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Narla Mohandas - One of the best experts on this subject based on the ideXlab platform.
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hereditary spherocytosis Elliptocytosis and other red cell membrane disorders
Blood Reviews, 2013Co-Authors: Lydie Da Costa, Julie Galimand, Odile Fenneteau, Narla MohandasAbstract:Hereditary spherocytosis and Elliptocytosis are the two most common inherited red cell membrane disorders resulting from mutations in genes encoding various red cell membrane and skeletal proteins. Red cell membrane, a composite structure composed of lipid bilayer linked to spectrin-based membrane skeleton is responsible for the unique features of flexibility and mechanical stability of the cell. Defects in various proteins involved in linking the lipid bilayer to membrane skeleton result in loss in membrane cohesion leading to surface area loss and hereditary spherocytosis while defects in proteins involved in lateral interactions of the spectrin-based skeleton lead to decreased mechanical stability, membrane fragmentation and hereditary Elliptocytosis. The disease severity is primarily dependent on the extent of membrane surface area loss. Both these diseases can be readily diagnosed by various laboratory approaches that include red blood cell cytology, flow cytometry, ektacytometry, electrophoresis of the red cell membrane proteins, and mutational analysis of gene encoding red cell membrane proteins.
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canine Elliptocytosis due to a mutant β spectrin
Veterinary Clinical Pathology, 2009Co-Authors: Roberta Di Terlizzi, Patrick G. Gallagher, Narla Mohandas, Laurie A. Steiner, Karen S. Dolce, Xinhua Guo, Melinda J. Wilkerson, Steven L. StockhamAbstract:A 5-year-old, spayed female, mixed-breed dog with persistent Elliptocytosis was evaluated at the Veterinary Medical Teaching Hospital at Kansas State University. The Elliptocytosis was asymptomatic and was detected during the evaluation of lameness. When subjected to shear stress in an ektacytometer, the dog's erythrocytes had reduced cellular deformability and erythrocyte membranes had decreased mechanical stability. Analysis of erythrocyte membrane spectrin by nondenaturing gel electrophoresis revealed an increased amount of spectrin dimers, indicating a defect in spectrin self-association. DNA analysis detected a beta-spectrin mutation in codon 2110 in which threonine was replaced by methionine. This mutation likely altered the molecular structure of the erythrocyte membrane, leading to impaired spectrin self-association and elliptocyte formation.
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Canine Elliptocytosis due to a mutant β‐spectrin
Veterinary clinical pathology, 2008Co-Authors: Roberta Di Terlizzi, Patrick G. Gallagher, Narla Mohandas, Laurie A. Steiner, Karen S. Dolce, Xinhua Guo, Melinda J. Wilkerson, Steven L. StockhamAbstract:A 5-year-old, spayed female, mixed-breed dog with persistent Elliptocytosis was evaluated at the Veterinary Medical Teaching Hospital at Kansas State University. The Elliptocytosis was asymptomatic and was detected during the evaluation of lameness. When subjected to shear stress in an ektacytometer, the dog's erythrocytes had reduced cellular deformability and erythrocyte membranes had decreased mechanical stability. Analysis of erythrocyte membrane spectrin by nondenaturing gel electrophoresis revealed an increased amount of spectrin dimers, indicating a defect in spectrin self-association. DNA analysis detected a beta-spectrin mutation in codon 2110 in which threonine was replaced by methionine. This mutation likely altered the molecular structure of the erythrocyte membrane, leading to impaired spectrin self-association and elliptocyte formation.
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disorders of red cell membrane
British Journal of Haematology, 2008Co-Authors: Xiuli An, Narla MohandasAbstract:Studies during the last three decades have enabled the development of detailed molecular insights into the structural basis of altered function in various inherited red cell membrane disorders. This review highlights our current understanding of molecular and mechanistic insights into various inherited red cell membrane disorders involving either altered membrane structural organization (hereditary spherocytosis, hereditary Elliptocytosis and hereditary ovalocytosis) or altered membrane transport function (hereditary stomatocytosis). The molecular basis for the vast majority of cases of hereditary spherocytosis, Elliptocytosis and ovalocytosis have been fully defined while little progress has been made in defining the molecular basis for hereditary stomatocytosis. Mutations in a number of distinct genes account for hereditary spherocytosis and Elliptocytosis, while a single genetic defect accounts for all cases of hereditary ovalocytosis. Based on these molecular insights, a comprehensive understanding of the structural basis for altered membrane function has been developed. Loss of vertical linkage between membrane skeleton and lipid bilayer leads to membrane loss in hereditary spherocytosis, while weakening of lateral linkages between skeletal proteins leads to membrane fragmentation and surface area loss in hereditary Elliptocytosis. Importantly, the severity of anaemia in both these disorders is directly related to extent of membrane surface area loss. Splenectomy results in amelioration of anaemia.
Didier Dhermy - One of the best experts on this subject based on the ideXlab platform.
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Spectrin-based skeleton in red blood cells and malaria.
Current Opinion in Hematology, 2007Co-Authors: Didier Dhermy, Joseph Schrével, Marie-christine LecomteAbstract:PURPOSE OF REVIEW: Malaria represents one of the most important selective factors affecting human populations. Several inherited diseases of red blood cells lead to resistance at the erythrocytic stage. Among patients who experience hereditary Elliptocytosis related to mutations of erythrocyte membrane proteins, molecular studies have shown the prevalence of particular spectrin mutations in patients from black ethnic extraction, leading one to question the selection of new malaria-resistant genes. RECENT FINDINGS: Prospective epidemiological and molecular studies in West Africa have confirmed the prevalence (between 0.6 and 1.6%) of particular spectrin mutations related to hereditary Elliptocytosis. These studies have also revealed the frequency of alpha-spectrin chain polymorphisms, associated in cis with elliptocytogenic spectrin mutations and defining particular spectrin allele haplotypes. Culture studies of Plasmodium falciparum in elliptocytes bearing such elliptocytogenic alleles of spectrin showed that these alleles are supplementary genetic factors of malaria resistance in vitro. SUMMARY: Certain instances of spectrin mutations or polymorphisms have not yet been shown to constitute new factors of innate resistance to malaria in vivo. Epidemiological surveys of hereditary Elliptocytosis and parasite culture studies, however, have argued that the relationships between parasite and spectrin-based skeleton should be examined more closely and the molecular interactions between parasite ligands and particular spectrin chain domains should be characterized.
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Coinheritance of α- and β-Spectrin Gene Mutations in a Case of Hereditary Elliptocytosis
Blood, 1998Co-Authors: Didier Dhermy, Odile Bournier, Colette Galand, May-jean King, Thérèse Cynober, Irene Roberts, Frederick Kanyike, Adekunle AdekileAbstract:To the Editor: Many mutations in the α- and β-spectrin genes are known to be associated with hereditary Elliptocytosis (HE). Spectrin abnormalities are detected as abnormal peptides after limited trypsin digestion of spectrin (Sp).[1][1] We had an opportunity to study a Filipino family living in
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A variant of spectrin low-expression allele αLELYcarrying a hereditary Elliptocytosis mutation in codon 28
British journal of haematology, 1994Co-Authors: J. Randon, J Maréchal, Didier Dhermy, M. Garbarz, L Boulanger, A. Vallier, Leticia Ribeiro, Gabriel Tamagnini, J. DelaunayAbstract:Allele alpha LELY is a low-expression allele of the erythroid spectrin alpha-gene. It carries mutations in exon 40 (alpha V/41 polymorphism) and intron 45, respectively, and is associated with partial skipping of exon 46. The latter phenomenon is thought to impair the recruitment of alpha-chains by beta-chains, and would eventually account for the low-expression character. When it occurs in trans to an alpha-allele responsible for hereditary Elliptocytosis (alpha HE allele; alpha HE/alpha LELY diplotype), allele alpha LELY enhances the severity of Elliptocytosis. Because allele alpha LELY is widespread, we anticipated that it would occasionally carry HE determinants. These variants of allele alpha LELY will be designated alpha HE-LELY allele. The HE component was the known alpha 28 Arg-->His mutation. This alpha HE-LELY allele was investigated within the alpha HE-LELY/alpha LELY diplotype, a diplotype not described before. Except for the neonatal period, the presentation was mild. In a consistent manner, the alpha LELY component in cis of the alpha HE mutation counteracted the like component in trans.
Jiri Palek - One of the best experts on this subject based on the ideXlab platform.
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Defective spectrin dimer-dimer as, hereditary Elliptocytosis (spectrin transformation/membrane skeleton)
2016Co-Authors: Shih-chun Liu, Jiri Palek, J PrchalAbstract:We examined erythrocytes from 18 patients with hereditary Elliptocytosis. Spectrin from eight patients (referred to as type 1) was defective in dimer-dimer association as dem- onstrated in two ways. First, there was an increased amount of spectrin dimer with a concomitant decrease in tetramer as mea- sured in erythrocyte membrane preparations extracted at 0?C under low-salt conditions (the amount of spectrin dimer was 15-33% of total spectrin species compared with a normal range of 3-7%). Second, the equilibrium constants of spectrin dimer- dimer association were decreased in both solution and in situ mem- brane. Spectrin from the remaining 10 patients (referred to as type 2) showed normal dimer-dimer association. Membrane skeletons, produced from ghosts of both types of hereditary Elliptocytosis by Triton X-100 extraction, were unstable when mechanically shaken. Because spectrin tetramers, but not dimers, can crosslink actin, we postulate that the defective spectrin dimer-dimer association in type 1 diminishes actin crosslinking and thus is responsible for membrane skeletal instability. A defective protein-protein asso- ciation in type 2, however, remains to be identified.
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β spectrinPRAGUE : a truncated β spectrin producing spectrin deficiency, defective spectrin heterodimer self-association and a phenotype of spherocytic Elliptocytosis
British journal of haematology, 1995Co-Authors: Petr Jarolim, H Wichterle, Manjit Hanspal, J. Murray, H. L. Rubin, Jiri PalekAbstract:Spherocytic Elliptocytosis is a phenotypic hybrid between hereditary spherocytosis (HS) and hereditary Elliptocytosis (HE) characterized by the presence of spheroovalocytes and spherocytes which exhibit increased osmotic fragility, indicating a deficiency of surface area. Both the spherocytic red cell morphology and the increased osmotic fragility distinguish this clinical entity from common HE. In contrast to common HE, the molecular basis of spherocytic Elliptocytosis is unknown. Here we describe two members of a family who both have the characteristic features of spherocytic HE. We show that the underlying defect involves a G to C transversion at the -1 position of the acceptor splice site upstream of exon X of beta spectrin leading to skipping of exon X from the mutant beta spectrin mRNA allele. The mutant mRNA is present in reticulocytes in similar amounts as the normal mRNA. Pulse-labelling of erythroblasts prepared from peripheral blood in a two-phase liquid-culture system reveals a decreased synthesis of the truncated beta spectrin, a finding which is likely to underlie the moderately severe spectrin deficiency in the two patients. In addition, this mutant spectrin, similar to the previously reported spectrins, is defective in spectrin heterodimer self-association. The spectrin deficiency, which represents a common finding in the majority of patients with HS, together with weakened spectrin heterodimer self-association, as found in the majority of patients with common HE, provides a molecular explanation for the phenotype of spherocytic Elliptocytosis in this kindred and, most likely, in other patients carrying similar beta spectrin mutations.
Marie-christine Lecomte - One of the best experts on this subject based on the ideXlab platform.
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Spectrin-based skeleton in red blood cells and malaria.
Current Opinion in Hematology, 2007Co-Authors: Didier Dhermy, Joseph Schrével, Marie-christine LecomteAbstract:PURPOSE OF REVIEW: Malaria represents one of the most important selective factors affecting human populations. Several inherited diseases of red blood cells lead to resistance at the erythrocytic stage. Among patients who experience hereditary Elliptocytosis related to mutations of erythrocyte membrane proteins, molecular studies have shown the prevalence of particular spectrin mutations in patients from black ethnic extraction, leading one to question the selection of new malaria-resistant genes. RECENT FINDINGS: Prospective epidemiological and molecular studies in West Africa have confirmed the prevalence (between 0.6 and 1.6%) of particular spectrin mutations related to hereditary Elliptocytosis. These studies have also revealed the frequency of alpha-spectrin chain polymorphisms, associated in cis with elliptocytogenic spectrin mutations and defining particular spectrin allele haplotypes. Culture studies of Plasmodium falciparum in elliptocytes bearing such elliptocytogenic alleles of spectrin showed that these alleles are supplementary genetic factors of malaria resistance in vitro. SUMMARY: Certain instances of spectrin mutations or polymorphisms have not yet been shown to constitute new factors of innate resistance to malaria in vivo. Epidemiological surveys of hereditary Elliptocytosis and parasite culture studies, however, have argued that the relationships between parasite and spectrin-based skeleton should be examined more closely and the molecular interactions between parasite ligands and particular spectrin chain domains should be characterized.
J Maréchal - One of the best experts on this subject based on the ideXlab platform.
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A variant of spectrin low-expression allele αLELYcarrying a hereditary Elliptocytosis mutation in codon 28
British journal of haematology, 1994Co-Authors: J. Randon, J Maréchal, Didier Dhermy, M. Garbarz, L Boulanger, A. Vallier, Leticia Ribeiro, Gabriel Tamagnini, J. DelaunayAbstract:Allele alpha LELY is a low-expression allele of the erythroid spectrin alpha-gene. It carries mutations in exon 40 (alpha V/41 polymorphism) and intron 45, respectively, and is associated with partial skipping of exon 46. The latter phenomenon is thought to impair the recruitment of alpha-chains by beta-chains, and would eventually account for the low-expression character. When it occurs in trans to an alpha-allele responsible for hereditary Elliptocytosis (alpha HE allele; alpha HE/alpha LELY diplotype), allele alpha LELY enhances the severity of Elliptocytosis. Because allele alpha LELY is widespread, we anticipated that it would occasionally carry HE determinants. These variants of allele alpha LELY will be designated alpha HE-LELY allele. The HE component was the known alpha 28 Arg-->His mutation. This alpha HE-LELY allele was investigated within the alpha HE-LELY/alpha LELY diplotype, a diplotype not described before. Except for the neonatal period, the presentation was mild. In a consistent manner, the alpha LELY component in cis of the alpha HE mutation counteracted the like component in trans.
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Spectrin Jendouba: an alpha II/31 spectrin variant that is associated with Elliptocytosis and carries a mutation distant from the dimer self- association site
Blood, 1992Co-Authors: N Alloisio, R Wilmotte, L Morlé, F Baklouti, J Maréchal, Mt Ducluzeau, L Denoroy, C Féo, Bg Forget, R KastallyAbstract:Spectrin Jendouba (alpha II/31) was found in a Tunisian family. In the heterozygous state, it is associated with asymptomatic Elliptocytosis and a minimal defect in spectrin dimer self-association. On partial digestion of spectrin with trypsin, an abnormal cleavage appeared following Lys 788. Peptide and DNA sequencing indicated that the responsible mutation is alpha 791 Asp----Glu (GAC----GAA). As in most alpha-spectrin variants associated with Elliptocytosis, the change alters helix 3 of the proposed triple helical model of spectrin structure. Modified helix 3 in repeat alpha 8 is the most distant from the N-terminus of alpha-spectrin in known variants associated with Elliptocytosis.
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spectrin jendouba an alpha ii 31 spectrin variant that is associated with Elliptocytosis and carries a mutation distant from the dimer self association site
Blood, 1992Co-Authors: N Alloisio, R Wilmotte, L Morlé, F Baklouti, J Maréchal, Mt Ducluzeau, L Denoroy, C Féo, Bg Forget, R KastallyAbstract:Spectrin Jendouba (alpha II/31) was found in a Tunisian family. In the heterozygous state, it is associated with asymptomatic Elliptocytosis and a minimal defect in spectrin dimer self-association. On partial digestion of spectrin with trypsin, an abnormal cleavage appeared following Lys 788. Peptide and DNA sequencing indicated that the responsible mutation is alpha 791 Asp----Glu (GAC----GAA). As in most alpha-spectrin variants associated with Elliptocytosis, the change alters helix 3 of the proposed triple helical model of spectrin structure. Modified helix 3 in repeat alpha 8 is the most distant from the N-terminus of alpha-spectrin in known variants associated with Elliptocytosis.
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sp alpha v 41 a common spectrin polymorphism at the alpha iv alpha v domain junction relevance to the expression level of hereditary Elliptocytosis due to alpha spectrin variants located in trans
Journal of Clinical Investigation, 1991Co-Authors: N Alloisio, L Morlé, J Maréchal, Mt Ducluzeau, A F Roux, D Guetarni, B Pothier, F Baklouti, A Ghanem, R KastallyAbstract:Spectrin alpha-chain mutants associated with hereditary Elliptocytosis are highly variable in their level of expression. It has been assumed that the degree of Elliptocytosis can be increased when the spectrin alpha chain, encoded by the alpha gene in trans to the variant, is expressed at a low level. We now provide strong evidence for the existence of low-level expression of spectrin alpha chains. This condition is referred to as the alpha V/41 polymorphism. It has been observed in 15 different families or individuals of French, North African, and African ancestry in which seven distinct elliptocytogenic alpha-spectrin variants were co-inherited. Whenever the alpha V/41 polymorphism was present, the severity of the biochemical, morphological, and, sometimes, the clinical phenotype of Elliptocytosis was increased. The alpha V/41 polymorphism was also frequently encountered among 36 unrelated control subjects in the heterozygous or homozygous states, and was entirely asymptomatic in both cases. The main biochemical feature was an increased susceptibility to proteolysis of the alpha IV-alpha V domain junction. Alteration of the facing beta IV domain of spectrin was demonstrated by in vitro spectrin dimer reconstitution experiments. It appears that the alpha V/41 polymorphism is often required for alpha-spectrin elliptocytogenic variants to become manifest in the heterozygous state. Thus, alpha-spectrin-related Elliptocytosis may be viewed as a bifactorial condition.