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FEBS Letters Aug 1995The red cell membrane is comprised of a lipid bilayer studded with transmembrane proteins, and laminated by a protein network, the membrane skeleton, at the surface of... (Review)
Review
The red cell membrane is comprised of a lipid bilayer studded with transmembrane proteins, and laminated by a protein network, the membrane skeleton, at the surface of the inner monolayer. The erythrocyte owes its mechanical properties to the membrane skeleton. Hereditary spherocytosis, hereditary elliptocytosis or poikilocytosis, Southeast Asian ovalocytosis are hereditary hemolytic anemias, due to mutations in the genes encoding ankyrin, the anion exchanger, spectrin, protein 4.1 or protein 4.2, which are main proteins of the membrane. Recent advances in the field have led to fundamental questions.
Topics: Anemia, Hemolytic, Congenital; Blood Proteins; Cytoskeletal Proteins; Elliptocytosis, Hereditary; Erythrocyte Membrane; Membrane Proteins; Spherocytosis, Hereditary
PubMed: 7641880
DOI: 10.1016/0014-5793(95)00460-q -
Internal Medicine (Tokyo, Japan) Nov 1994We present findings in the ninth known Japanese family with lecithin:cholesterol acyltransferase (LCAT) deficiency. A 54-year-old man (proband) and his 58-year-old...
We present findings in the ninth known Japanese family with lecithin:cholesterol acyltransferase (LCAT) deficiency. A 54-year-old man (proband) and his 58-year-old brother presented with corneal opacity. Both subjects showed a marked decrease in serum high density lipoprotein (HDL)-cholesterol and in the cholesteryl ester ratio. Although apo A-I and A-II were low, apo E tended to be high. Serum LCAT activity and mass were not detectable. Urinary examination showed microhematuria or proteinuria. Renal function was normal and no anemia was demonstrated, but blood smears showed poikilocytosis with target cells. The serum LCAT activity of the proband's three sons, obligate heterozygotes of LCAT deficiency, was about one-half the normal level, and HDL-cholesterol and apo A-I levels were low normal.
Topics: Adult; Cholesterol, HDL; Corneal Opacity; Female; Heterozygote; Homozygote; Humans; Japan; Lecithin Cholesterol Acyltransferase Deficiency; Lipoproteins; Male; Middle Aged; Pedigree; Phosphatidylcholine-Sterol O-Acyltransferase
PubMed: 7849380
DOI: 10.2169/internalmedicine.33.677 -
Internal Medicine (Tokyo, Japan) Nov 1993Three subjects in a family with microcytic and hypochromic anemia were studied; red blood cell morphology indicated aniso-poikilocytosis and hypochromasia. Target and...
Three subjects in a family with microcytic and hypochromic anemia were studied; red blood cell morphology indicated aniso-poikilocytosis and hypochromasia. Target and tear-drop cells were also noted. In all three cases evaluated, there was an increase in HbA2 levels and a decline in the beta/alpha synthesis ratio. Direct cloning and DNA sequencing identified a point mutation (G-->T) at position 1 of intervening sequence I. The resulting reduction of beta-globin chain synthesis is considered to give rise to beta 0-thalassemia phenotype. This point mutation is to our knowledge, the first case in Japan.
Topics: Base Sequence; DNA; Female; Globins; Heterozygote; Humans; Introns; Japan; Male; Middle Aged; Molecular Sequence Data; Pedigree; Point Mutation; RNA Splicing; beta-Thalassemia
PubMed: 8012089
DOI: 10.2169/internalmedicine.32.865 -
Blood Sep 1993We present two Spanish children with hereditary elliptopoikilocytosis. The mother displayed a symptomless elliptocytosis. Spectrin maps showed the alpha I/50-46b...
We present two Spanish children with hereditary elliptopoikilocytosis. The mother displayed a symptomless elliptocytosis. Spectrin maps showed the alpha I/50-46b abnormality in the mother and in the children. The change was more conspicuous in the children than in the mother. The father carried the alpha V/41 allele, which is a common allele endowed with low expression. The alpha V/41 allele was also present in the children accounting for the much more severe expression of the alpha I/50-46b variant. The responsible mutation yielding the latter appeared to be the alpha 469 His-->Pro substitution (CAT-->CCT), which is a novel abnormality. The corresponding spectrin was designated spectrin Barcelona. As is often the case in hereditary elliptocytosis or poikilocytosis related to alpha-spectrin variants, the change involved a helix 3; namely, helix 3 of repeating segment alpha 5.
Topics: Alleles; Base Sequence; Child; Child, Preschool; Elliptocytosis, Hereditary; Exons; Family Health; Female; Heterozygote; Humans; Male; Molecular Sequence Data; Mutation; Pedigree; Spain; Spectrin
PubMed: 8364215
DOI: No ID Found -
Blood Sep 1993Hereditary pyropoikilocytosis (HPP) is a recessively inherited hemolytic anemia characterized by severe poikilocytosis and red blood cell fragmentation. HPP red blood...
Hereditary pyropoikilocytosis (HPP) is a recessively inherited hemolytic anemia characterized by severe poikilocytosis and red blood cell fragmentation. HPP red blood cells are partially deficient in spectrin and contain a mutant alpha or beta-spectrin that is defective in terms of spectrin self-association. Although the nature of the latter defect has been studied in considerable detail and many mutations of alpha-spectrin and beta spectrin have been identified, the molecular basis of spectrin deficiency is unknown. Here we report two mechanisms underlying spectrin deficiency in HPP. The first mechanism involves a thalassemia-like defect characterized by a reduced synthesis of alpha-spectrin as shown by studies involving synthesis of spectrin in two unrelated HPP probands and their parents: One parent carries the elliptocytogenic spectrin mutation, whereas the other parent is fully asymptomatic. Peripheral blood mononuclear cells as a source of erythroid burst-forming unit (BFUe) were cultured in a two-phase liquid culture system that gives rise to terminally differentiated erythroblasts. Pulse-labeling studies of an equal number of erythroblasts or morphologically identical maturity showed that the synthesis of alpha-spectrin as well as the mRNA levels as measured by the competitive polymerase chain reaction (PCR) method are markedly reduced in the presumed asymptomatic carriers and the HPP probands. In contrast, the synthesis and mRNA levels of beta-spectrin were normal. These results constitute a direct demonstration of an alpha-spectrin synthetic defect in a subset of asymptomatic carriers of HPP and HPP probands. The second mechanism underlying spectrin deficiency involves increased degradation of mutant spectrin before its assembly on the membrane. This is evidenced by pulse labeling studies of erythroblasts from a patient with HPP associated with a homozygous state for spectrin alpha I/46 mutation (leu-pro mutation at AA 207 of alpha-spectrin). These studies showed that although spectrin is synthesized in the cytosol in normal amounts, the rate of turnover of alpha-spectrin is faster resulting in about 40% to 50% reduced assembly of alpha-spectrin and beta-spectrin on the membrane. Thus, spectrin deficiency in this case is at least in part caused by increased susceptibility of the mutant spectrin to degradation before its assembly on the membrane. We conclude that at least two separate mechanisms underlie the molecular basis of spectrin deficiency in HPP.
Topics: Adolescent; Adult; Anemia, Hemolytic, Congenital; Base Sequence; Cells, Cultured; Erythroblasts; Erythrocytes; Erythrocytes, Abnormal; Female; Humans; Membrane Proteins; Molecular Sequence Data; Mutation; RNA, Messenger; Spectrin
PubMed: 8364214
DOI: No ID Found -
Journal of Veterinary Internal Medicine 1992The hematologic toxicity of doxorubicin, 30 mg/m2 body surface area (BSA) every 21 days to a cumulative dose of 300 mg/m2, was evaluated in six cats. Complete blood and...
The hematologic toxicity of doxorubicin, 30 mg/m2 body surface area (BSA) every 21 days to a cumulative dose of 300 mg/m2, was evaluated in six cats. Complete blood and platelet counts were performed daily during the first treatment cycle. They were monitored before treatment for all remaining cycles, and at the average neutrophil nadir (day 8) starting with cycle 4. Significant poikilocytosis developed after the first treatment and remained throughout the study, although anemia did not occur. No other red blood cell abnormalities were seen. Platelet counts remained within the reference range throughout the first treatment cycle, but mild thrombocytopenia (88,000-288,000/uL) was found in 11.3% of subsequent complete blood counts (CBCs). Thrombocytosis was seen in 30.9% of CBCs. Neutropenia did not occur during the first treatment cycle although neutrophil counts did decrease, with the nadir occurring between days 8 and 11. All neutrophil counts returned to pretreatment values by day 14. Neutropenia was documented after 14 of 46 (30.4%) doxorubicin treatments, and was associated with fever in 5 cats (10.9%). All fevers responded to oral antibiotic therapy. Neutropenia that lasted more than 14 days developed in two cats, necessitating dosage reduction to 25 mg/m2 BSA. At the dose used in this study, doxorubicin administration was associated with acceptable hematologic toxicosis in most cats.
Topics: Animals; Blood Platelets; Cat Diseases; Cats; Doxorubicin; Erythrocytes; Female; Leukocyte Count; Male; Neutropenia; Neutrophils; Platelet Count; Thrombocytopenia
PubMed: 1432901
DOI: 10.1111/j.1939-1676.1992.tb00352.x -
British Journal of Sports Medicine Dec 1991Intravascular haemolysis has been found to result from prolonged endurance competition, rigorous military training and participation in impact sports. Haematological...
Intravascular haemolysis has been found to result from prolonged endurance competition, rigorous military training and participation in impact sports. Haematological research involving the recreational runner is sparse. Recreational runners frequently vary their training to avoid monotony and improve endurance capacity. This study investigated the haematological effects of a typical day of increased distance training in 15 male recreational runners (62.4(3.1) ml kg-1 min-1 treadmill VO2max; 44.6(8.4) km per week training (means(s.d.)). Venous blood samples were collected before, immediately after, 1 day, 4 days, and 10 days after a 13-km training run (about twice the subjects' typical running distance) and analysed for changes in bilirubin, serum potassium, haematocrit, haemoglobin, red blood cell count, haptoglobin, poikilocytosis and reticulocytosis. Urine samples were collected at the same times as the blood samples and analysed for urobilinogen. Significant (P less than 0.05) 1-day and 4-day decreases in mean haemoglobin, red blood cell count, and haptoglobin values, compared to before training venous blood values and significant (P less than 0.05) post-training increases in bilirubin, serum potassium, urobilinogen and poikilocytosis provided evidence for increased intravascular haemolysis. After 10 days the values for haematocrit, bilirubin, serum potassium, red blood cell count, urobilinogen and poikilocytosis were not significantly (P less than 0.05) different from pre-training values while haemoglobin remained significantly (P less than 0.05) lower, exhibiting a constant but not significant increase over the period from 1 to 10 days. The results indicate that mild intravascular 'footstrike' haemolysis can occur in the recreational runner when typical training distance is increased. This condition appears to be transient and benign.
Topics: Anemia; Exercise Test; Hemolysis; Humans; Male; Oxygen Consumption; Physical Endurance; Running; Urinalysis
PubMed: 1810610
DOI: 10.1136/bjsm.25.4.183 -
The Journal of Clinical Investigation Sep 1990alpha I/74 hereditary elliptocytosis (HE) is a subgroup of HE in which patients exhibit an impaired self-association of spectrin dimers and an abnormal proteolytic...
alpha I/74 hereditary elliptocytosis (HE) is a subgroup of HE in which patients exhibit an impaired self-association of spectrin dimers and an abnormal proteolytic cleavage of the alpha I domain of spectrin. We studied a family in which the proband presented with a severe neonatal hemolytic anemia with poikilocytosis. Biochemical analysis of erythrocytes from the proband and his family members allowed us to ascertain a diagnosis of homozygosity for alpha I/74 HE in the proband and heterozygosity in his parents and several of their offspring. Results of polymorphism linkage analysis suggested that the defect in this family was located in beta rather than alpha spectrin. We analyzed the 3' end of the beta-spectrin gene of the proband and detected a mutation that changes a codon for alanine to one for proline. Allele-specific oligomer hybridization on slot blots of DNA from other family members confirmed the presence of the mutation only in members heterozygous for the disorder. This is the first example of a point mutation in the beta-spectrin chain that is associated with defective spectrin dimer self-association and an abnormal proteolytic cleavage of the alpha chain. Based on this finding, we propose a model for the mechanism of interaction between the alpha- and beta-spectrin chains.
Topics: Amino Acid Sequence; Base Sequence; Electrophoresis, Gel, Two-Dimensional; Elliptocytosis, Hereditary; Genetic Linkage; Humans; Macromolecular Substances; Molecular Sequence Data; Mutation; Oligonucleotides; Pedigree; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Protein Conformation; Restriction Mapping; Spectrin
PubMed: 1975598
DOI: 10.1172/JCI114792 -
Japanese Journal of Medicine 1990We studied a patient with severe anemia and jaundice who exhibited a high hemoglobin A1 (HbA1) level secondary to an increase in HbF despite normal glucose tolerance....
We studied a patient with severe anemia and jaundice who exhibited a high hemoglobin A1 (HbA1) level secondary to an increase in HbF despite normal glucose tolerance. The red blood cells showed anisocytosis, poikilocytosis and polychromasia; target cells, Howell-Jolly bodies, Heints bodies and punctate basophilia were observed. No defect or reduction in activity was observed in 19 red cell enzymes. A family history of similar anemia in the patient's daughter and cousins on the mother's side indicated an involvement of genetic factors. Gene cloning and DNA analysis showed that the condition is a new type of beta 0-thalassemia caused by a nonsense mutation (GAG----TAG) in codon 90 of the beta-globin gene.
Topics: Adult; Base Composition; Base Sequence; Codon; Erythrocytes; Female; Globins; Hemoglobin A; Humans; Jaundice; Male; Molecular Sequence Data; Mutation; Pedigree; Thalassemia
PubMed: 2214342
DOI: 10.2169/internalmedicine1962.29.2