Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0024530 (malaria)
44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two recently published reports have described findings which will have a profound impact on the understanding of molecular mechanisms of human resistance to malaria infection. In Melanesian ovalocytosis, a genetic polymorphism found in Papua New Guinea and parts of South East Asia, the red cells are highly resistant to invasion by various species of malaria parasite. The molecular nature of the defect in ovalocytic erythrocytes was not known. Recent reports by Liu et al. (Liu, S.-C., Zhai, S., Palek, J., Golan, D., Amato, D., Hassan, K., Nurse, G., Babona, D., Coetzer, T., Jarolim, P. Zaik, M. and Borwein, S. (1990) N. Engl. J. Med. 323, 1530-1538.) and Jones et al. (Jones, G.L., Edmundson, H.M., Wesche, D. and Saul, A. (1991) Biochim. Biophys. Acta 1096, 33-40.) have now identified the abnormality in the band 3 protein of ovalocytic red cell membranes. A major discovery in the Jones et al. study is the presence of an extended peptide at the N-terminus of ovalocyte band 3 protein. This novel 13 amino acid extended sequence is not found in the primary structure of normal band 3 protein and was suggested to be the cause of band 3 defect in ovalocytes. We have analyzed this extended sequence through Genbank using SWISS-PROT database and found that an almost identical sequence exists in a malaria parasite protein called RESA.
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PMID:Malaria and ovalocytosis--molecular mimicry? 201

Southeast Asian ovalocytosis (SAO) is an asymptomatic trait characterized by rigid, poorly deformable red cells that resist invasion by several strains of malaria parasites. The underlying molecular genetic defect involves simple heterozygous state for a mutant band 3 protein, which contains a deletion of amino acids 400 through 408, linked with a Lys 56-to-Glu substitution (band 3-Memphis polymorphism). To elucidate the contribution of the mutant SAO band 3 protein to increased SAO red blood cell (RBC) rigidity, we examined the participation of the mutant SAO band 3 protein in increased band 3 attachment to the skeleton and band 3 oligomerization. We found first that SAO RBC skeletons retained more band 3 than normal cells and that this increased retention preferentially involved the mutant SAO band 3 protein. Second, SAO RBCs contained a higher percentage of band 3 oligomer-ankyrin complexes than normal cells, and these oligomers were preferentially enriched by the mutant SAO protein. At the ultrastructural level, the increased oligomer formation of SAO RBCs was reflected by stacking of band 3-containing intramembrane particles (IMP) into longitudinal strands. The IMP stacking was not reversed by treating SAO RBCs in alkaline pH (pH 11), which is known to weaken ankyrin-band 3 interactions, or by removing the cytoplasmic domain of band 3 from SAO membranes with trypsin. Finally, we found that band 3 protein in intact SAO RBCs exhibited a markedly decreased rotational mobility, presumably reflecting the increased oligomerization and the membrane skeletal association of the SAO band 3 protein. We propose that the mutant SAO band 3 has an increased propensity to form oligomers, which appear as longitudinal strands of IMP and exhibit increased association with membrane skeleton. This band 3 oligomerization underlies the increase in membrane rigidity by precluding membrane skeletal extension, which is necessary for membrane deformation.
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PMID:Molecular basis of altered red blood cell membrane properties in Southeast Asian ovalocytosis: role of the mutant band 3 protein in band 3 oligomerization and retention by the membrane skeleton. 779 44

Southeast Asian ovalocytosis (SAO) is a hereditary form of elliptocytosis resulting in rigid, oval-shaped erythrocytes resistant to invasion by malaria parasites. The molecular defect is due to deletion of codons 400-408, encoding a 9-amino-acid sequence located at the boundary between the cytosol and the first transmembrane segment in Band 3, the erythrocyte anion transport protein. We have carried out an extensive characterization of Band 3 isolated from SAO erythrocytes which contain about 50% mutant Band 3. A slightly higher proportion of Band 3 in SAO erythrocytes was left associated with the cytoskeleton after extraction of ghost membranes with non-ionic detergents. Size exclusion high performance liquid chromatography analysis showed that SAO Band 3 contained a higher proportion of tetramers relative to dimers (50% tetramer) than normal Band 3 (33% tetramer). The circular dichroism spectrum of Band 3 from SAO erythrocytes was very similar to the spectrum for normal Band 3. Enzymatic deglycosylation and tomato lectin binding showed that SAO Band 3 lacked the polylactosaminyl oligosaccharide found on normal Band 3. SAO Band 3 was unable to bind the anion transport inhibitor 4-benzamido-4'-aminostilbene-2,2'-disulfonate, suggesting a dramatic alteration in the inhibitor binding site. In conclusion, deletion of 9 amino acids from Band 3 on the cytosolic side of the membrane affects the properties (glycosylation and inhibitor binding) of Band 3 on the opposite side of the membrane without dramatic changes in the secondary and quaternary structure of the protein.
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PMID:Molecular characterization of the band 3 protein from Southeast Asian ovalocytes. 848 16

This review discusses recent advances in our understanding of the structure, function and molecular genetics of the membrane domain of red cell anion exchanger, band 3 (AE1), and its role in red cell and kidney disease. A new model for the topology of band 3 has been proposed, which suggests the membrane domain has 12 membrane spans, rather than the 14 membrane spans of earlier models. The major difference between the models is in the topology of the region on the C-terminal side of membrane spans 1-7. Two dimensional crystals of the deglycosylated membrane domain of band 3 have yielded two and three dimensional projection maps of the membrane domain dimer at low resolution. The human band 3 gene has been completely sequenced and this has facilitated the study of natural band 3 mutations and their involvement in disease. About 20% of hereditary spherocytosis cases arise from heterozygosity for band 3 mutations, and result in the absence or decrease of the mutant protein in the red cell membrane. Several other natural band 3 mutations are known that appear to be clinically benign, but alter red cell phenotype or are associated with altered red cell blood group antigens. These include the mutant band 3 present in Southeast Asian ovalocytosis, a condition which provides protection against cerebral malaria in children. Familial distal renal tubular acidosis, a condition associated with kidney stones, has been shown to result from a novel group of band 3 mutations. The total absence of band 3 has been described in animals-occurring naturally in cattle and after targeted disruption in mice. Some of these severely anaemic animals survive, so band 3 is not strictly essential for life. Although the band 3-negative red cells were very unstable, they contained a normally-assembled red cell skeleton, suggesting that the bilayer of the normal red cell membrane is stabilized by band 3 interactions with membrane lipids, rather than by interactions with the spectrin skeleton.
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PMID:The structure and function of band 3 (AE1): recent developments (review). 949 67

Southeast Asian ovalocytosis (SAO) occurs at high frequency in malarious regions of the western Pacific and may afford a survival advantage against malaria. It is caused by a deletion of the erythrocyte membrane band 3 gene and the band 3 protein mediates the cytoadherence of parasitized erythrocytes in vitro. The SAO band 3 variant may prevent cerebral malaria but it exacerbates malaria anemia and may also increase acidosis, a major determinant of mortality in malaria. We undertook a case-control study of children admitted to hospital in a malarious region of Papua New Guinea. The SAO band 3, detected by the polymerase chain reaction, was present in 0 of 68 children with cerebral malaria compared with six (8.8%) of 68 matched community controls (odds ratio = 0, 95% confidence interval = 0-0.85). Median hemoglobin levels were 1.2 g/dl lower in malaria cases with SAO than in controls (P = 0.035) but acidosis was not affected. The remarkable protection that SAO band 3 affords against cerebral malaria may offer a valuable approach to a better understanding of the mechanisms of adherence of parasitized erythrocytes to vascular endothelium, and thus of the pathogenesis of cerebral malaria.
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PMID:Prevention of cerebral malaria in children in Papua New Guinea by southeast Asian ovalocytosis band 3. 1040 43

Erythrocyte polymorphisms, including ovalocytosis, have been associated with protection against malaria. This study in the Wosera, a malaria holoendemic region of Papua New Guinea, examined the genetic basis of ovalocytosis and its influence on susceptibility to malaria infection. Whereas previous studies showed significant associations between Southeast Asian ovalocytosis (caused by a 27- base pair deletion in the anion exchanger 1 protein gene) and protection from cerebral malaria, this mutation was observed in only 1 of 1019 individuals in the Wosera. Polymerase chain reaction strategies were developed to genotype individuals for the glycophorin C exon 3 deletion associated with Melanesian Gerbich negativity (GPCDeltaex3). This polymorphism was commonly observed in the study population (GPCDeltaex3 frequency = 0.465, n = 742). Although GPCDeltaex3 was significantly associated with increased ovalocytosis, it was not associated with differences in either Plasmodium falciparum or P vivax infection measured over the 7-month study period. Future case-control studies will determine if GPCDeltaex3 reduces susceptibility to malaria morbidity.
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PMID:The association of the glycophorin C exon 3 deletion with ovalocytosis and malaria susceptibility in the Wosera, Papua New Guinea. 1171 95

Distribution of a 27-bp deletion in the band 3 gene (B3Delta27) that causes Southeast Asian/Melanesian ovalocytosis has scarcely been studied in remote insular Southeast Asia and New Guinea. Here the presence of the B3Delta27 was surveyed among a total of 756 subjects from the indigenous populations inhabiting New Guinean islands and remote insular Southeast Asia by using a polymerase chain reaction method. In remote insular Southeast Asia where Austronesian-speaking peoples inhabit, the B3Delta27 frequency ranged between 0.04 and 0.15. In New Guinea Island, hinterland or Papuan groups showed the absence of the B3Delta27 or a very low gene frequency (0.01 in the Gidra) of the B3Delta27. However, groups of the coastal regions (Asmat, Sorong, and others) and of the nearby islands (Biak and Manus) where Austronesian infiltration had occurred showed substantial frequencies of the deletion (0.02-0.09). It is likely that the B3Delta27 was introduced into this region about 3,500 years ago with the arrival of Austronesian-speaking peoples. Once being introduced, the B3Delta27 may have been selected because of its resistance against malaria, while founder effect and genetic drift might have occurred in the New Guinean tribes with small population size, which helped to generate a variety of the B3Delta27 frequencies.
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PMID:Distribution of a 27-bp deletion in the band 3 gene in South Pacific islanders. 1461 18

Southeast Asian ovalocytosis (SAO) is a red blood cell abnormality common in malaria-endemic regions and caused by a 27 nt deletion of the band 3 protein gene. Since band 3 protein, also known as anion exchanger 1, is expressed in renal distal tubules, the incidence of SAO was examined in distal renal tubular acidosis (dRTA) in Malays in Kelantan, Malaysia. Twenty-two patients with dRTA and 50 healthy volunteers were examined for complication of SAO by both morphological and genetic analyses. SAO was identified in 18 of the 22 dRTA patients (81.8%), but only two of the 50 controls (4%). The incidence of SAO was significantly high in those with dRTA (p<0.001), indicating a dysfunctional role for band 3 protein/anion exchanger 1 in the development of dRTA.
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PMID:High prevalence of Southeast Asian ovalocytosis in Malays with distal renal tubular acidosis. 1461 20

The geographic overlap between the prevalence of erythrocyte polymorphisms and malaria endemicity is thought to be an example of natural selection on human populations. In Papua New Guinea (PNG), the Gerbich-negative phenotype is caused by an exon 3 deletion in the glycophorin C gene (GYPCDeltaex3) while heterozygosity for a 27-base pair deletion in the SLC4A1 gene (anion exchanger 1 or erythrocyte membrane protein, band 3), SLC4A1Delta27, results in Southeast Asian ovalocytosis. Two geographically and ethnically distinct malaria endemic regions of PNG (the Wosera [East Sepik Province] and Liksul [Madang Province]) were studied to illustrate the distribution of two prominent deletion polymorphisms (GYPCDeltaex3 and SLC4A1Delta27) and to determine if the genetic load associated with SLC4A1Delta27 would constrain independent assortment of GYPCDeltaex3 heterozygous and homozygous genotypes. The frequency of the GYPCDeltaex3 allele was higher in the Wosera (0.463) than Liksul (0.176) (chi(2); P < 0.0001). Conversely, the frequency of the SLC4A1Delta27 allele was higher in Liksul (0.0740) than the Wosera (0.0005) (chi(2); P < 0.0001). No individuals were homozygous for SLC4A1Delta27. In 355 Liksul residents, independent assortment of these two deletion polymorphisms resulted in 14 SLC4A1Delta27 carriers heterozygous for GYPCDeltaex3 and one SLC4A1Delta27 carrier homozygous for GYPCDeltaex3 (Fisher's exact test; P = 0.8040). While homozygosity for SLC4A1Delta27 appears to be nonviable, the GYPCDeltaex3 allele is not lethal when combined with SLC4A1Delta27. Neither mutation was associated with altered susceptibility to asymptomatic Plasmodium falciparum or P. vivax infection. While these erythrocyte polymorphisms apparently have no effect on blood-stage malaria infection, their contribution to susceptibility to clinical malaria morbidity requires further study.
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PMID:Glycophorin C (Gerbich antigen blood group) and band 3 polymorphisms in two malaria holoendemic regions of Papua New Guinea. 1469 25

Plasmodium falciparum, the causative agent of the most lethal form of human malaria, uses multiple ligand-receptor interactions to invade host red blood cells (RBCs). We studied the invasion of P falciparum into abnormal RBCs from humans carrying the Southeast Asian ovalocytosis (SAO) trait. One particular parasite line, 3D7-A, invaded these cells efficiently, whereas all other lines studied invaded SAO RBCs to only about 20% of the extent of normal (non-SAO) cells. This result is consistent with the clinical observation that SAO individuals can experience high-density P falciparum infections and provides an explanation for previous discrepant results on invasion of SAO RBCs. Characterization of the invasion phenotype of 3D7-A revealed that efficient invasion of SAO RBCs was paralleled by relatively efficient invasion of normal RBCs treated with either neuraminidase, trypsin, or chymotrypsin and a novel capacity to invade normal RBCs treated sequentially with both neuraminidase and trypsin. Our results suggest that only parasites able to use some particular invasion pathways can invade SAO RBCs efficiently in culture. A similar situation might occur in the field.
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PMID:Ability of Plasmodium falciparum to invade Southeast Asian ovalocytes varies between parasite lines. 1526 96


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