic anemia. Compared to patients with isolated eosinophilic fasciitis, patients with eosinophilic fasciitis and associated aplastic anemia were more likely to be men (70%) and older (mean age, 56 yr; range, 18–71 yr). Corticosteroid-containing regimens improved skin symptoms in 5 (42%) of 12 cases but were ineffective in the treatment of associated aplastic anemia in all but 1 case. Aplastic anemia was profound in 13 cases (57%) and was the cause of death in 8 cases (35%). Only 5 patients (22%) achieved long-term remission (allogeneic hematopoietic stem cell transplantation: n = 2; cyclosporine-containing regimen: n = 2; high-dose corticosteroid-based regimen: n = 1). PMID:23429351

  18. Genetics Home Reference: X-linked sideroblastic anemia and ataxia

    MedlinePlus

    ... linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Enable Javascript to view the expand/ ... Open All Close All Description X-linked sideroblastic anemia and ataxia is a rare condition characterized by ...

  19. Do You Know about Sickle Cell Anemia? (For Kids)

    MedlinePlus

    ... Lunch Recipes Do You Know About Sickle Cell Anemia? KidsHealth > For Kids > Do You Know About Sickle ... stay in the hospital. What Causes Sickle Cell Anemia? Sickle cell anemia is an inherited (say: in- ...

  20. Genetics Home Reference: X-linked sideroblastic anemia

    MedlinePlus

    ... Conditions X-linked sideroblastic anemia X-linked sideroblastic anemia Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description X-linked sideroblastic anemia is an inherited disorder that prevents developing red ...

  1. Pearson syndrome in a Diamond-Blackfan anemia cohort.

    PubMed

    Alter, Blanche P

    2014-07-17

    In this issue of Blood, Gagne et al describe a cohort of 362 patients clinically classified as having Diamond-Blackfan anemia (DBA), in which 175 (48%) were found to have mutations and deletions in ribosomal protein genes or GATA1, and 8 of the remaining patients (2.2% overall) had mitochondrial gene deletions consistent with Pearson marrow-pancreas syndrome (PS). The authors propose that all patients with presumptive DBA should be tested for mitochondrial DNA (mtDNA) deletion during their initial genetic evaluation. PMID:25035146

  2. Rachitic chest in a young adult male: Fanconi's syndrome—idiopathic type

    PubMed Central

    Lo, Tom Edward Ngo

    2013-01-01

    Presented in this paper is a case of a 36-year-old Filipino man presenting with a chronic history of intermittent proximal muscle weakness and paralysis which was associated with failure to thrive, severe bony deformities, muscle wasting and multiple electrolyte abnormalities (hypokalaemia, hypocalcaemia, hypomagnesaemia). Severe skeletal deformities led to a pathological fracture of the femoral bone and restrictive chest wall expansion during inspiration necessitating admission and consult at our institution. Correction of multiple electrolyte abnormalities was the mainstay of treatment for this case and resulted into full reversal of paralytic symptoms but skeletal and osseous abnormalities persisted. This case highlights the insidious course and subtle signs of Fanconi's syndrome leading to disfiguring skeletal deformities and abnormalities if not diagnosed early. Early suspicion and eventual diagnosis might be the key for these patients to have normal productive life devoid of crippling complications. PMID:23761609

  3. Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy.

    PubMed

    Assmann, Nadine; Dettmer, Katja; Simbuerger, Johann M B; Broeker, Carsten; Nuernberger, Nadine; Renner, Kathrin; Courtneidge, Holly; Klootwijk, Enriko D; Duerkop, Axel; Hall, Andrew; Kleta, Robert; Oefner, Peter J; Reichold, Markus; Reinders, Joerg

    2016-05-17

    We recently reported an autosomal dominant form of renal Fanconi syndrome caused by a missense mutation in the third codon of the peroxisomal protein EHHADH. The mutation mistargets EHHADH to mitochondria, thereby impairing mitochondrial energy production and, consequently, reabsorption of electrolytes and low-molecular-weight nutrients in the proximal tubule. Here, we further elucidate the molecular mechanism underlying this pathology. We find that mutated EHHADH is incorporated into mitochondrial trifunctional protein (MTP), thereby disturbing β-oxidation of long-chain fatty acids. The resulting MTP deficiency leads to a characteristic accumulation of hydroxyacyl- and acylcarnitines. Mutated EHHADH also limits respiratory complex I and corresponding supercomplex formation, leading to decreases in oxidative phosphorylation capacity, mitochondrial membrane potential maintenance, and ATP generation. Activity of the Na(+)/K(+)-ATPase is thereby diminished, ultimately decreasing the transport activity of the proximal tubule cells. PMID:27160910

  4. Aplastica Anemia And Viral Hepatitis

    PubMed Central

    Cudillo, Laura

    2009-01-01

    Acquired aplastic anemia (aAA) is a severe and rare disease, characterized by hematopoietic bone marrow failure and peripheral cytopenia. The pathophysiology is immune mediated in most cases, activated T1 lymphocytes have been identified as effector cells. The disease can be successfully treated with combined immunosuppressive therapy or allogeneic hematopoietic stem cell transplantation. Hepatitis-associated aplastic anemia (HAA) is a syndrome of bone marrow failure following the development of acute seronegative hepatitis. HAA syndrome most often affects young males who presented severe pancytopenia two to three months after an episode of acute hepatitis. The clinical course of hepatitis is more frequently benign but a fulminant severe course is also described. The bone marrow failure can be explosive and severe and it is usually fatal if untreated, no correlations have been observed between severity of hepatitis and AA. In none of the studies a specific virus could be identified and most cases are seronegative for known hepatitis viruses. The clinical characteristics and response to immunotherapy indicate a central role for immune-mediated mechanism in the pathogenesis of HAA. The initial target organ of the immune response is the liver as suggested by the time interval between hepatitis and the onset of bone marrow failure. Liver histology is characterized by T cell infiltrating the parenchyma as reported in acute hepatitis. Recently in HAA it has been demonstrated intrahepatic and blood lymphocytes with T cell repertoire similar to that of confirmed viral acute hepatitis. The expanded T cell clones return to a normal distribution after response to immunosuppressive treatment, suggesting the antigen or T cell clearance. Therapeutic options are the same as acquired aplastic anemia. PMID:21415960

  5. [Abdominal pain, constipation and anemia].

    PubMed

    Barresi, Fabio; Kunz Caflish, Isabel; Bayly-Schinzel, Leena; Dressel, Holger

    2016-03-30

    We present the case of a 42-year old man who went to the emergency department because of spasmodic abdominal pain. The abdomen was soft. A gastroscopy and a colonoscopy were without pathological findings. The laboratory analyses indicated anemia. The differential blood count showed basophilic granules in the red blood cells. The blood lead level was elevated. A lead poisoning was diagnosed. The cause was the oral intake of an ayurvedic medication which the patient had received in Bangladesh to treat his vitiligo. PMID:27005735

  6. Anemia in children with down syndrome.

    PubMed

    Tenenbaum, Ariel; Malkiel, Sarah; Wexler, Isaiah D; Levy-Khademi, Floris; Revel-Vilk, Shoshana; Stepensky, Polina

    2011-01-01

    Background. Iron deficiency anemia impacts on cognitive development. The objective of this study was to determine the prevalence of anemia and iron deficiency in children with Down syndrome and identify risk factors for anemia. Methods. We conducted a prolective cross-sectional study of children attending a multidisciplinary Down syndrome medical center. One hundred and forty nine children with Down syndrome aged 0-20 years were enrolled in the study. Information obtained included a medical history, physical and developmental examination, nutritional assessment, and the results of blood tests. Results. Of the patients studied, 8.1% were found to have anemia. Among the 38 children who had iron studies, 50.0% had iron deficiency. In a multivariate analysis, Arab ethnicity and low weight for age were significantly associated with anemia. Gender, height, the presence of an eating disorder, and congenital heart disease were not risk factors for anemia. Conclusions. Children with Down syndrome are at risk for anemia and iron deficiency similar to the general population. Children with Down syndrome should be monitored for anemia and iron deficiency so that prompt intervention can be initiated. PMID:21941570

  7. The Student with Sickle Cell Anemia.

    ERIC Educational Resources Information Center

    Tetrault, Sylvia M.

    1981-01-01

    Sickle cell anemia is the most common and severe of inherited chronic blood disorders. In the United States, sickle cell anemia is most common among the Black population. Among the most commonly occurring symptoms are: an enlarged spleen, episodes of severe pain, easily contracted infections, skin ulcers, and frequent urination. (JN)

  8. 9 CFR 311.34 - Anemia.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Anemia. 311.34 Section 311.34 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY ORGANIZATION... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.34 Anemia. Carcasses...

  9. 9 CFR 311.34 - Anemia.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Anemia. 311.34 Section 311.34 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY ORGANIZATION... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.34 Anemia. Carcasses...

  10. 9 CFR 311.34 - Anemia.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Anemia. 311.34 Section 311.34 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY ORGANIZATION... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.34 Anemia. Carcasses...

  11. 9 CFR 311.34 - Anemia.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Anemia. 311.34 Section 311.34 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY ORGANIZATION... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.34 Anemia. Carcasses...

  12. 9 CFR 311.34 - Anemia.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Anemia. 311.34 Section 311.34 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY ORGANIZATION... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.34 Anemia. Carcasses...

  13. Preoperative anemia and postoperative outcomes after hepatectomy

    PubMed Central

    Tohme, Samer; Varley, Patrick R.; Landsittel, Douglas P.; Chidi, Alexis P.; Tsung, Allan

    2015-01-01

    Background Preoperative anaemia is associated with adverse outcomes after surgery but outcomes after liver surgery specifically are not well established. We aimed to analyze the incidence of and effects of preoperative anemia on morbidity and mortality in patients undergoing liver resection. Methods All elective hepatectomies performed for the period 2005–2012 recorded in the American College of Surgeons' National Surgical Quality Improvement Program (ACS-NSQIP) database were evaluated. We obtained anonymized data for 30-day mortality and major morbidity (one or more major complication), demographics, and preoperative and perioperative risk factors. We used multivariable logistic regression models to assess the adjusted effect of anemia, which was defined as (hematocrit <39% in men, <36% in women), on postoperative outcomes. Results We obtained data for 12,987 patients, of whom 4260 (32.8%) had preoperative anemia. Patients with preoperative anemia experienced higher postoperative major morbidity and mortality rates compared to those without anemia. After adjustment for predefined variables, preoperative anemia was an independent risk factor for postoperative major morbidity (adjusted OR 1.21, 1.09–1.33). After adjustment, there was no significant difference in postoperative mortality for patients with or without preoperative anemia (adjusted OR 0.88, 0.66–1.16). Conclusion Preoperative anemia is independently associated with an increased risk of major morbidity in patients undergoing hepatectomy. Therefore, it is crucial to readdress preoperative blood management in anemic patients prior to hepatectomy. PMID:27017165

  14. Duodenal Amyloidosis Masquerading as Iron Deficiency Anemia

    PubMed Central

    Hurairah, Abu

    2016-01-01

    The present study is a unique illustration of duodenal amyloidosis initially manifesting with iron deficiency anemia. It underscores the importance of clinical suspicion of amyloidosis while performing upper gastrointestinal endoscopy with a biopsy to establish the definite diagnosis in patients with unexplained iron deficiency anemia. PMID:27625911

  15. Hereditary spherocytic anemia with deletion of the short arm of chromosome 8

    SciTech Connect

    Okamoto, Nobuhiko; Wada, Yoshinao; Nakamura, Yoich

    1995-09-11

    We describe a 30-month-old boy with multiple anomalies and mental retardation with hereditary spherocytic anemia. His karyotype was 46,XYdel(8)(p11.23p21.1). Genes for ankyrin and glutathione reductase (GSR) were localized to chromosome areas 8p11.2 and 8p21.1, respectively. Six patients with spherocytic anemia and interstitial deletion of 8p- have been reported. In these patients, severe mental retardation and multiple anomalies are common findings. This is a new contiguous gene syndrome. Lux established that ankyrin deficiency and associated deficiencies of spectrin and protein 4.2 were responsible for spherocytosis in this syndrome. We reviewed the manifestations of this syndrome. Patients with spherocytic anemia and multiple congenital anomalies should be investigated by high-resolution chromosomal means to differentiate this syndrome. 14 refs., 3 figs., 2 tabs.

  16. Current concepts in the pathophysiology and treatment of aplastic anemia

    PubMed Central

    Young, Neal S.; Calado, Rodrigo T.; Scheinberg, Phillip

    2006-01-01

    Aplastic anemia, an unusual hematologic disease, is the paradigm of the human bone marrow failure syndromes. Almost universally fatal just a few decades ago, aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. The molecular basis of the aberrant immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways. Immunosuppression with antithymocyte globulins and cyclosporine is effective at restoring blood-cell production in the majority of patients, but relapse and especially evolution of clonal hematologic diseases remain problematic. Allogeneic stem-cell transplant from histocompatible sibling donors is curative in the great majority of young patients with severe aplastic anemia; the major challenges are extending the benefits of transplantation to patients who are older or who lack family donors. Recent results with alternative sources of stem cells and a variety of conditioning regimens to achieve their engraftment have been promising, with survival in small pediatric case series rivaling conventional transplantation results. PMID:16778145

  17. Fanconi syndrome

    MedlinePlus

    ... chain deposition disease Multiple myeloma Primary amyloidosis Symptoms Symptoms include: Passing large amounts of urine, which can lead to dehydration Bone pain Weakness Exams and Tests Laboratory tests ...

  18. Treatment of autoimmune hemolytic anemias

    PubMed Central

    Zanella, Alberto; Barcellini, Wilma

    2014-01-01

    Autoimmune hemolytic anemia (AIHA) is a relatively uncommon disorder caused by autoantibodies directed against self red blood cells. It can be idiopathic or secondary, and classified as warm, cold (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria) or mixed, according to the thermal range of the autoantibody. AIHA may develop gradually, or have a fulminant onset with life-threatening anemia. The treatment of AIHA is still not evidence-based. The first-line therapy for warm AIHA are corticosteroids, which are effective in 70–85% of patients and should be slowly tapered over a time period of 6–12 months. For refractory/relapsed cases, the current sequence of second-line therapy is splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%), rituximab (effective in approx. 80–90% of cases), and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are intravenous immunoglobulins, danazol, plasma-exchange, and alemtuzumab and high-dose cyclophosphamide as last resort option. As the experience with rituximab evolves, it is likely that this drug will be located at an earlier point in therapy of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some cases. In CAD, rituximab is now recommended as first-line treatment. PMID:25271314

  19. Iron deficiency anemia's effect on bone formation in zebrafish mutant.

    PubMed

    Bo, Lin; Liu, Zhichun; Zhong, Yingbin; Huang, Jian; Chen, Bin; Wang, Han; Xu, Youjia

    2016-07-01

    Iron is one of the essential elements of life. Iron metabolism is related to bone metabolism. Previous studies have confirmed that iron overload is a risk factor for osteoporosis. But the correlation between iron deficiency and bone metabolism remains unclear. Ferroportin 1 is identified as a cellular iron exporter and required for normal iron cycling. In zebrafish, the mutant of ferroportin 1 gene (fpn1), weh(tp85c) exhibited the defective iron transport, leading to developing severe hypochromic anemia. We used weh(tp85c) as a model for investigating iron deficiency and bone metabolism. In this study, we examined the morphology of the developing cartilage and vertebrae of the Weh(tp85) compared to the wild type siblings by staining the larvae with alcian blue for cartilage and alizarin red for the bone. In addition, we evaluated the expression patterns of the marker genes of bone development and cell signaling in bone formation. Our results showed that weh(tp85c) mutant larvae exhibited the defects in bone formation, revealing by decreases in the number of calcified vertebrae along with decreased expression of osteoblast novel genes: alpl, runx2a and col1a1a and BMPs signaling genes in osteoblast differentiation: bmp2a and bmp2b. Our data suggest that iron deficiency anemia affects bone formation, potentially through the BMPs signaling pathway in zebrafish. PMID:27184405

  20. Untangling the Phenotypic Heterogeneity of Diamond Blackfan Anemia

    PubMed Central

    Farrar, Jason E; Dahl, Niklas

    2011-01-01

    Diamond Blackfan anemia (DBA) is a lineage-selective inherited bone-marrow failure syndrome characterized primarily by anemia and physical malformations. Recent advances in identifying the genetic abnormalities underlying DBA have demonstrated involvement of genes encoding both large (RPL) and small (RPS) ribosomal subunit proteins, including mutations of RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26 in 50–60% of affected patients. Despite significant progress, identification of gene abnormalities in the remaining patients remains an important question since present data suggests that mutations in other members of the ribosomal protein gene complement do not explain those cases without an identified genetic lesion in these genes. Genetic studies have also raised new questions with the recognition of substantial variability in the manifestations of DBA, ranging from ribosomal protein mutations in otherwise asymptomatic individuals to those with classic severe red-cell aplasia with characteristic malformations, at times within the same kindred. In this review, we summarize the genetic basis of DBA and discuss mechanisms by which the phenotype of DBA might be modified. PMID:21435509

  1. Inborn anemias in mice: (Annual report, 1983-1984)

    SciTech Connect

    Bernstein, S.E.

    1984-09-01

    The hypotranserrinemic-hemochromatosis mutation in mice discovered in our laboratory is an almost exact duplicate of human atransferrinemia. Just as in man, the condition is inherited as a recessive lethal. The disease appears to stem from a congenital deficiency in transferrin. The new mutation arose spontaneously in BALB/c mice and results in death before 12 days of age. It is characterized by stunted growth, low numbers of erythrocytes, hypochromia, and in the absence of jaundice. Treatments with Imferon or other iron preparations were uniformly unsuccessful, but the use of normal mouse serum proved successful as a therapeutic measure. We find that we are able to keep these afflicted mice alive for more than a year with small amounts of normal serum, and transferrin bands are missing on cellulose acetate electrophoresis of serum proteins from affected individuals receiving no treatment. Genetic tests indicated that the new mutation was not an allele of any of the other known iron deficiency anemias in the mouse: sex linked anemia (sla), microcytic anemia (mk), or flexed anemia (f) or any of the members of the hemolytic disease group (sph, sph/sup ha/, nb, or ja). Biochemical and genetic analyses carried out during the past year indicate that the new mutation, tentatively designated hpx is not likely to be a mutation at the transferrin (Trf) locus on Chromosome 9. We observed no unusual serum proteins on cellulose acetate electrophoresis, such as might be expected if the Trf gene had mutated. Moreover, radial immunodiffusion examination and Ouchterlony analysis did not show the presence of smaller molecules (or fragments) with transferrin antigenic specificities. Instead they showed a total loss in serum transferrin. 14 refs., 5 tabs.

  2. Anemia of Chronic Disease and Iron Deficiency Anemia in Inflammatory Bowel Diseases: Pathophysiology, Diagnosis, and Treatment.

    PubMed

    Murawska, Natalia; Fabisiak, Adam; Fichna, Jakub

    2016-05-01

    Anemia coexists with inflammatory bowel disease (IBD) in up to two-thirds of patients, significantly impairing quality of life. The most common types of anemia in patients with IBD are iron deficiency anemia and anemia of chronic disease, which often overlap. In most cases, available laboratory tests allow successful diagnosis of iron deficiency, where difficulties appear, recently established indices such as soluble transferrin-ferritin ratio or percentage of hypochromic red cells are used. In this review, we discuss the management of the most common types of anemia in respect of the latest available data. Thus, we provide the mechanisms underlying pathophysiology of these entities; furthermore, we discuss the role of hepcidin in developing anemia in IBD. Next, we present the treatment options for each type of anemia and highlight the importance of individual choice of action. We also focus on newly developed intravenous iron preparations and novel, promising drug candidates targeting hepcidin. Concurrently, we talk about difficulties in differentiating between the true and functional iron deficiency, and discuss tools facilitating the process. Finally, we emphasize the importance of proper diagnosis and treatment of anemia in IBD. We conclude that management of anemia in patients with IBD is tricky, and appropriate screening of patients regarding anemia is substantial. PMID:26818422

  3. Anemia

    MedlinePlus

    ... vitamin C pills or eating foods high in vitamin C, such as citrus fruits or juice, at the same time you eat ... vitamins contain at least this amount.) Foods with vitamin C—such as strawberries and citrus fruits—help your body absorb iron. Eat these foods ...

  4. Anemia

    MedlinePlus

    ... body needs extra folate. Folate is a B vitamin found in foods such as leafy green vegetables, fruits, and dried beans and peas. Folic acid is ... iron, like orange juice, strawberries, broccoli, or other fruits and vegetables with vitamin C. Don't drink coffee or tea with ...

  5. Anemia

    MedlinePlus

    ... Tips Getting More Help Related Topics Kidney Problems Nutrition ... when you have low numbers of red blood cells. These cells carry oxygen to your body’s organs and tissues. This can happen due to ...

  6. Anemia

    MedlinePlus

    ... and webinars ASH Image Bank Educational Web-based library of hematologic imagery In This Section: Resources for Clinicians Resources for Trainees Resources for Educators Resources for Patients Resources for Industry Professionals View all Guidelines & Quality Care Resources to ...

  7. Anemia in the Neonate: The Differential Diagnosis and Treatment.

    PubMed

    Nassin, Michele L; Lapping-Carr, Gabrielle; de Jong, Jill L O

    2015-07-01

    Anemia is a common problem in the neonatal period. Presenting symptoms may suggest numerous possible diagnoses ranging from anemia seen as a normal part of development to anemia due to critical pathology. An illustrative case is presented to highlight the appropriate evaluation of the neonate with significant anemia. Several important features of the evaluation of neonatal anemia are highlighted. The constellation of signs and symptoms that occur in conjunction with the anemia are critical for the evaluation. The evaluation should be performed in a step-wise process that starts by eliminating common causes of anemia. Manual review of the peripheral blood smear with a hematologist can be helpful. PMID:26171704

  8. Inborn anemias in mice. Comprehensive progress report, 1 August 1979-1 June 1982, to accompany twenty-seventh renewal proposal

    SciTech Connect

    Bernstein, S.E.; Russell, E.S.; Barker, J.E.

    1982-07-01

    Hereditary anemias of mice have been investigated including four macrocytic anemias, three hemolytic anemias, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, an ..cap alpha..-thalassemia, and a new target-cell anemia. Each of these blood dyscrasias is caused by the action of a unique mutant gene, which determines the structure of different intracellular molecules controlling a different metabolic process. Thus the wide range of different hereditary anemias has considerable potential for uncovering many different aspects of hemopoietic homeostatic mechanisms in the mouse and by extension to man from an understanding of mammalian mechanisms utilized in the control of erythropoiesis. Each of the different anemias is studied through: (a) biochemical and biophysical characterization of peripheral blood cells; (b) determinations of cellular and organismic radiosensitivity under a variety of conditions; (c) measurements of iron metabolism and heme biosynthesis; (d) morphological and biochemical study of blood-forming tissue; (e) functional tests of the stem cell component; (f) examination of responses to erythroid stimuli and inhibitors; and (g) physiological complementation analysis via transplantation of tissue between individuals of differently affected genotypes.

  9. Inborn anemias in mice: (Annual report, 1981-1982)

    SciTech Connect

    Bernstein, S.E.

    1982-07-19

    Hereditary anemias of mice are the chief objects of investigation, specificially four macrocytic anemias, 3 types of hemolytic anemia, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, the autoimmune hemolytic anemia of NZB mice, an ..cap alpha..-thalassemia and a new hypochromic anemia with hemochromatosis. New types of anemia may be analyzed as new mutations appear. Three new mutations have been identified during the past 18 months. These anemias are studied through characterization of peripheral blood values, determinations of radiosensitivity under a variety of conditions, measurements of iron metabolism and heme synthesis, study of normal and abnormal erythrocyte membrane proteins, histological and biochemical characterization of blood-forming tissue, functional tests of the stem-cell component, examination of responses to erythroid stimuli, and transplantation of tissue and parabiosis between individuals of differently affected genotypes. 31 refs.

  10. Diamond Blackfan Anemia: Diagnosis, Treatment and Molecular Pathogenesis

    PubMed Central

    Lipton, Jeffrey M.; Ellis, Steven R.

    2009-01-01

    Synopsis Diamond Blackfan anemia (DBA) is a genetically and clinically heterogeneous disorder characterized by erythroid failure, congenital anomalies and a predisposition to cancer. Faulty ribosome biogenesis, resulting in pro-apoptotic erythropoiesis leading to erythroid failure, is hypothesized to be the underlying defect. The genes identified to date that are mutated in DBA all encode ribosomal proteins associated with either the small (RPS) or large (RPL) subunit and in these cases haploinsufficiency gives rise to the disease. Extraordinarily robust laboratory and clinical investigations have recently led to demonstrable improvements in clinical care for patients with DBA. PMID:19327583

  11. The Clinical Pictures of Autoimmune Hemolytic Anemia.

    PubMed

    Packman, Charles H

    2015-09-01

    Autoimmune hemolytic anemia is characterized by shortened red blood cell survival and a positive Coombs test. The responsible autoantibodies may be either warm reactive or cold reactive. The rate of hemolysis and the severity of the anemia may vary from mild to severe and life-threatening. Diagnosis is made in the laboratory by the findings of anemia, reticulocytosis, a positive Coombs test, and specific serologic tests. The prognosis is generally good but renal failure and death sometimes occur, especially in cases mediated by drugs. PMID:26696800

  12. The Clinical Pictures of Autoimmune Hemolytic Anemia

    PubMed Central

    Packman, Charles H.

    2015-01-01

    Summary Autoimmune hemolytic anemia is characterized by shortened red blood cell survival and a positive Coombs test. The responsible autoantibodies may be either warm reactive or cold reactive. The rate of hemolysis and the severity of the anemia may vary from mild to severe and life-threatening. Diagnosis is made in the laboratory by the findings of anemia, reticulocytosis, a positive Coombs test, and specific serologic tests. The prognosis is generally good but renal failure and death sometimes occur, especially in cases mediated by drugs. PMID:26696800

  13. Protrusio acetabuli in sickle-cell anemia

    SciTech Connect

    Martinez, S.; Apple, J.S.; Baber, C.; Putman, C.E.; Rosse, W.F.

    1984-04-01

    Of 155 adults with sickle-cell anemia (SS, SC), radiographs of the pelvis or hip demonstrated protrusio acetabuli on at least one side in 14 (3 men and 11 women), as indicated by projection of the acetabular line medial to the ilio-ischial line. All 14 patients had bone changes attributable to sickle-cell anemia, including marrow hyperplasia and osteonecrosis; however, the severity of femoral or acetabular osteonecrosis did not appear directly related to the protrusion. The authors conclude that sickle-cell anemia can predispose to development of protrusio acetabuli.

  14. Imaging Manifestations of Neurologic Complications in Anemia.

    PubMed

    Patel, Ritesh; Sabat, Shyam; Kanekar, Sangam

    2016-08-01

    The hallmark signs and symptoms of anemia are directly related to a decrease in oxygen delivery to vital tissues and organs and include pallor, fatigue, lightheadedness, and shortness of breath. Neurologic complications are often nonspecific and can include poor concentration, irritability, faintness, tinnitus, and headache. If undiagnosed or untreated, anemia can progress to cognitive dysfunction, psychosis, encephalopathy, myelopathy, peripheral neuropathy, and more focal syndromes, such as stroke, seizures, chorea, and transverse myelitis. Imaging can play an important role in the early diagnosis and treatment of these neurologic and systemic complications associated with anemia, and hence, better outcome. PMID:27443995

  15. Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility.

    PubMed

    Vuorela, Mikko; Pylkäs, Katri; Hartikainen, Jaana M; Sundfeldt, Karin; Lindblom, Annika; von Wachenfeldt Wäppling, Anna; Haanpää, Maria; Puistola, Ulla; Rosengren, Annika; Anttila, Maarit; Kosma, Veli-Matti; Mannermaa, Arto; Winqvist, Robert

    2011-12-01

    RAD51C, a RAD51 paralogue involved in homologous recombination, is a recently established Fanconi anemia and breast cancer predisposing factor. In the initial report, RAD51C mutations were shown to confer a high risk for both breast and ovarian tumors, but most of the replication studies published so far have failed to identify any additional susceptibility alleles. Here, we report a full mutation screening of the RAD51C gene in 147 Finnish familial breast cancer cases and in 232 unselected ovarian cancer cases originating from Finland and Sweden. In addition, in order to resolve whether common RAD51C SNPs are risk factors for breast cancer, we genotyped five tagging single nucleotide polymorphisms, rs12946522, rs304270, rs304283, rs17222691, and rs28363312, all located within the gene, from 993 Finnish breast cancer cases and 871 controls for cancer associated variants. Whereas, none of the studied common SNPs associated with breast cancer susceptibility, mutation analysis revealed two clearly pathogenic alterations. RAD51C c.-13_14del27 was observed in one familial breast cancer case and c.774delT in one unselected ovarian cancer case, thus confirming that RAD51C mutations are implicated in breast and ovarian cancer predisposition, although their overall frequency seems to be low. Independent identification of the very recently reported RAD51C c.774delT mutation in yet another patient originating from Sweden suggests that it might be a recurrent mutation in that population and should be studied further. The reliable estimation of the clinical implications of carrying a defective RAD51C allele still requires the identification of additional mutation positive families. PMID:21750962

  16. Polymorphisms in the glucocerebrosidase gene and pseudogene urge caution in clinical analysis of Gaucher disease allele c.1448T>C (L444P)

    PubMed Central

    Brown, Justin T; Lahey, Cora; Laosinchai-Wolf, Walairat; Hadd, Andrew G

    2006-01-01

    Background Gaucher disease is a potentially severe lysosomal storage disorder caused by mutations in the human glucocerebrosidase gene (GBA). We have developed a multiplexed genetic assay for eight diseases prevalent in the Ashkenazi population: Tay-Sachs, Gaucher type I, Niemann-Pick types A and B, mucolipidosis type IV, familial dysautonomia, Canavan, Bloom syndrome, and Fanconi anemia type C. This assay includes an allelic determination for GBA allele c.1448T>C (L444P). The goal of this study was to clinically evaluate this assay. Methods Biotinylated, multiplex PCR products were directly hybridized to capture probes immobilized on fluorescently addressed microspheres. After incubation with streptavidin-conjugated fluorophore, the reactions were analyzed by Luminex IS100. Clinical evaluations were conducted using de-identified patient DNA samples. Results We evaluated a multiplexed suspension array assay that includes wild-type and mutant genetic determinations for Gaucher disease allele c.1448T>C. Two percent of samples reported to be wild-type by conventional methods were observed to be c.1448T>C heterozygous using our assay. Sequence analysis suggested that this phenomenon was due to co-amplification of the functional gene and a paralogous pseudogene (ΨGBA) due to a polymorphism in the primer-binding site of the latter. Primers for the amplification of this allele were then repositioned to span an upstream deletion in the pseudogene, yielding a much longer amplicon. Although it is widely reported that long amplicons negatively impact amplification or detection efficiency in recently adopted multiplex techniques, this assay design functioned properly and resolved the occurrence of false heterozygosity. Conclusion Although previously available sequence information suggested GBA gene/pseudogene discrimination capabilities with a short amplified product, we identified common single-nucleotide polymorphisms in the pseudogene that required amplification of a

  17. [A simple algorithm for anemia].

    PubMed

    Egyed, Miklós

    2014-03-01

    The author presents a novel algorithm for anaemia based on the erythrocyte haemoglobin content. The scheme is based on the aberrations of erythropoiesis and not on the pathophysiology of anaemia. The hemoglobin content of one erytrocyte is between 28-35 picogram. Any disturbance in hemoglobin synthesis can lead to a lower than 28 picogram hemoglobin content of the erythrocyte which will lead to hypochromic anaemia. In contrary, disturbances of nucleic acid metabolism will result in a hemoglobin content greater than 36 picogram, and this will result in hyperchromic anaemia. Normochromic anemia, characterised by hemoglobin content of erythrocytes between 28 and 35 picogram, is the result of alteration in the proliferation of erythropoeisis. Based on these three categories of anaemia, a unique system can be constructed, which can be used as a model for basic laboratory investigations and work-up of anaemic patients. PMID:24583558

  18. Bacteremia Caused by Microbacterium binotii in a Patient with Sickle Cell Anemia

    PubMed Central

    Buss, Sarah N.; Starlin, Richard

    2014-01-01

    Microbacterium species are non-spore-forming, Gram-positive rods rarely associated with human disease. In this report, we describe the first case of bacteremia caused by Microbacterium binotii in a patient with sickle cell anemia. The utility of using 16S rRNA gene sequence analysis along with phenotypic methods for identification is shown. PMID:24197889

  19. [Molecular mechanisms underlying the pathology of Diamond-Blackfan anemia].

    PubMed

    Toki, Tsutomu; Ito, Etsuro

    2015-07-01

    Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome, characterized by red blood cell aplasia. Macrocytic anemia is a prominent feature of DBA but the disease is also characterized by growth retardation and congenital anomalies that are present in approximately 40% of affected patients. DBA is associated with single, monoallelic, inactivating mutations in ribosomal protein (RP) genes. In DBA, mutations or large deletions in RP genes include RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPL5, RPL11, RPL26 and RPL35A. These mutations have been reported in up to 60% of DBA patients. To date, no known pathogenic mutations have been found in the remaining patients. In an effort to identify new mutations responsible for DBA, we performed whole-exome sequencing analysis of 48 patients with no documented mutations/deletions in our first screening and identified a de novo splicing error mutation in RPL27 and a frameshift deletion in RPS27 in sporadic patients with DBA. In vitro knockdown of the gene expression disturbed pre-ribosomal RNA processing. Zebrafish models of rpl27 and rps27 mutations showed impairments of erythrocyte production and tail and/or brain development. In this report, we also discuss current knowledge regarding pathways from the impairment of ribosomal biogenesis to the pathology of DBA. PMID:26251151

  20. Clonal hematopoiesis in acquired aplastic anemia.

    PubMed

    Ogawa, Seishi

    2016-07-21

    Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1 Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA. PMID:27121470

  1. Role of Complement in Autoimmune Hemolytic Anemia.

    PubMed

    Berentsen, Sigbjørn

    2015-09-01

    The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorders. In cold agglutinin disease, efficient therapies have been developed in order to target the pathogenic B-cell clone, but complement modulation remains promising in some clinical situations. No established therapy exists for secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, and the possibility of therapeutic complement inhibition is interesting. Currently, complement modulation is not clinically documented in any autoimmune hemolytic anemia. The most relevant candidate drugs and possible target levels of action are discussed. PMID:26696798

  2. [Clinical evaluation of anemia in the aged].

    PubMed

    Pentimone, F; Del Corso, L; Frustaci, G; Gnesi, A; Romanelli, A M; Sabbatini, A R

    1992-01-01

    Of 533 patients over 65 years old (153 males and 380 females), admitted to geriatric units for various medical diseases, 111 (20.8%) were anemic. Among males the prevalence of anemia was 30.1%, among females 17.1%. Three principal causes of anemia were revealed. The most frequent (42.3%) was microcytic, hypochromic anemia, with low levels of serum iron concentrations, related to gastrointestinal diseases (with chronic occult blood loss). 38.7% of anemic elderly people was affected by chronic diseases. In 19.0% a folate (16 case) and iron (5 cases) deficiency was revealed. These results suggest that anemia in the elderly is always pathological; hemoglobin values lower than 12 g/dl should be considered abnormal and investigated. PMID:1545920

  3. [Anemia and transfusion therapy: an update].

    PubMed

    Madrazo-González, Z; García-Barrasa, A; Rodríguez-Lorenzo, L; Rafecas-Renau, A; Alonso-Fernández, G

    2011-01-01

    Anemia is one of the most prevalent diseases in the general population and is a very frequently found condition in medical and surgical patients in all medical specialties. A good evaluation of its clinical impact and its therapeutic possibilities is essential. Allogenic blood transfusion is a useful procedure in anemia management, although it has important adverse effects. It is the responsibility of the clinician to know and to take into account all the available alternatives for the treatment of anemia. Blood transfusions, erythropoiesis-stimulating agents, iron therapy (oral and endovenous) and other therapeutic alternatives must be rationally used, in accordance with the currently available clinical evidence. This review article summarizes some epidemiological characteristics of anemia, its clinical evaluation and the main therapeutic possibilities based on the present knowledge, placing special emphasis on the critically ill patient. PMID:20483506

  4. Role of Complement in Autoimmune Hemolytic Anemia

    PubMed Central

    Berentsen, Sigbjørn

    2015-01-01

    Summary The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorders. In cold agglutinin disease, efficient therapies have been developed in order to target the pathogenic B-cell clone, but complement modulation remains promising in some clinical situations. No established therapy exists for secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, and the possibility of therapeutic complement inhibition is interesting. Currently, complement modulation is not clinically documented in any autoimmune hemolytic anemia. The most relevant candidate drugs and possible target levels of action are discussed. PMID:26696798

  5. Alleviating anemia and thrombocytopenia in myelofibrosis patients.

    PubMed

    Cervantes, Francisco; Correa, Juan-Gonzalo; Hernandez-Boluda, Juan Carlos

    2016-05-01

    Anemia and thrombocytopenia are frequent clinical manifestations of myelofibrosis as well as important prognostic factors of the disease. Concerning the treatment of anemia, the first step should be the correction of reversible contributing factors, such as possible iron, folate and vitamin B12 deficiency. Then, treatment options include erythropoiesis stimulating agents, androgens, immunomodulating drugs, corticosteroids, and splenectomy. Anemia responses may also be observed in some patients treated with JAK inhibitors. However, most patients eventually fail to such therapies and become transfusion dependent. Some of the aforementioned therapies can also improve thrombocytopenia, but the responses are usually observed in patients with moderate platelet count decrease. Allogeneic hematopoietic stem cell transplantation, the only curative treatment of myelofibrosis, can be an alternative for selected patients with cytopenias who are refractory to conventional therapies. However, for the majority of patients, the management of anemia and severe thrombocytopenia remains an unmet need. PMID:26891375

  6. [Anemias in chronic obstructive pulmonary disease].

    PubMed

    Budnevsky, A V; Esaulenko, I E; Ovsyannikov, E S; Zhusina, Yu G

    2016-01-01

    According to different studies, anemia occurs in 8--33% of patients with chronic obstructive pulmonary disease (COPD). The paper describes the most important various causes of anemia in COPD, such as systemic inflammation and endocrine disorders, the use of some medications (theophylline, angiotensin-converting enzyme inhibitors), frequent COPD exacerbations, and long-term oxygen therapy. Lower hemoglobin levels in COPD patients are accompanied by increased shortness of breath, reduced exercise tolerance, and lower quality of life. Furthermore, some investigations have shown that anemia is an independent predictor of death in patients with COPD. In spite of the fact that anemia may be successfully in these patients, the evidence suggesting the importance of its impact on the prognosis of COPD is limited. PMID:27191018

  7. Anemia caused by low iron - children

    MedlinePlus

    Anemia - iron deficiency - children ... able to absorb iron well, even though the child is eating enough iron Slow blood loss over ... bleeding in the digestive tract Iron deficiency in children can also be related to lead poisoning .

  8. Adult-onset Diamond-Blackfan anemia with a novel mutation in the exon 5 of RPL11: too late and too rare

    PubMed Central

    Flores Ballester, Elena; Gil-Fernández, Juan José; Vázquez Blanco, Miguel; Mesa, José M; de Dios García, Juan; Tamayo, Ana T; Burgaleta, Carmen

    2015-01-01

    Key Clinical Message Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia usually diagnosed in the early infancy and associated with mutations or large deletions in 11 ribosomal protein (RP) genes. Adult patients with severe, transfusion dependence, aregenerative anemia might have a genetic-in-origin disease with an atypical presentation. Late onset nonclassical DBA should be ruled out and mutations of RP genes studied. PMID:26185635

  9. Adult-onset Diamond-Blackfan anemia with a novel mutation in the exon 5 of RPL11: too late and too rare.

    PubMed

    Flores Ballester, Elena; Gil-Fernández, Juan José; Vázquez Blanco, Miguel; Mesa, José M; de Dios García, Juan; Tamayo, Ana T; Burgaleta, Carmen

    2015-06-01

    Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia usually diagnosed in the early infancy and associated with mutations or large deletions in 11 ribosomal protein (RP) genes. Adult patients with severe, transfusion dependence, aregenerative anemia might have a genetic-in-origin disease with an atypical presentation. Late onset nonclassical DBA should be ruled out and mutations of RP genes studied. PMID:26185635

  10. Hypokalemic paralysis as primary presentation of Fanconi syndrome associated with Sjögren syndrome.

    PubMed

    Wang, Chih-Chiang; Shiang, Jeng-Chuan; Huang, Wen-Te; Lin, Shih-Hua

    2010-06-01

    Hypokalemic paralysis is a rare presentation of Fanconi syndrome (FS) caused by Sjögren Syndrome (SS). We describe a 39-year-old man who manifested flaccid paralysis of 4 limbs. Laboratory investigations showed profound hypokalemia (1.6 mmol/L) with renal K wasting, hyperchloremic metabolic acidosis with positive urine anion gap, hypophosphatemia with hyperphosphaturia, hypouricemia with hyperuricosuria, normoglycemic glycosuria, and abnormal serum creatinine concentration 2.2 mg/dL. A thorough survey for the cause of FS revealed that he had xerophthalmia and xerostomia accompanied by high anti-Ro antibody, positive Schirmer test, and delayed saliva excretion on sialoscintigraphy, confirming the diagnosis of SS. Potassium citrate, active vitamin D3, and high phosphate diet for his FS coupled with mycophenolate mofetil for SS resolved clinical symptoms and ameliorated renal function. Early recognition of HP due to the underlying SS-related FS with prompt therapy not only could terminate potentially life-threatening hypokalemia, but also improve renal outcome. PMID:20414123

  11. Renal cell carcinoma and autoimmune hemolytic anemia.

    PubMed

    Lands, R; Foust, J

    1996-04-01

    A previously healthy man who became bedridden because of malaise, fatigue, and weakness was found to have an autoimmune hemolytic anemia (AIHA). In the course of his evaluation for the AIHA, he was found, coincidentally, to have a renal cell carcinoma. The AIHA was marginally responsive to therapy with corticosteroids, but it resolved promptly after excision of the cancer. This case represents probably a rarely observed association between a nonhematologic malignancy and autoimmune hemolytic anemia. PMID:8614893

  12. Cerebral Microcirculation during Experimental Normovolaemic Anemia

    PubMed Central

    Bellapart, Judith; Cuthbertson, Kylie; Dunster, Kimble; Diab, Sara; Platts, David G.; Raffel, O. Christopher; Gabrielian, Levon; Barnett, Adrian; Paratz, Jenifer; Boots, Rob; Fraser, John F.

    2016-01-01

    Anemia is accepted among critically ill patients as an alternative to elective blood transfusion. This practice has been extrapolated to head injury patients with only one study comparing the effects of mild anemia on neurological outcome. There are no studies quantifying microcirculation during anemia. Experimental studies suggest that anemia leads to cerebral hypoxia and increased rates of infarction, but the lack of clinical equipoise, when testing the cerebral effects of transfusion among critically injured patients, supports the need of experimental studies. The aim of this study was to quantify cerebral microcirculation and the potential presence of axonal damage in an experimental model exposed to normovolaemic anemia, with the intention of describing possible limitations within management practices in critically ill patients. Under non-recovered anesthesia, six Merino sheep were instrumented using an intracardiac transeptal catheter to inject coded microspheres into the left atrium to ensure systemic and non-chaotic distribution. Cytometric analyses quantified cerebral microcirculation at specific regions of the brain. Amyloid precursor protein staining was used as an indicator of axonal damage. Animals were exposed to normovolaemic anemia by blood extractions from the indwelling arterial catheter with simultaneous fluid replacement through a venous central catheter. Simultaneous data recording from cerebral tissue oxygenation, intracranial pressure, and cardiac output was monitored. A regression model was used to examine the effects of anemia on microcirculation with a mixed model to control for repeated measures. Homogeneous and normal cerebral microcirculation with no evidence of axonal damage was present in all cerebral regions, with no temporal variability, concluding that acute normovolaemic anemia does not result in short-term effects on cerebral microcirculation in the ovine brain. PMID:26869986

  13. Mouse Models of Anemia of Cancer

    PubMed Central

    Kim, Airie; Rivera, Seth; Shprung, Dana; Limbrick, Donald; Gabayan, Victoria; Nemeth, Elizabeta; Ganz, Tomas

    2014-01-01

    Anemia of cancer (AC) may contribute to cancer-related fatigue and impair quality of life. Improved understanding of the pathogenesis of AC could facilitate better treatment, but animal models to study AC are lacking. We characterized four syngeneic C57BL/6 mouse cancers that cause AC. Mice with two different rapidly-growing metastatic lung cancers developed the characteristic findings of anemia of inflammation (AI), with dramatically different degrees of anemia. Mice with rapidly-growing metastatic melanoma also developed a severe anemia by 14 days, with hematologic and inflammatory parameters similar to AI. Mice with a slow-growing peritoneal ovarian cancer developed an iron-deficiency anemia, likely secondary to chronically impaired nutrition and bleeding into the peritoneal cavity. Of the four models, hepcidin mRNA levels were increased only in the milder lung cancer model. Unlike in our model of systemic inflammation induced by heat-killed Brucella abortus, ablation of hepcidin in the ovarian cancer and the milder lung cancer mouse models did not affect the severity of anemia. Hepcidin-independent mechanisms play an important role in these murine models of AC. PMID:24681760

  14. Family structure and child anemia in Mexico.

    PubMed

    Schmeer, Kammi K

    2013-10-01

    Utilizing longitudinal data from the nationally-representative Mexico Family Life Survey, this study assesses the association between family structure and iron-deficient anemia among children ages 3-12 in Mexico. The longitudinal models (n = 4649), which control for baseline anemia status and allow for consideration of family structure transitions, suggest that children living in stable-cohabiting and single-mother families and those who have recently experienced a parental union dissolution have higher odds of anemia than those in stable-married, father-present family structures. Interaction effects indicate that unmarried family contexts have stronger associations with anemia in older children (over age five); and, that the negative effects of parental union dissolution are exacerbated in poorer households. Resident maternal grandparents have a significant beneficial effect on child anemia independent of parental family structure. These results highlight the importance of family structure for child micronutrient deficiencies and suggest that understanding social processes within households may be critical to preventing child anemia in Mexico. PMID:23294876

  15. Renal anemia: from incurable to curable.

    PubMed

    Sato, Yuki; Yanagita, Motoko

    2013-11-01

    Renal anemia has been recognized as a characteristic complication of chronic kidney disease. Although many factors are involved in renal anemia, the predominant cause of renal anemia is a relative deficiency in erythropoietin (EPO) production. To date, exogenous recombinant human (rh)EPO has been widely used as a powerful drug for the treatment of patients with renal anemia. Despite its clinical effectiveness, a potential risk for increased mortality has been suggested in patients who receive rhEPO, in addition to the economic burden of rhEPO administration. The induction of endogenous EPO is another therapeutic approach that might have advantages over rhEPO administration. However, the physiological and pathophysiological regulation of EPO are not fully understood, and this lack of understanding has hindered the development of an endogenous EPO inducer. In this review, we will discuss the current treatment for renal anemia and its drawbacks, provide an overview of EPO regulation in healthy and diseased conditions, and propose future directions for therapeutic trials that more directly target the underlying pathophysiology of renal anemia. PMID:23884144

  16. Iron deficiency anemia in celiac disease

    PubMed Central

    Freeman, Hugh James

    2015-01-01

    Iron is an important micronutrient that may be depleted in celiac disease. Iron deficiency and anemia may complicate well-established celiac disease, but may also be the presenting clinical feature in the absence of diarrhea or weight loss. If iron deficiency anemia occurs, it should be thoroughly evaluated, even if celiac disease has been defined since other superimposed causes of iron deficiency anemia may be present. Most often, impaired duodenal mucosal uptake of iron is evident since surface absorptive area in the duodenum is reduced, in large part, because celiac disease is an immune-mediated disorder largely focused in the proximal small intestinal mucosa. Some studies have also suggested that blood loss may occur in celiac disease, sometimes from superimposed small intestinal disorders, including ulceration or neoplastic diseases, particularly lymphoma. In addition, other associated gastric or colonic disorders may be responsible for blood loss. Rarely, an immune-mediated hemolytic disorder with increased urine iron loss may occur that may respond to a gluten-free diet. Reduced expression of different regulatory proteins critical in iron uptake has also been defined in the presence and absence of anemia. Finally, other rare causes of microcytic anemia may occur in celiac disease, including a sideroblastic form of anemia reported to have responded to a gluten-free diet. PMID:26309349

  17. Molecular and clinical aspects of iron homeostasis: From anemia to hemochromatosis.

    PubMed

    Nairz, Manfred; Weiss, Günter

    2006-08-01

    The discovery in recent years of a plethora of new genes whose products are implicated in iron homeostasis has led to rapid expansion of our knowledge in the field of iron metabolism and its underlying complex regulation in both health and disease. Abnormalities of iron metabolism are among the most common disorders encountered in practical medicine and may have significant negative impact on physical condition and life expectancy. Basic insights into the principles of iron homeostasis and the pathophysiological and clinical consequences of iron overload, iron deficiency and misdistribution are thus of crucial importance in modern medicine. This review summarizes our current understanding of human iron metabolism and focuses on the clinically relevant features of hereditary and secondary hemochromatosis, iron deficiency anemia, anemia of chronic disease and anemia of critical illness. The interconnections between iron metabolism and immunity are also addressed, in as much as they may affect the risk and course of infections and malignancies. PMID:16957974

  18. [Prevalence and causal factors of anemia in children in Tunisia].

    PubMed

    El Ati, Jalila; Gaigi, Sadok; Beji, Chiraz; Haddad, Samira; Cherif, Samia; Farhat, Amina; Fattoum, Slaheddine; Ben Abdeladhim, Abdeladhim

    2005-09-01

    Anemia continue to be prevalent among children under five years despite the improvement of socioeconomic and sanitary indicators. The purpose of the present cross-sectorial study is to assess the etiologic factors responsible for anemia. Knowledge of the relative importance of the different causes should form a basis for intervention strategies to prevent and control anemia. The survey covered 955 children under the age of five years, native of two regions with the highest prevalent of anemia, the Southwest and the District of Tunis. The results showed that 29% of children suffered from anemia. About 70% of them were iron deficient. The fractions of the deficiency in vitamin B12 and in folates were insignificant. Only 3% of children had chronic inflammation associated with (and possibly responsible for) their anemia A little fraction of anemia (approximately 5%) was due to thalassemia or drepanocytosis. Picawasan important causal factor of iron deficiency anemia. The parasites identified instool could not cause anemia. PMID:16383194

  19. Iron, Anemia, and Iron Deficiency Anemia among Young Children in the United States.

    PubMed

    Gupta, Priya M; Perrine, Cria G; Mei, Zuguo; Scanlon, Kelley S

    2016-01-01

    Iron deficiency and anemia are associated with impaired neurocognitive development and immune function in young children. Total body iron, calculated from serum ferritin and soluble transferrin receptor concentrations, and hemoglobin allow for monitoring of the iron and anemia status of children in the United States. The purpose of this analysis is to describe the prevalence of iron deficiency (ID), anemia, and iron deficiency anemia (IDA) among children 1-5 years using data from the 2007-2010 National Health and Nutrition Examination Survey (NHANES). Prevalence of ID, anemia, and IDA among children 1-5 years was 7.1% (5.5, 8.7), 3.2% (2.0, 4.3), and 1.1% (0.6, 1.7), respectively. The prevalence of both ID and anemia were higher among children 1-2 years (p < 0.05). In addition, 50% of anemic children 1-2 years were iron deficient. This analysis provides an update on the prevalence of ID, anemia, and IDA for a representative sample of US children. Our results suggest little change in these indicators over the past decade. Monitoring of ID and anemia is critical and prevention of ID in early childhood should remain a public health priority. PMID:27249004

  20. Iron, Anemia, and Iron Deficiency Anemia among Young Children in the United States

    PubMed Central

    Gupta, Priya M.; Perrine, Cria G.; Mei, Zuguo; Scanlon, Kelley S.

    2016-01-01

    Iron deficiency and anemia are associated with impaired neurocognitive development and immune function in young children. Total body iron, calculated from serum ferritin and soluble transferrin receptor concentrations, and hemoglobin allow for monitoring of the iron and anemia status of children in the United States. The purpose of this analysis is to describe the prevalence of iron deficiency (ID), anemia, and iron deficiency anemia (IDA) among children 1–5 years using data from the 2007–2010 National Health and Nutrition Examination Survey (NHANES). Prevalence of ID, anemia, and IDA among children 1–5 years was 7.1% (5.5, 8.7), 3.2% (2.0, 4.3), and 1.1% (0.6, 1.7), respectively. The prevalence of both ID and anemia were higher among children 1–2 years (p < 0.05). In addition, 50% of anemic children 1–2 years were iron deficient. This analysis provides an update on the prevalence of ID, anemia, and IDA for a representative sample of US children. Our results suggest little change in these indicators over the past decade. Monitoring of ID and anemia is critical and prevention of ID in early childhood should remain a public health priority. PMID:27249004

  1. Telomere length in inherited bone marrow failure syndromes.

    PubMed

    Alter, Blanche P; Giri, Neelam; Savage, Sharon A; Rosenberg, Philip S

    2015-01-01

    Telomeres are long DNA repeats and a protein complex at chromosome ends that are essential for genome integrity. Telomeres are very short in patients with dyskeratosis congenita due to germline mutations in telomere biology genes. We compared telomere length in patients with Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome with telomere length in dyskeratosis congenita. Telomere length was measured in six leukocyte subsets by automated multicolor flow fluorescence in situ hybridization, and age-adjusted using Z-scores (-2.326 = 1(st) percentile) were created. We examined individual data, and used canonical variate analysis for group comparisons and outlier detection. Most dyskeratosis congenita telomere lengths were below the 1(st) percentile, while only 2 Fanconi anemia and one each Diamond-Blackfan anemia and Shwachman-Diamond syndrome were that low. However, Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome clustered in the bottom half of the normal range. Canonical variate analysis separated dyskeratosis congenita widely from the other three syndromes by the first canonical variable (89.7% of the variance); the second variable (10.0%) separated Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and Fanconi anemia from each other. Overall, unlike in dyskeratosis congenita, telomere lengths in patients with non-dyskeratosis congenita inherited bone marrow failure syndromes were usually in the normal range, albeit shorter than in unaffected individuals. Clinicaltrials.gov identifier: 00027274. PMID:25304614

  2. Telomere length in inherited bone marrow failure syndromes

    PubMed Central

    Alter, Blanche P.; Giri, Neelam; Savage, Sharon A.; Rosenberg, Philip S.

    2015-01-01

    Telomeres are long DNA repeats and a protein complex at chromosome ends that are essential for genome integrity. Telomeres are very short in patients with dyskeratosis congenita due to germline mutations in telomere biology genes. We compared telomere length in patients with Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome with telomere length in dyskeratosis congenita. Telomere length was measured in six leukocyte subsets by automated multicolor flow fluorescence in situ hybridization, and age-adjusted using Z-scores (−2.326 = 1st percentile) were created. We examined individual data, and used canonical variate analysis for group comparisons and outlier detection. Most dyskeratosis congenita telomere lengths were below the 1st percentile, while only 2 Fanconi anemia and one each Diamond-Blackfan anemia and Shwachman-Diamond syndrome were that low. However, Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome clustered in the bottom half of the normal range. Canonical variate analysis separated dyskeratosis congenita widely from the other three syndromes by the first canonical variable (89.7% of the variance); the second variable (10.0%) separated Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and Fanconi anemia from each other. Overall, unlike in dyskeratosis congenita, telomere lengths in patients with non-dyskeratosis congenita inherited bone marrow failure syndromes were usually in the normal range, albeit shorter than in unaffected individuals. clinicaltrials.gov identifier: 00027274 PMID:25304614

  3. Anemia, tumor hypoxemia, and the cancer patient

    SciTech Connect

    Varlotto, John . E-mail: jvarlott@bidmc.harvard.edu; Stevenson, Mary Ann

    2005-09-01

    Purpose: To review the impact of anemia/tumor hypoxemia on the quality of life and survival in cancer patients, and to assess the problems associated with the correction of this difficulty. Methods: MEDLINE searches were performed to find relevant literature regarding anemia and/or tumor hypoxia in cancer patients. Articles were evaluated in order to assess the epidemiology, adverse patient effects, anemia correction guidelines, and mechanisms of hypoxia-induced cancer cell growth and/or therapeutic resistance. Past and current clinical studies of radiosensitization via tumor oxygenation/hypoxic cell sensitization were reviewed. All clinical studies using multi-variate analysis were analyzed to show whether or not anemia and/or tumor hypoxemia affected tumor control and patient survival. Articles dealing with the correction of anemia via transfusion and/or erythropoietin were reviewed in order to show the impact of the rectification on the quality of life and survival of cancer patients. Results: Approximately 40-64% of patients presenting for cancer therapy are anemic. The rate of anemia rises with the use of chemotherapy, radiotherapy, and hormonal therapy for prostate cancer. Anemia is associated with reductions both in quality of life and survival. Tumor hypoxemia has been hypothesized to lead to tumor growth and resistance to therapy because it leads to angiogenesis, genetic mutations, resistance to apoptosis, and a resistance to free radicals from chemotherapy and radiotherapy. Nineteen clinical studies of anemia and eight clinical studies of tumor hypoxemia were found that used multi-variate analysis to determine the effect of these conditions on the local control and/or survival of cancer patients. Despite differing definitions of anemia and hypoxemia, all studies have shown a correlation between low hemoglobin levels and/or higher amounts of tumor hypoxia with poorer prognosis. Radiosensitization through improvements in tumor oxygenation/hypoxic cell

  4. Frequency of anemia in chronic psychiatry patients

    PubMed Central

    Korkmaz, Sevda; Yıldız, Sevler; Korucu, Tuba; Gundogan, Burcu; Sunbul, Zehra Emine; Korkmaz, Hasan; Atmaca, Murad

    2015-01-01

    Purpose Anemia could cause psychiatric symptoms such as cognitive function disorders and depression or could deteriorate an existing psychiatric condition when it is untreated. The objective of this study is to scrutinize the frequency of anemia in chronic psychiatric patients and the clinical and sociodemographic factors that could affect this frequency. Methods All inpatients in our clinic who satisfied the study criteria and received treatment between April 2014 and April 2015 were included in this cross-sectional study. Sociodemographic data for 378 patients included in the study and hemoglobin (Hb) and hematocrit values observed during their admission to the hospital were recorded in the forms. Male patients with an Hb level of <13 g/dL and nonpregnant female patients with an Hb level of <12 g/dL were considered as anemic. Findings Axis 1 diagnoses demonstrated that 172 patients had depressive disorder, 51 patients had bipolar disorder, 54 patients had psychotic disorder, 33 patients had conversion disorder, 19 patients had obsessive-compulsive disorder, 25 patients had generalized anxiety disorder, and 24 patients had other psychiatric conditions. It was also determined that 25.4% of the patients suffered from anemia. Thirty-five percent of females and 10% of males were considered as anemic. The frequency of anemia was the highest among psychotic disorder patients (35%), followed by generalized anxiety disorder patients (32%), and obsessive-compulsive disorder patients (26%). Anemia was diagnosed in 22% of depressive disorder patients, 25% of bipolar disorder patients, and 24% of conversion disorder patients. Results The prevalence of anemia among chronic psychiatry patients is more frequent than the general population. Thus, the study concluded that it would be beneficial to consider the physical symptoms and to conduct the required examinations to determine anemia among this patient group. PMID:26543367

  5. Impaired Lysosomal Function Underlies Monoclonal Light Chain-Associated Renal Fanconi Syndrome.

    PubMed

    Luciani, Alessandro; Sirac, Christophe; Terryn, Sara; Javaugue, Vincent; Prange, Jenny Ann; Bender, Sébastien; Bonaud, Amélie; Cogné, Michel; Aucouturier, Pierre; Ronco, Pierre; Bridoux, Frank; Devuyst, Olivier

    2016-07-01

    Monoclonal gammopathies are frequently complicated by kidney lesions that increase the disease morbidity and mortality. In particular, abnormal Ig free light chains (LCs) may accumulate within epithelial cells, causing proximal tubule (PT) dysfunction and renal Fanconi syndrome (RFS). To investigate the mechanisms linking LC accumulation and PT dysfunction, we used transgenic mice overexpressing human control or RFS-associated κLCs (RFS-κLCs) and primary cultures of mouse PT cells exposed to low doses of corresponding human κLCs (25 μg/ml). Before the onset of renal failure, mice overexpressing RFS-κLCs showed PT dysfunction related to loss of apical transporters and receptors and increased PT cell proliferation rates associated with lysosomal accumulation of κLCs. Exposure of PT cells to RFS-κLCs resulted in κLC accumulation within enlarged and dysfunctional lysosomes, alteration of cellular dynamics, defective proteolysis and hydrolase maturation, and impaired lysosomal acidification. These changes were specific to the RFS-κLC variable (V) sequence, because they did not occur with control LCs or the same RFS-κLC carrying a single substitution (Ala30→Ser) in the V domain. The lysosomal alterations induced by RFS-κLCs were reflected in increased cell proliferation, decreased apical expression of endocytic receptors, and defective endocytosis. These results reveal that specific κLCs accumulate within lysosomes, altering lysosome dynamics and proteolytic function through defective acidification, thereby causing dedifferentiation and loss of reabsorptive capacity of PT cells. The characterization of these early events, which are similar to those encountered in congenital lysosomal disorders, provides a basis for the reported differential LC toxicity and new perspectives on LC-induced RFS. PMID:26614382

  6. Anemia management after acute brain injury.

    PubMed

    Lelubre, Christophe; Bouzat, Pierre; Crippa, Ilaria Alice; Taccone, Fabio Silvio

    2016-01-01

    Anemia is frequent among brain-injured patients, where it has been associated with an increased risk of poor outcome. The pathophysiology of anemia in this patient population remains multifactorial; moreover, whether anemia merely reflects a higher severity of the underlying disease or is a significant determinant of the neurological recovery of such patients remains unclear. Interestingly, the effects of red blood cell transfusions (RBCT) in moderately anemic patients remain controversial; although hemoglobin levels are increased, different studies observed only a modest and inconsistent improvement in cerebral oxygenation after RBCT and raised serious concerns about the risk of increased complications. Thus, considering this "blood transfusion anemia paradox", the optimal hemoglobin level to trigger RBCT in brain-injured patients has not been defined yet; also, there is insufficient evidence to provide strong recommendations regarding which hemoglobin level to target and which associated transfusion strategy (restrictive versus liberal) to select in this patient population. We summarize in this review article the more relevant studies evaluating the effects of anemia and RBCT in patients with an acute neurological condition; also, we propose some potential strategies to optimize transfusion management in such patients. PMID:27311626

  7. What Are the Signs and Symptoms of Aplastic Anemia?

    MedlinePlus

    ... What Are the Signs and Symptoms of Aplastic Anemia? Lower than normal numbers of red blood cells, ... most of the signs and symptoms of aplastic anemia. Signs and Symptoms of Low Blood Cell Counts ...

  8. Distinct Roles of Urinary Liver-Type Fatty Acid-Binding Protein in Non-Diabetic Patients with Anemia

    PubMed Central

    Imai, Naohiko; Yasuda, Takashi; Kamijo-Ikemori, Atsuko; Shibagaki, Yugo; Kimura, Kenjiro

    2015-01-01

    Background Various stresses including ischemia are known to up-regulate renal L-FABP gene expression and increase the urinary excretion of L-FABP. In diabetic patients with anemia, the urinary excretion of L-FABP is significantly increased. We studied the clinical significance of urinary L-FABP and its relationship with anemia in non-diabetic patients. Subjects and Methods A total of 156 patients were studied in this retrospective cross-sectional analysis. The associations between anemia and urinary L-FABP levels, and the predictors of urinary L-FABP levels in non-diabetic patients were evaluated. Results Urinary L-FABP levels were significantly higher in patients with anemia compared to those in patients without anemia. Similarly, the urinary L-FABP levels were significantly higher in patients with albuminuria compared to those in patients without albuminuria. Urinary L-FABP levels correlated with urinary albumin-to-creatinine ratios, estimated glomerular filtration rates, body mass index, and hemoglobin levels. Multivariate linear regression analysis determined that hemoglobin levels (β = -0.249, P = 0.001) and urinary albumin-to-creatinine ratios (β = 0.349, P < 0.001) were significant predictors of urinary L-FABP levels. Conclusions Urinary L-FABP is strongly associated with anemia in non-diabetic patients. PMID:26010898

  9. Nucleolar stress in Diamond Blackfan anemia pathophysiology.

    PubMed

    Ellis, Steven R

    2014-06-01

    Diamond Blackfan anemia is a red cell hypoplasia that typically presents within the first year of life. Most cases of Diamond Blackfan anemia are caused by ribosome assembly defects linked to haploinsufficiency for structural proteins of either ribosomal subunit. Nucleolar stress associated with abortive ribosome assembly leads to p53 activation via the interaction of free ribosomal proteins with HDM2, a negative regulator of p53. Significant challenges remain in linking this nucleolar stress signaling pathway to the clinical features of Diamond Blackfan anemia. Defining aspects of disease presentation may relate to developmental and physiological triggers that work in conjunction with nucleolar stress signaling to heighten the p53 response in the developing erythron after birth. The growing number of ribosomopathies provides additional challenges for linking molecular mechanisms with clinical phenotypes. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease. PMID:24412987

  10. Very severe aplastic anemia appearing after thymectomy.

    PubMed

    Park, Chi Young; Kim, Hee Je; Kim, Yoo Jin; Park, Yoon Hee; Lee, Jong Wook; Min, Woo Sung; Kim, Chun Choo

    2003-03-01

    Aplastic anemia is a rare complication of thymoma and is extremely infrequent after thymectomy. We present a case of a 60-year-old woman with very severe aplastic anemia appearing sixteen months after thymectomy for a thymoma. She underwent thymectomy for a thymoma in April 2000. Preoperative examination revealed no hematologic abnormality. About sixteen months after the operation, she was readmitted because of pancytopenia with cough and fever. Bone marrow aspiration revealed a very severe hypoplasia in all the three cell lines with over 80% fatty tissue, and chest CT revealed no recurrence of thymoma. Her aplastic anemia had responded to cyclosporine A and granulocyte-colony stimulating factor (G-CSF). PMID:12760272

  11. Anemia in hospitalized patients with pulmonary tuberculosis*

    PubMed Central

    Oliveira, Marina Gribel; Delogo, Karina Neves; de Oliveira, Hedi Marinho de Melo Gomes; Ruffino-Netto, Antonio; Kritski, Afranio Lineu; Oliveira, Martha Maria

    2014-01-01

    OBJECTIVE: To describe the prevalence of anemia and of its types in hospitalized patients with pulmonary tuberculosis. METHODS: This was a descriptive, longitudinal study involving pulmonary tuberculosis inpatients at one of two tuberculosis referral hospitals in the city of Rio de Janeiro, Brazil. We evaluated body mass index (BMI), triceps skinfold thickness (TST), arm muscle area (AMA), ESR, mean corpuscular volume, and red blood cell distribution width (RDW), as well as the levels of C-reactive protein, hemoglobin, transferrin, and ferritin. RESULTS: We included 166 patients, 126 (75.9%) of whom were male. The mean age was 39.0 ± 10.7 years. Not all data were available for all patients: 18.7% were HIV positive; 64.7% were alcoholic; the prevalences of anemia of chronic disease and iron deficiency anemia were, respectively, 75.9% and 2.4%; and 68.7% had low body weight (mean BMI = 18.21 kg/m2). On the basis of TST and AMA, 126 (78.7%) of 160 patients and 138 (87.9%) of 157 patients, respectively, were considered malnourished. Anemia was found to be associated with the following: male gender (p = 0.03); low weight (p = 0.0004); low mean corpuscular volume (p = 0.03);high RDW (p = 0; 0003); high ferritin (p = 0.0005); and high ESR (p = 0.004). We also found significant differences between anemic and non-anemic patients in terms of BMI (p = 0.04), DCT (p = 0.003), and ESR (p < 0.001). CONCLUSIONS: In this sample, high proportions of pulmonary tuberculosis patients were classified as underweight and malnourished, and there was a high prevalence of anemia of chronic disease. In addition, anemia was associated with high ESR and malnutrition. PMID:25210963

  12. Correlates of Anemia in American Blacks and Whites

    PubMed Central

    Zakai, Neil A.; McClure, Leslie A.; Prineas, Ronald; Howard, George; McClellan, William; Holmes, Chris E.; Newsome, Britt B.; Warnock, David G.; Audhya, Paul

    2009-01-01

    For unclear reasons, anemia is more common in American blacks than whites. The authors evaluated anemia prevalence (using World Health Organization criteria) among 19,836 blacks and whites recruited in 2003–2007 for the REasons for Geographic And Racial Differences in Stroke Renal Ancillary study and characterized anemia by 3 anemia-associated conditions (chronic kidney disease, inflammation, and microcytosis). They used multivariable models to assess potential causes of race differences in anemia. Anemia was 3.3-fold more common in blacks than whites, with little attenuation after adjusting for demographic variables, socioeconomic factors, and comorbid conditions. Increasing age, residence in the US southeast, lower income, vascular disease, diabetes, hypertension, and never smoking were associated with anemia. Age, diabetes, and vascular disease were stronger correlates of anemia among whites than blacks (P < 0.05). Among those with anemia, chronic kidney disease was less common among blacks than whites (22% vs. 34%), whereas inflammation (18% vs. 14%) and microcytosis (22% vs. 11%) were more common. In this large, geographically diverse cohort, anemia was 3-fold more common in blacks than whites with different characteristics and correlates. Race differences in anemia prevalence were not explained by the factors studied. Future research into the causes and consequences of anemia in different racial groups is needed. PMID:19066309

  13. The Invisible Malady: Sickle Cell Anemia

    PubMed Central

    Savitt, Todd L.

    1981-01-01

    Though several articles have appeared on the history of sickle cell anemia in the United States, none has dealt with the dissemination of information from the scientific community to the public. It is an interesting commentary on our society that 60 years have passed before this important but racially oriented disease has reached the public forum. In this article, the author tries to describe the major events in the history of sickle cell anemia and to explain why it has not been publicized. PMID:7021863

  14. Anemia in pediatric renal transplant recipients.

    PubMed

    Kausman, Joshua Yehuda; Powell, Harley Robert; Jones, Colin Lindsay

    2004-05-01

    The aim of this study was to establish the prevalence of anemia in stable pediatric renal transplant recipients and to examine the association of anemia with renal function, immunosuppressants, angiotensin converting enzyme inhibitors, and growth, as well as iron, vitamin B(12), and folate stores. This is a cross-sectional study of the 50 renal transplant recipients currently followed at our center. Patient data were collected regarding hematological parameters, growth, medications, renal function, underlying renal disease, delayed graft function, episodes of rejection, and iron or erythropoietin therapy post transplantation. The mean hemoglobin level (Hb) was 110 g/l and the overall prevalence of anemia was 60%, including 30% who were severely anemic (Hb<100 g/l). There was a high rate of iron deficiency (34%) and serum iron was the parameter of iron metabolism most closely associated with anemia. Hb in patients with low serum iron was 90.7 g/l versus 114.4 g/l in those with normal serum iron ( P<0.01). Both univariate and multiple linear regression determined tacrolimus dose and creatinine clearance to be significant factors associated with anemia. Tacrolimus dose correlated with a 10 g/l reduction in Hb for every increase of tacrolimus dose of 0.054 mg/kg per day ( P=0.001). The dose of mycophenolate was positively correlated with Hb, but this was likely to be confounded by our practice of dose reduction in the setting of anemia. Angiotensin converting enzyme inhibitor use was not associated with anemia. Severely anemic patients tended to be shorter, with a mean Z-score for height of -1.8 compared with -0.9 for those with normal Hb ( P=0.02). Anemia is a significant and common problem in pediatric renal transplant patients. Deteriorating renal function is an important cause, but other factors like iron deficiency and immunosuppression are involved. Definition of iron deficiency is difficult and serum iron may be a valuable indicator. Medication doses

  15. Hematologically and genetically distinct forms of sickle cell anemia in Africa. The Senegal type and the Benin type.

    PubMed

    Nagel, R L; Fabry, M E; Pagnier, J; Zohoun, I; Wajcman, H; Baudin, V; Labie, D

    1985-04-01

    Patients with sickle cell anemia vary in the hematologic and clinical features of their disease, in part because of variability in the presence of linked and unlinked genes that modify the expression of the disease. The hemoglobin S gene is strongly linked to three different haplotypes of polymorphic endonuclease-restriction sites of the beta-like gene cluster (genes in the vicinity of the beta-globin gene)--one prevalent in Atlantic West Africa, another in central West Africa, and yet another in Bantu-speaking Africa (equatorial, East, and southern Africa). We have studied the differences in the hematologic characteristics of patients with sickle cell anemia from the first two geographical areas. We find that the Senegalese (Atlantic West Africa) patients have higher levels of hemoglobin F, a preponderance of G gamma chains in hemoglobin F, a lower proportion of very dense red cells, and a lower percentage of irreversibly sickled cells than those from Benin (central West Africa). We interpret these data to mean that the gamma-chain composition and the hemoglobin F level are haplotype linked and that the decrease in the percentage of dense cells and irreversibly sickled cells is secondary to the elevation in the hemoglobin F level. Patients with sickle cell anemia in the New World probably correspond to various combinations of these types, in addition to the still hematologically undefined haplotype associated with sickle cell anemia in the Bantu-speaking areas of Africa. PMID:2579336

  16. `Untangling Sickle-cell Anemia and the Teaching of Heterozygote Protection'

    NASA Astrophysics Data System (ADS)

    Howe, Eric Michael

    2007-01-01

    Introductory biology textbooks often use the example of sickle-cell anemia to illustrate the concept of heterozygote protection. Ordinarily scientists expect the frequency of a gene associated with a debilitating illness would be low owing to its continual elimination by natural selection. The gene that causes sickle-cell anemia, however, has a relatively high frequency in many parts of the world. Historically, scientists proposed and defended several alternative theories to account for this anomaly, though it is now widely recognized among the scientific community that high frequencies of the gene reflect its benefit to heterozygotes against malaria. Textbooks normally develop this concept with reference to the often-used maps of Africa showing how in areas where the frequency of the sickle-cell gene is high, there is also higher exposure to the disease malaria. While sickle-cell anemia is often the example of choice for explaining and illustrating the concept of heterozygote protection, the present paper argues that exploring the history of scientific research behind our contemporary understanding has advantages for helping students understand multiple factors related to population genetics (e.g. mutation, gene flow, drift) in addition to heterozygote protection. In so doing, this approach invites students to evaluate the legitimacy of their own alternative conceptions about introductory population genetics or about the genetics of the disease sickle-cell anemia. The various historical theories scientists proposed and defended often resemble those of students who first learn about the disease. As such, a discussion of how scientists reached consensus about the role of heterozygote protection may help students understand and appreciate what are now recognized to be limitations in the views they bring to their classrooms. The paper concludes by discussing the ramifications of this approach in potentially helping students to examine certain aspects of the nature of

  17. The Evidence-Based Evaluation of Iron Deficiency Anemia.

    PubMed

    Hempel, Eliana V; Bollard, Edward R

    2016-09-01

    Anemia is a prevalent disease with multiple possible etiologies and resultant complications. Iron deficiency anemia is a common cause of anemia and is typically due to insufficient intake, poor absorption, or overt or occult blood loss. Distinguishing iron deficiency from other causes of anemia is integral to initiating the appropriate treatment. In addition, identifying the underlying cause of iron deficiency is also necessary to help guide management of these patients. We review the key components to an evidence-based, cost-conscious evaluation of suspected iron deficiency anemia. PMID:27542426

  18. Iron deficiency anemia in inflammatory bowel disease

    PubMed Central

    Kaitha, Sindhu; Bashir, Muhammad; Ali, Tauseef

    2015-01-01

    Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD) and is frequently overlooked as a complication. Patients with IBD are commonly found to have iron deficiency anemia (IDA) secondary to chronic blood loss, and impaired iron absorption due to tissue inflammation. Patients with iron deficiency may not always manifest with signs and symptoms; so, hemoglobin levels in patients with IBD must be regularly monitored for earlier detection of anemia. IDA in IBD is associated with poor quality of life, necessitating prompt diagnosis and appropriate treatment. IDA is often associated with inflammation in patients with IBD. Thus, commonly used laboratory parameters are inadequate to diagnose IDA, and newer iron indices, such as reticulocyte hemoglobin content or percentage of hypochromic red cells or zinc protoporphyrin, are required to differentiate IDA from anemia of chronic disease. Oral iron preparations are available and are used in patients with mild disease activity. These preparations are inexpensive and convenient, but can produce gastrointestinal side effects, such as abdominal pain and diarrhea, that limit their use and patient compliance. These preparations are partly absorbed due to inflammation. Non-absorbed iron can be toxic and worsen IBD disease activity. Although cost-effective intravenous iron formulations are widely available and have improved safety profiles, physicians are reluctant to use them. We present a review of the pathophysiologic mechanisms of IDA in IBD, improved diagnostic and therapeutic strategies, efficacy, and safety of iron replacement in IBD. PMID:26301120

  19. Aplastic anemia associated with lithium therapy

    PubMed Central

    Hussain, M. Z.; Khan, A. G.; Chaudhry, Z. A.

    1973-01-01

    A case is reported of fatal aplastic anemia developing in a 50-year-old woman who received lithium carbonate in the generally accepted dosage for a manic-depressive disorder. The serum lithium had been determined at regular intervals and never exceeded what is considered a safe level. Patients for whom lithium is prescribed should have periodic hematologic examinations. PMID:4691107

  20. Iron deficiency anemia in inflammatory bowel disease.

    PubMed

    Kaitha, Sindhu; Bashir, Muhammad; Ali, Tauseef

    2015-08-15

    Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD) and is frequently overlooked as a complication. Patients with IBD are commonly found to have iron deficiency anemia (IDA) secondary to chronic blood loss, and impaired iron absorption due to tissue inflammation. Patients with iron deficiency may not always manifest with signs and symptoms; so, hemoglobin levels in patients with IBD must be regularly monitored for earlier detection of anemia. IDA in IBD is associated with poor quality of life, necessitating prompt diagnosis and appropriate treatment. IDA is often associated with inflammation in patients with IBD. Thus, commonly used laboratory parameters are inadequate to diagnose IDA, and newer iron indices, such as reticulocyte hemoglobin content or percentage of hypochromic red cells or zinc protoporphyrin, are required to differentiate IDA from anemia of chronic disease. Oral iron preparations are available and are used in patients with mild disease activity. These preparations are inexpensive and convenient, but can produce gastrointestinal side effects, such as abdominal pain and diarrhea, that limit their use and patient compliance. These preparations are partly absorbed due to inflammation. Non-absorbed iron can be toxic and worsen IBD disease activity. Although cost-effective intravenous iron formulations are widely available and have improved safety profiles, physicians are reluctant to use them. We present a review of the pathophysiologic mechanisms of IDA in IBD, improved diagnostic and therapeutic strategies, efficacy, and safety of iron replacement in IBD. PMID:26301120

  1. X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation

    PubMed Central

    Sankaran, Vijay G.; Ulirsch, Jacob C.; Tchaikovskii, Vassili; Ludwig, Leif S.; Wakabayashi, Aoi; Kadirvel, Senkottuvelan; Lindsley, R. Coleman; Bejar, Rafael; Shi, Jiahai; Lovitch, Scott B.; Bishop, David F.; Steensma, David P.

    2015-01-01

    Macrocytic anemia with abnormal erythropoiesis is a common feature of megaloblastic anemias, congenital dyserythropoietic anemias, and myelodysplastic syndromes. Here, we characterized a family with multiple female individuals who have macrocytic anemia. The proband was noted to have dyserythropoiesis and iron overload. After an extensive diagnostic evaluation that did not provide insight into the cause of the disease, whole-exome sequencing of multiple family members revealed the presence of a mutation in the X chromosomal gene ALAS2, which encodes 5′-aminolevulinate synthase 2, in the affected females. We determined that this mutation (Y365C) impairs binding of the essential cofactor pyridoxal 5′-phosphate to ALAS2, resulting in destabilization of the enzyme and consequent loss of function. X inactivation was not highly skewed in wbc from the affected individuals. In contrast, and consistent with the severity of the ALAS2 mutation, there was a complete skewing toward expression of the WT allele in mRNA from reticulocytes that could be recapitulated in primary erythroid cultures. Together, the results of the X inactivation and mRNA studies illustrate how this X-linked dominant mutation in ALAS2 can perturb normal erythropoiesis through cell-nonautonomous effects. Moreover, our findings highlight the value of whole-exome sequencing in diagnostically challenging cases for the identification of disease etiology and extension of the known phenotypic spectrum of disease. PMID:25705881

  2. Hematopoietic Stem Cell Transplantation in Thalassemia and Sickle Cell Anemia

    PubMed Central

    Lucarelli, Guido; Isgrò, Antonella; Sodani, Pietro; Gaziev, Javid

    2012-01-01

    The globally widespread single-gene disorders β-thalassemia and sickle cell anemia (SCA) can only be cured by allogeneic hematopoietic stem cell transplantation (HSCT). HSCT treatment of thalassemia has substantially improved over the last two decades, with advancements in preventive strategies, control of transplant-related complications, and preparative regimens. A risk class–based transplantation approach results in disease-free survival probabilities of 90%, 84%, and 78% for class 1, 2, and 3 thalassemia patients, respectively. Because of disease advancement, adult thalassemia patients have a higher risk for transplant-related toxicity and a 65% cure rate. Patients without matched donors could benefit from haploidentical mother-to-child transplantation. There is a high cure rate for children with SCA who receive HSCT following myeloablative conditioning protocols. Novel non-myeloablative transplantation protocols could make HSCT available to adult SCA patients who were previously excluded from allogeneic stem cell transplantation. PMID:22553502

  3. Structural analysis of the 5 prime flanking region of the. beta. -globin gene in African sickle cell anemia patients: Further evidence for three origins of the sickle cell mutation in Africa

    SciTech Connect

    Chebloune, Y.; Pagnier, J.; Trabuchet, G.; Faure, C.; Verdier, G.; Labie, D.; Nigon, V. )

    1988-06-01

    Haplotype analysis of the {beta}-globin gene cluster shows two regions of DNA characterized by nonrandom association of restriction site polymorphisms. These regions are separated by a variable segment containing the repeated sequences (ATTTT){sub n} and (AT){sub x}T{sub y}, which might be involved in recombinational events. Studies of haplotypes linked to the sickle cell gene in Africa provide strong argument for three origins of the mutation: Benin, Senegal, and the Central African Republic. The structure of the variable segment in the three African populations was studied by S1 nuclease mapping of genomic DNA, which allows a comparison of several samples. A 1080-base-pair DNA segment was sequenced for one sample from each population. S1 nuclease mapping confirmed the homogeneity of each population with regard to both (ATTTT){sub n} and (AT){sub x}T{sub y} repeats. The authors found three additional structures for (AT){sub x}T{sub y} correlating with the geographic origin of the patients. Ten other nucleotide positions, 5{prime} and 3{prime} to the (AT){sub x}T{sub y} copies, were found to be variable when compared to homologous sequences from human and monkey DNAs. These results allow us to propose an evolutionary scheme for the polymorphisms in the 5{prime} flanking region of the {beta}-globin gene. The results strongly support the hypothesis of three origins for the sickle mutation in Africa.

  4. Investigation of the Genetics of Hematologic Diseases

    ClinicalTrials.gov

    2016-03-25

    Bone Marrow Failure Syndromes; Erythrocyte Disorder; Leukocyte Disorder; Hemostasis; Blood Coagulation Disorder; Sickle Cell Disease; Dyskeratosis Congenita; Diamond-Blackfan Anemia; Congenital Thrombocytopenia; Severe Congenital Neutropenia; Fanconi Anemia

  5. Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer

    ClinicalTrials.gov

    2012-10-09

    Chronic Myeloproliferative Disorders; Diamond-blackfan Anemia; Fanconi Anemia; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases

  6. A case of Fanconi syndrome accompanied by crystal depositions in tubular cells in a patient with multiple myeloma

    PubMed Central

    Kim, Do Hee; Lim, A Young; Gwag, Hye Bin; Lee, Ji Hyeon; Jung, Ki Sun; Lee, Keol; Huh, Wooseong; Kim, Dae Joong; Kim, Yoon-Goo; Oh, Ha Young; Kim, Kihyun; Kwon, Gee-Young; Lee, Jung Eun

    2014-01-01

    Fanconi syndrome (FS) is a rare condition that is characterized by defects in the proximal tubular function. A 48-year-old woman was admitted for evaluation of proteinuria. The patient showed normal anion gap acidosis, normoglycemic glycosuria, hypophosphatemia, and hypouricemia. Thus, her condition was compatible with FS. The M peak was found behind the beta globulin region in urine protein electrophoresis. Upon bone marrow examination, we found that 24% of cells were CD138+ plasma cells with kappa restriction. From a kidney biopsy, we found crystalline inclusions within proximal tubular epithelial cells. Thereafter, she was diagnosed with FS accompanied by multiple myeloma. The patient received chemotherapy and autologous stem cell transplantation, and obtained very good partial hematologic response. However, proximal tubular dysfunction was persistent until 1 year after autologous stem cell transplantation. In short, we report a case of FS accompanied by multiple myeloma, demonstrating crystalline inclusion in proximal tubular cells on kidney biopsy. PMID:26877961

  7. Erythropoietin Levels in Elderly Patients with Anemia of Unknown Etiology

    PubMed Central

    Sriram, Swetha; Martin, Alison; Xenocostas, Anargyros; Lazo-Langner, Alejandro

    2016-01-01

    Background In many elderly patients with anemia, a specific cause cannot be identified. This study investigates whether erythropoietin levels are inappropriately low in these cases of “anemia of unknown etiology” and whether this trend persists after accounting for confounders. Methods This study includes all anemic patients over 60 years old who had erythropoietin measured between 2005 and 2013 at a single center. Three independent reviewers used defined criteria to assign each patient’s anemia to one of ten etiologies: chronic kidney disease, iron deficiency, chronic disease, confirmed myelodysplastic syndrome (MDS), suspected MDS, vitamin B12 deficiency, folate deficiency, anemia of unknown etiology, other etiology, or multifactorial etiology. Iron deficiency anemia served as the comparison group in all analyses. We used linear regression to model the relationship between erythropoietin and the presence of each etiology, sequentially adding terms to the model to account for the hemoglobin concentration, estimated glomerular filtration rate (eGFR) and Charlson Comorbidity Index. Results A total of 570 patients met the inclusion criteria. Linear regression analysis showed that erythropoietin levels in chronic kidney disease, anemia of chronic disease and anemia of unknown etiology were lower by 48%, 46% and 27%, respectively, compared to iron deficiency anemia even after adjusting for hemoglobin, eGFR and comorbidities. Conclusions We have shown that erythropoietin levels are inappropriately low in anemia of unknown etiology, even after adjusting for confounders. This suggests that decreased erythropoietin production may play a key role in the pathogenesis of anemia of unknown etiology. PMID:27310832

  8. Anemia among Primary School Children in Eastern Ethiopia

    PubMed Central

    2015-01-01

    Background Anemia during childhood impairs physical growth, cognitive development and school performance. Identifying the causes of anemia in specific contexts can help efforts to prevent negative consequences of anemia among children. The objective of this study was to assess prevalence and identify correlates of anemia among school children in Eastern Ethiopia. Methods A cross sectional study was conducted from January 2012 to February 2012 in Kersa, Eastern Ethiopia. The study included randomly selected primary school students. Hemoglobin concentration was measured using a Hemocue haemoglobinometer. A child was identified as anemic if the hemoglobin concentration was <11.5 g/dl for children (5–11 yrs) and < 12 g/dl for child older than 12 years age. Poisson regression model with robust variance was used to calculate prevalence ratios. Result The overall prevalence of anemia was 27.1% (95% CI: 24.98, 29.14): 13.8% had mild, 10.8% moderate, and 2.3% severe anemia. Children with in the age group of 5-9 years (APR, 1.083; 95% CI, 1.044- 1.124) were at higher risk for anemia. Paternal education (Illiterate, 1.109; 1.044 - 1.178) was positively associated with anemia. Children who had irregular legume consumption (APR, 1.069; 95% CI, 1.022 -1.118) were at higher risk for anemia. Conclusion About a quarter of school children suffer from anemia and their educational potential is likely to be affected especially for those with moderate and severe anemia. Child age, irregular legume consumption, and low paternal schooling were associated with anemia. Intervention programmes aimed to reduce anemia among school children are crucial to ensure proper growth and development of children. PMID:25902055

  9. Autoimmune hemolytic anemia: classification and therapeutic approaches.

    PubMed

    Sève, Pascal; Philippe, Pierre; Dufour, Jean-François; Broussolle, Christiane; Michel, Marc

    2008-12-01

    Autoimmune hemolytic anemia (AIHA) is a relatively uncommon cause of anemia. Classifications of AIHA include warm AIHA, cold AIHA (including mainly chronic cold agglutinin disease and paroxysmal cold hemoglobinuria), mixed-type AIHA and drug-induced AIHA. AIHA may also be further subdivided on the basis of etiology. Management of AIHA is based mainly on empirical data and on small, retrospective, uncontrolled studies. The therapeutic options for treating AIHA are increasing with monoclonal antibodies and, potentially, complement inhibitory drugs. Based on data available in the literature and our experience, we propose algorithms for the treatment of warm AIHA and cold agglutinin disease in adults. Therapeutic trials are needed in order to better stratify treatment, taking into account the promising efficacy of rituximab. PMID:21082924

  10. Schilling evaluation of pernicious anemia: current status

    SciTech Connect

    Zuckier, L.S.; Chervu, L.R.

    1984-09-01

    The Schilling examination remains a popular means of evaluating in vivo absorption of vitamin B/sub 12/. When absorption is abnormally low, the test may be repeated with addition to exogenous intrinsic factor (IF) in order to correct the IF deficiency that characterizes pernicious anemia. A dual-isotope variation provides a means of performing both stages of the test simultaneously, thereby speeding up the test and reducing dependence on complete urine collection. In vivo studies indicate that, when administered simultaneously, the absorption of unbound B/sub 12/ is elevated, and IF-bound B/sub 12/ is reduced, in pernicious-anemia patients, relative to the classic two-stage examination. A number of clinical studies indicate significant difficulty in resolving clincial diagnoses with the dual-tracer test. An algorithm is offered for selecting the most suitable variation of the Schilling test to improve the accuracy of test results and the ease of performance.

  11. Intestine-specific Disruption of Hypoxia-inducible Factor (HIF)-2α Improves Anemia in Sickle Cell Disease.

    PubMed

    Das, Nupur; Xie, Liwei; Ramakrishnan, Sadeesh K; Campbell, Andrew; Rivella, Stefano; Shah, Yatrik M

    2015-09-25

    Sickle cell disease (SCD) is caused by genetic defects in the β-globin chain. SCD is a frequently inherited blood disorder, and sickle cell anemia is a common type of hemoglobinopathy. During anemia, the hypoxic response via the transcription factor hypoxia-inducible factor (HIF)-2α is highly activated in the intestine and is essential in iron absorption. Intestinal disruption of HIF-2α protects against tissue iron accumulation in iron overload anemias. However, the role of intestinal HIF-2α in regulating anemia in SCD is currently not known. Here we show that in mouse models of SCD, disruption of intestinal HIF-2α significantly decreased tissue iron accumulation. This was attributed to a decrease in intestinal iron absorptive genes, which were highly induced in a mouse model of SCD. Interestingly, disruption of intestinal HIF-2α led to a robust improvement in anemia with an increase in RBC, hemoglobin, and hematocrit. This was attributed to improvement in RBC survival, hemolysis, and insufficient erythropoiesis, which is evident from a significant decrease in serum bilirubin, reticulocyte counts, and serum erythropoietin following intestinal HIF-2α disruption. These data suggest that targeting intestinal HIF-2α has a significant therapeutic potential in SCD pathophysiology. PMID:26296885

  12. Anemia - Multiple Languages: MedlinePlus

    MedlinePlus

    ... 简体中文) French (français) Hindi (हिन्दी) Japanese (日本語) Korean (한국어) Russian (Русский) Somali (af Soomaali) Spanish (español) ... 貧血症 - 日本語 (Japanese) Bilingual PDF Health Information Translations Korean (한국어) Anemia 빈혈 - 한국어 (Korean) Bilingual PDF Health ...

  13. Autosomal Dominant Mutation in the Signal Peptide of Renin in a Kindred with Anemia, Hyperuricemia, and CKD

    PubMed Central

    Beck, Bodo B.; Trachtman, Howard; Gitman, Michael; Miller, Ilene; Sayer, John A.; Pannes, Andrea; Baasner, Anne; Hildebrandt, Friedhelm; Wolf, Matthias T.F.

    2012-01-01

    Homozygous or compound heterozygous Renin (REN) mutations cause renal tubular dysgenesis (RTD), which is characterized by death in utero due to renal failure and pulmonary hypoplasia. The phenotype resembles the fetopathy caused by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker intake during pregnancy. Recently, heterozygous REN mutations were shown to result in early-onset hyperuricemia, anemia and chronic renal failure. So far, only three different heterozygous REN mutations were reported. We performed mutation analysis of the REN gene in 39 kindreds with hyperuricemia and chronic kidney disease (CKD) previously tested negative for mutations in the UMOD and HNF1β genes. We identified one kindred with a novel c.28T>C (p.W10R) REN mutation in the signal sequence, concluding that REN mutations are rare events in CKD patients. Affected individuals over four generations were identified carrying the novel REN mutation and were characterized by significant anemia, hyperuricemia and CKD. Anemia was severe and disproportional to the degree of renal impairment. Moreover all heterozygous REN mutations are localized in the signal sequence. Therefore, screening of the REN gene for CKD patients with hyperuricemia and anemia may be focusing on exon 1 sequencing, which encodes the signal peptide. PMID:21903317

  14. Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia, hyperuricemia, and CKD.

    PubMed

    Beck, Bodo B; Trachtman, Howard; Gitman, Michael; Miller, Ilene; Sayer, John A; Pannes, Andrea; Baasner, Anne; Hildebrandt, Friedhelm; Wolf, Matthias T F

    2011-11-01

    Homozygous or compound heterozygous mutations in renin (REN) cause renal tubular dysgenesis, which is characterized by death in utero due to kidney failure and pulmonary hypoplasia. The phenotype resembles the fetopathy caused by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker intake during pregnancy. Recently, heterozygous REN mutations were shown to result in early-onset hyperuricemia, anemia, and chronic kidney disease (CKD). To date, only 3 different heterozygous REN mutations have been published. We report mutation analysis of the REN gene in 39 kindreds with hyperuricemia and CKD who previously tested negative for mutations in the UMOD (uromodulin) and HNF1B (hepatocyte nuclear factor 1β) genes. We identified one kindred with a novel thymidine to cytosine mutation at position 28 in the REN complementary DNA, corresponding to a tryptophan to arginine substitution at amino acid 10, which is found within the signal sequence (c.28T>C; p.W10R). On this basis, we conclude that REN mutations are rare events in patients with CKD. Within the kindred, we found affected individuals over 4 generations who carried the novel REN mutation and were characterized by significant anemia, hyperuricemia, and CKD. Anemia was severe and disproportional to the degree of decreased kidney function. Because all heterozygous REN mutations that have been described are localized in the signal sequence, screening of the REN gene for patients with CKD with hyperuricemia and anemia may best be focused on sequencing of exon 1, which encodes the signal peptide. PMID:21903317

  15. [Drug induced hemolytic anemia associated with agranulocytosis].

    PubMed

    Satoh, S; Takahashi, T; Hayashi, T; Okada, Y; Tokunoh, T; Adachi, M; Hinoda, Y; Endoh, T; Imai, K

    1996-10-01

    A 27-year-old female was admitted to a hospital because of severe anemia (hemoglobin 4.9 g/dl) after taking PL (a drug for common cold consisted of Salicylamide, Acetaminophen, Caffeine and Promethazine methylene di-salicylate) and Cefadroxil (an oral antibiotic) for ten days. History and laboratory data leaded to a diagnosis of drug induced hemolytic anemia. 6 units of concentrated red blood cells were transfused and the suspected drugs were discontinued immediately. Though resolution of anemia and no further hemolysis were observed, progressive leukocytopenia developed since four days after the admission. Bone marrow aspiration revealed marked decrease of granulocytic series. The patient was transferred to our hospital and was isolated under laminar air-flow to prevent her from bacterial and fungal infections. She was treated with prednisolone and granulocyte-colony stimulating factor. She recovered from leukocytopenia in two weeks without suffering from any life-threatening infection. We extensively analyzed the suspected drugs and mechanism of hemolysis and granulocytopenia. Cefadroxil is turned out to be contributed to hemolysis by an immune complex mechanism. Cefadroxil and Salicylamide were suggested to be involved in granulocytopenia by the induction of antibodies against the leukocytes to which these drugs were bound. Thus Cefadroxil was regarded as a causative drug of both hemolysis and granulocytopenia. This case is of interest for analyzing drug-induced blood abnormality because it is very rare that two lineage of blood were injured by one drug at the same time as far as we know. PMID:8952318

  16. Communicating about chemotherapy-induced anemia.

    PubMed

    Davidson, Brad; Blum, Diane; Cella, David; Hamilton, Heidi; Nail, Lillian; Waltzman, Roger

    2007-01-01

    Many validated instruments exist for determining the impact of chemotherapy-induced anemia and related fatigue on patient quality of life, but few studies analyze how healthcare providers actually discuss these subjects with patients. The authors share their study results on patterns of communication between participating patients and their physicians and allied health professionals. Letters of invitation were mailed to over 1,000 community-based oncologists, 15 of whom met the criteria and agreed to participate in this study on a first-enrolled basis until sufficient participation was ensured. In total, 36 of their patients were audio- and/or video-recorded during their regularly scheduled visits. Post-visit interviews were conducted separately with patients and participating healthcare professionals. Interviews were transcribed and analyzed using sociolinguistic techniques. Although 52% of visit time was spent discussing side effects and symptoms, most discussions of anemia and fatigue lacked specificity necessary to determine their true impact on patients' lives. Physician inquiries regarding fatigue also tended to be too brief to elicit patients' chief concerns. Vocabulary used to discuss anemia and related fatigue was variable and imprecise, and no fatigue assessment instrument was used or referenced in any visit. Community-based oncologists are encouraged to modify their vocabulary and consider incorporating a validated fatigue instrument, either within or before the consultation, to improve the quality of such communication. PMID:17265785

  17. Reassessment of the microcytic anemia of lead poisoning

    SciTech Connect

    Cohen, A.R.; Trotzky, M.S.; Pincus, D.

    1981-06-01

    Hematologic abnormalities in childhood lead poisoning may be due, in part, to the presence of other disorders, such as iron deficiency or thalassemia minor. In order to reassess increased lead burden as a cause of microcytic anemia, we studied 58 children with class III or IV lead poisoning, normal iron stores, and no inherited hemoglobinopathy. Anemia occurred in 12% and microcytosis in 21% of these children. The combination of anemia and microcytosis was found in only one of 58 patients (2%). When only children with class IV lead poisoning were studied, the occurrence of microcytosis increased to 46%. However, the combination of microcytosis and anemia was found in only one of these 13 more severely affected patients. Microcytic anemia was similarly uncommon in children with either blood lead concentration greater than or equal to 50 microgram/100 ml. These data indicate that microcytosis and anemia occur much less commonly than previously reported in childhood lead poisoning uncomplicated by other hematologic disorders.

  18. Iron-hepcidin dysmetabolism, anemia and renal hypoxia, inflammation and fibrosis in the remnant kidney rat model.

    PubMed

    Garrido, Patrícia; Ribeiro, Sandra; Fernandes, João; Vala, Helena; Bronze-da-Rocha, Elsa; Rocha-Pereira, Petronila; Belo, Luís; Costa, Elísio; Santos-Silva, Alice; Reis, Flávio

    2015-01-01

    Anemia is a common complication of chronic kidney disease (CKD) that develops early and its severity increases as renal function declines. It is mainly due to a reduced production of erythropoietin (EPO) by the kidneys; however, there are evidences that iron metabolism disturbances increase as CKD progresses. Our aim was to study the mechanisms underlying the development of anemia of CKD, as well as renal damage, in the remnant kidney rat model of CKD induced by 5/6 nephrectomy. This model of CKD presented a sustained degree of renal dysfunction, with mild and advanced glomerular and tubulointerstitial lesions. Anemia developed 3 weeks after nephrectomy and persisted throughout the protocol. The remnant kidney was still able to produce EPO and the liver showed an increased EPO gene expression. In spite of the increased EPO blood levels, anemia persisted and was linked to low serum iron and transferrin levels, while serum interleukin (IL)-6 and high sensitivity C-reactive protein (hs-CRP) levels showed the absence of systemic inflammation. The increased expression of duodenal ferroportin favours iron absorption; however, serum iron is reduced which might be due to iron leakage through advanced kidney lesions, as showed by tubular iron accumulation. Our data suggest that the persistence of anemia may result from disturbances in iron metabolism and by an altered activity/function of EPO as a result of kidney cell damage and a local inflammatory milieu, as showed by the increased gene expression of different inflammatory proteins in the remnant kidney. In addition, this anemia and the associated kidney hypoxia favour the development of fibrosis, angiogenesis and inflammation that may underlie a resistance to EPO stimuli and reduced iron availability. These findings might contribute to open new windows to identify putative therapeutic targets for this condition, as well as for recombinant human EPO (rHuEPO) resistance, which occurs in a considerable percentage of CKD

  19. Expansion of CD8+ cells in autoimmune hemolytic anemia.

    PubMed

    Smirnova, S Ju; Sidorova, Ju V; Tsvetaeva, N V; Nikulina, O F; Biderman, B V; Nikulina, E E; Kulikov, S M; Sudarikov, A B

    2016-05-01

    Autoimmune hemolytic anemia (AIHA) is a rare blood disease associated with the production of auto-antibodies and autoimmune hemolysis. A critical role of B-cells in the development of AIHA has been demonstrated before. Here, we present the analysis of the clonal T-cell populations in patients with AIHA. Thirty-three patients with AIHA were included in this study. Thirteen patients with other anemias, 14 patients with other autoimmune conditions (SLE - 6, RA - 8) and 20 healthy donors were included in the study as a control group. The clonality of T-cell was evaluated by the assessment of the T-cell receptor gamma and beta chain gene rearrangements (TCRG and TCRB). The incidence of T-cell monoclonality detected in patients with AIHA was significantly higher compared to the control group. The persistence of T-cell clones did not correlate with the level of hemoglobin and other signs of remission or relapse and did not disappear after the therapy and clinical improvement (observation period was between 1 and 10 years). There was no correlation between the T-cell clonality and the gender, age, splenectomy, duration or severity of the disease. Fractionation of T-lymphocytes (CD4+, CD8+, CD4+25+) revealed that the monoclonal T-cells belonged to the CD8+ sub-population. We assume that besides a possible causative role of the T-cell clones in AIHA to autoimmune process, these clones do not directly participate in the development and maintenance of hemolysis. Most of the AIHA patients (48.5%) demonstrated a T-cell monoclonality, which requires monitoring and should be distinguished from T-cell tumors. PMID:26829107

  20. The role of TMPRSS6 polymorphisms in iron deficiency anemia partially responsive to oral iron treatment.

    PubMed

    Poggiali, Erika; Andreozzi, Fabio; Nava, Isabella; Consonni, Dario; Graziadei, Giovanna; Cappellini, Maria Domenica

    2015-04-01

    Iron refractory iron deficiency anemia (IRIDA) is a rare hereditary disease caused by mutations in TMPRSS6 gene encoding Matriptase-2, a negative regulator of hepcidin transcription. Up to now, 53 IRIDA patients from 35 families with different ethnic origins have been reported and 41 TMPRSS6 mutations have been identified. TMPRSS6 polymorphisms are more frequent than mutations, and have been associated with variation in iron and hematologic parameters. Our study evaluated their presence in 113 subjects with iron deficiency anemia (IDA) partially responsive to oral iron therapy and in 50 healthy blood donors. Thalassemic trait was diagnosed in 38 patients. Sequencing analysis of TMPRSS6 gene revealed that the frequency of several polymorphisms was markedly different between IDA subjects and controls. In particular, the V736A TMPRSS6 polymorphism was associated to moderately lower hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin levels, and in thalassemia carriers with marked anemia and microcytosis. A new variant-H448R- and two uncommon polymorphisms -A719T and V795I- were also identified. These results indicate that TMPRSS6 polymorphisms are more frequent in subjects with persistent IDA than in healthy controls, and in thalassemia carriers V736A variant may account for lower hemoglobin and MCV levels. Further studies in larger court of patients are necessary to identify potential haplotypes and polymorphisms responsible for low response to oral iron treatment and may be useful for planning a correct iron supplementation. PMID:25557470