Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A microcytic hypochromic anemic state was observed in an 8-year old Black female of Surinam origin during pre-operative Hb S [beta6(A3)Glu-->Val] screening. Her high zinc protoporphyrin (ZPP) level suggested a chronic iron depletion but, in contrast, the high red blood cell (RBC) count (5.85 x 10(12)/L) was indicative of a possible coexisting thalassemia. No abnormal hemoglobin (Hb) bands were present on high performance liquid chromatography (HPLC) or alkaline electrophoresis and the Hb A2 level was normal. Break point polymerase chain reaction (PCR) failed to reveal any of the common alpha-thalassemia (thal) mutations but selective DNA sequencing of both alpha-globin genes disclosed a TGC-->AGC transversion at codon 104 of the alpha1 gene. Cystine at codon 104 is involved in alpha/beta globin contact and has been described to be a critical amino acid of the alpha2 chain when substituted by a tyrosine (Hb Sallanches), inducing Hb H (beta4) disease in the homozygous state. Our heterozygous patient had a moderate anemia of 12.2 g/dL and a borderline haptoglobin suggesting some degree of hemolysis.
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PMID:Hb Oegstgeest [alpha104(G11)Cys-->Ser (alpha1)]. A new hemoglobin variant associated with a mild alpha-thalassemia phenotype. 1611 79

Family members in multiple generations of an Irish-American family were investigated for moderate to severe microcytic anaemia, inherited in an autosomal dominant fashion. A novel frameshift mutation of the beta globin gene was discovered. This study highlights the importance of considering dominantly inherited beta thalassemia in the investigation of anaemia, even in patients with ethnic backgrounds not usually associated with beta thalassaemia.
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PMID:Dominantly inherited beta thalassaemia intermedia caused by a new single nucleotide deletion in exon 2 of the beta globin gene: Hb morgantown (beta91 CTG>CG). 1618 62

Gene transfer for beta-thalassemia requires gene transfer into hematopoietic stem cells using integrating vectors that direct regulated expression of beta globin at therapeutic levels. Among integrating vectors, oncoretroviral vectors carrying the human beta-globin gene and portions of the locus control region (LCR) have suffered from problems of vector instability, low titers and variable expression. In recent studies, human immunodeficiency virus-based lentiviral (LV) vectors were shown to stably transmit the human beta-globin gene and a large LCR element, resulting in correction of beta-thalassemia intermedia in mice. Several groups have since demonstrated correction of the mouse thalassemia intermedia phenotype, with variable levels of beta-globin expression. These levels of expression were insufficient to fully correct the anemia in thalassemia major mouse model. Insertion of a chicken hypersensitive site-4 chicken insulator element (cHS4) in self-inactivating (SIN) LV vectors resulted in higher and less variable expression of human beta-globin, similar to the observations with cHS4-containing retroviral vectors carrying the human gamma-globin gene. The levels of beta-globin expression achieved from insulated SIN-LV vectors were sufficient to phenotypically correct the thalassemia phenotype from 4 patients with human thalassemia major in vitro, and this correction persisted long term for up to 4 months, in xeno-transplanted mice in vivo. In summary, LV vectors have paved the way for clinical gene therapy trials for Cooley's anemia and other beta-globin disorders. SIN-LV vectors address several safety concerns of randomly integrating viral vectors by removing viral transcriptional elements and providing lineage-restricted expression. Flanking the proviral cassette with chromatin insulator elements, which additionally have enhancer-blocking properties, may further improve SIN-LV vector safety.
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PMID:Gene Therapy for beta-thalassemia. 1630 58

The details of the molecular events regulating normal human hemoglobin switching and reactivation of fetal hemoglobin in adult hematopoietic cells are unclear. The potential role of sequences between the human gamma- and delta-globin genes (intergenic gamma-delta sequences) in this process has been in question until the recent finding that two patients homozygous for the Corfu deletion, involving the loss of 7.2 kb of the intergenic gamma-delta region upstream of the delta gene, have 88% and 90% fetal hemoglobin, only mild anemia, and no transfusion requirements. These results provide the first strong evidence in humans that the gamma-delta intergenic sequences alone have a role in the reactivation of fetal hemoglobin in adult-type cells, and perhaps are involved in normal hemoglobin switching as well. The polypyrimidine (PYR) complex is a hematopoietic cell-specific and stage-specific chromatin remodeling complex that binds upstream of the human delta-globin gene within the Corfu deletion. Deletion of the PYR binding site has been shown to delay human gamma-to-beta globin switching. The PYR complex is present in adult human hematopoietic cells and absent in fetal-embryonic cells: properties of a globin-switching complex. Taken together, the data from patients with the Corfu deletion and the PYR complex results suggest that intergenic gamma-delta sequences are involved in human gamma-to-beta globin switching and reactivation of fetal hemoglobin in adult cells.
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PMID:Role of intergenic human gamma-delta-globin sequences in human hemoglobin switching and reactivation of fetal hemoglobin in adult erythroid cells. 1633 51

Sickle cell disease results from the presence of abnormal beta globin chains within hemoglobin and may be manifested in anemia, vaso-occlusion, and superimposed infection. The gene that causes sickle cell disease is particularly prevalent in populations of African origin; approximately 8% of African Americans and 40% of the members of some African tribes carry the gene for hemoglobin S. Over time, the disease produces various musculoskeletal abnormalities as a result of chronic anemia; these include marrow hyperplasia, reversion of yellow marrow to red marrow, and, occasionally, extramedullary hematopoiesis. Familiarity with the imaging features of sickle cell disease is important for the diagnosis and management of complications. Ischemia and infarction are common complications that may have long-term effects on the growth of bone; these conditions have characteristic radiographic appearances. Infection may be more difficult to identify. Both infection and infarction may occur in muscle and soft tissue alone, without involving bone. However, osteomyelitis must be diagnosed early and treated immediately to prevent bone destruction and deformity; therefore, care must be taken to achieve an accurate diagnosis by identifying or excluding bone involvement. The clinical and radiographic features of acute osteomyelitis may be particularly difficult to distinguish from those of bone infarction. In that context, magnetic resonance (MR) imaging may be useful. At MR imaging, findings of cortical defects, adjacent fluid collections in soft tissue, and bone marrow enhancement are suggestive of infection.
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PMID:Musculoskeletal manifestations of sickle cell disease. 1762 Apr 64

Thalassemia is a hereditary anemia resulting from defect in hemoglobin production. Beta thalassemia is due to impaired production of beta globin chains, leading to a relative excess of alpha globin chains. The term beta thalassemia minor is used to describe heterozygotes, who carry one normal beta globin allele and one beta thalassemic allele. The vast majority of these patients are asymptomatic. However, a variety of renal tubular abnormalities including hypercalciuria, hypo-magnesemia with renal magnesium wasting, decreased tubular absorption of phosphorus, hypo-uricemia with renal uric acid wasting, renal glycosuria and tubular proteinuria have been described even in patients with beta thalassemia minor. We here in report a 24-year old female patient who was found to have thalassemia minor and nephrocalcinosis with evidence of renal tubular dysfunction. Investigations revealed normal renal function, hypercalciuria, reduced tubular reabsorption of phosphorus, hypomagnesemia and renal magnesium wasting. Screening for aminoaciduria was found to be negative. An acid loading test revealed normal urinary acidification. Ultrasonogram of the abdomen revealed nephrocalcinosis and splenomegaly. Detailed work up for anemia showed normal white cell and platelet count while peripheral smear showed microcytic hypochromic anemia with few target cells. Hemoglobin electrophoresis revealed hemoglobin A of 92%, hemoglobin A2 of 6.2% and hemo-globin F of 1.8% consistent with beta thalassemia minor. Her parental screening was normal. A diagnosis of beta thalassemia minor with renal tubular dysfunction was made and the patient was started on thiazide diuretics to reduce hypercalciuria and advised regular follow-up.
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PMID:Renal tubular dysfunction with nephrocalcinosis in a patient with beta thalassemia minor. 1897 85

Hereditary anemias show considerable variation in their clinical presentation. In some cases, the causes of these variations are easily apparent. In thalassemia (or in HbE/thalassemia), genetic variation is primarily caused by the severity of the thalassemia mutation. However, not uncommonly, there is variation unexplained by the globin gene mutations themselves, which may be caused by genetic modifiers. In sickle cell disease, the primary mutation is the same in all patients. Therefore, variations in disease severity generally are due to genetic modifiers. In most genetic diseases involving beta globin, the most clearcut influence on phenotype results from elevated fetal hemoglobin levels. In addition, alpha globin gene number can influence disease phenotype. In thalassemia major or intermedia, reduction in the number of alpha globin genes can ameliorate the disease phenotype; conversely, excess alpha globin genes can convert beta thalassemia trait to a clinical picture of thalassemia intermedia. In sickle cell disease, the number of alpha globin genes has both ameliorating and exacerbating effects, depending on which disease manifestation is being examined. Unlinked genetic factors have substantial effects on the phenotype of hereditary anemias, both on the anemia and other disease manifestations. Recently, studies using genome-wide techniques, particularly studying QTLs causing elevated HbF, or affecting HbE/thalassemia, have revealed other genetic elements whose mechanisms are under study. The elucidation of genetic modifiers will hopefully lead to more rational and effective management of these diseases.
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PMID:Genetic modifiers in hemoglobinopathies. 1899 46

A preclinical humanized mouse model of beta thalassemia major or Cooley anemia (CA) was generated by targeted gene replacement of the mouse adult globin genes in embryonic stem cells. The mouse adult alpha and beta globin genes were replaced with adult human alpha globin genes (alpha2alpha1) and a human fetal to adult hemoglobin (Hb)-switching cassette (gamma(HPFH)deltabeta(0)), respectively. Similar to human infants with CA, fully humanized mice survived postnatally by synthesizing predominantly human fetal Hb, HbF (alpha(2)gamma(2)), with a small amount of human minor adult Hb, HbA2 (alpha(2)delta(2)). Completion of the human fetal to adult Hb switch after birth resulted in severe anemia marked by erythroid hyperplasia, ineffective erythropoiesis, hemolysis, and death. Similar to human patients, CA mice were rescued from lethal anemia by regular blood transfusion. Transfusion corrected the anemia and effectively suppressed the ineffective erythropoiesis, but led to iron overload. This preclinical humanized animal model of CA will be useful for the development of new transfusion and iron chelation regimens, the study of iron homeostasis in disease, and testing of cellular and genetic therapies for the correction of thalassemia.
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PMID:Preclinical transfusion-dependent humanized mouse model of beta thalassemia major. 1925 91

Alpha hemoglobin stabilizing protein (AHSP) reversibly binds nascent alpha globin to maintain its native structure and facilitate its incorporation into hemoglobin A. Previous studies indicate that some naturally occurring human alpha globin mutations may destabilize the protein by inhibiting its interactions with AHSP. However, these mutations could also affect hemoglobin A production through AHSP-independent effects, including reduced binding to beta globin. We analyzed 6 human alpha globin variants with altered AHSP contact surfaces. Alpha globin amino acid substitutions H103Y, H103R, F117S, and P119S impaired interactions with both AHSP and beta globin. These mutations are destabilizing in biochemical assays and are associated with microcytosis and anemia in humans. By contrast, K99E and K99N alpha globins bind beta globin normally but exhibit attenuated binding to AHSP. These mutations impair protein folding and expression in vitro and appear to be mildly destabilizing in vivo. In Escherichia coli and erythroid cells, alpha globin K99E stability is rescued on coexpression with AHSP mutants in which binding to the abnormal globin chain is restored. Our results better define the biochemical properties of some alpha globin variants and support the hypothesis that AHSP promotes alpha globin chain stability during human erythropoiesis.
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PMID:Analysis of human alpha globin gene mutations that impair binding to the alpha hemoglobin stabilizing protein. 1934 19

Severe intrauterine anemia of unknown cause presents a diagnostic challenge. We describe a Norwegian case, managed successfully by intrauterine transfusions, that further investigations demonstrated to be due to a rare type of thalassemia. A deletion of the 5' end of the beta globin gene cluster was characterized, the breakpoints sequenced and a new type of epsilongammagammadeltabeta thalassemia identified. This case highlights the need to consider diagnoses of rare conditions not normally associated with a particular population.
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PMID:Severe intrauterine anemia: a new form of epsilongammagammadeltabeta thalassemia presenting in utero in a Norwegian family. 1954 34


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