Significant advances have been made in diagnosis and clinical management of inherited red cell membrane disorders that result in hemolytic anemia. Membrane structural defects lead to hereditary ...spherocytosis (HS) and hereditary elliptocytosis (HE), whereas altered membrane transport function accounts for hereditary xerocytosis (HX) and hereditary overhydrated stomatocytosis (OHS). The degrees of membrane loss and resultant increases in cell sphericity determine the severity of anemia in HS and HE, and splenectomy leads to amelioration of anemia by increasing the circulatory red cell life span. Alterations in cell volume as a result of disordered membrane cation permeability account for reduced life span red cells in HX and OHS. Importantly, splenectomy is not beneficial in these 2 membrane transport disorders and is not recommended because it is ineffective and may lead to an increased risk of life-threatening thrombosis. Rational approaches are now available for the diagnosis and management of these inherited red cell disorders, and these will be discussed in this review.
Erythroblastic islands, the specialized niches in which erythroid precursors proliferate, differentiate, and enucleate, were first described 50 years ago by analysis of transmission electron ...micrographs of bone marrow. These hematopoietic subcompartments are composed of erythroblasts surrounding a central macrophage. A hiatus of several decades followed, during which the importance of erythroblastic islands remained unrecognized as erythroid progenitors were shown to possess an autonomous differentiation program with a capacity to complete terminal differentiation in vitro in the presence of erythropoietin but without macrophages. However, as the extent of proliferation, differentiation, and enucleation efficiency documented in vivo could not be recapitulated in vitro, a resurgence of interest in erythroid niches has emerged. We now have an increased molecular understanding of processes operating within erythroid niches, including cell-cell and cell-extracellular matrix adhesion, positive and negative regulatory feedback, and central macrophage function. These features of erythroblast islands represent important contributors to normal erythroid development, as well as altered erythropoiesis found in such diverse diseases as anemia of inflammation and chronic disease, myelodysplasia, thalassemia, and malarial anemia. Coupling of historical, current, and future insights will be essential to understand the tightly regulated production of red cells both in steady state and stress erythropoiesis.
Diamond-Blackfan anemia (DBA) was the first ribosomopathy described and is a constitutional inherited bone marrow failure syndrome. Erythroblastopenia is the major characteristic of the disease, ...which is a model for ribosomal diseases, related to a heterozygous allelic variation in 1 of the 20 ribosomal protein genes of either the small or large ribosomal subunit. The salient feature of classical DBA is a defect in ribosomal RNA maturation that generates nucleolar stress, leading to stabilization of p53 and activation of its targets, resulting in cell-cycle arrest and apoptosis. Although activation of p53 may not explain all aspects of DBA erythroid tropism, involvement of GATA1/HSP70 and globin/heme imbalance, with an excess of the toxic free heme leading to reactive oxygen species production, account for defective erythropoiesis in DBA. Despite significant progress in defining the molecular basis of DBA and increased understanding of the mechanistic basis for DBA pathophysiology, progress in developing new therapeutic options has been limited. However, recent advances in gene therapy, better outcomes with stem cell transplantation, and discoveries of putative new drugs through systematic drug screening using large chemical libraries provide hope for improvement.
As a result of natural selection driven by severe forms of malaria, 1 in 6 humans in the world, more than 1 billion people, are affected by red cell abnormalities, making them the most common of the ...inherited disorders. The non-nucleated red cell is unique among human cell type in that the plasma membrane, its only structural component, accounts for all of its diverse antigenic, transport, and mechanical characteristics. Our current concept of the red cell membrane envisions it as a composite structure in which a membrane envelope composed of cholesterol and phospholipids is secured to an elastic network of skeletal proteins via transmembrane proteins. Structural and functional characterization of the many constituents of the red cell membrane, in conjunction with biophysical and physiologic studies, has led to detailed description of the way in which the remarkable mechanical properties and other important characteristics of the red cells arise, and of the manner in which they fail in disease states. Current studies in this very active and exciting field are continuing to produce new and unexpected revelations on the function of the red cell membrane and thus of the cell in health and disease, and shed new light on membrane function in other diverse cell types.
Disorders of red cell membrane An, Xiuli; Mohandas, Narla
British journal of haematology,
20/May , Volume:
141, Issue:
3
Journal Article, Conference Proceeding
Peer reviewed
Summary
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.
Abstract 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.
Summary Hereditary spherocytosis is a common inherited disorder that is characterised by anaemia, jaundice, and splenomegaly. It is reported worldwide and is the most common inherited anaemia in ...individuals of northern European ancestry. Clinical severity is variable with most patients having a well-compensated haemolytic anaemia. Some individuals are asymptomatic, whereas others have severe haemolytic anaemia requiring erythrocyte transfusion. The primary lesion in hereditary spherocytosis is loss of membrane surface area, leading to reduced deformability due to defects in the membrane proteins ankyrin, band 3, β spectrin, α spectrin, or protein 4.2. Many isolated mutations have been identified in the genes encoding these membrane proteins; common hereditary spherocytosis-associated mutations have not been identified. Abnormal spherocytes are trapped and destroyed in the spleen and this is the main cause of haemolysis in this disorder. Common complications are cholelithiasis, haemolytic episodes, and aplastic crises. Splenectomy is curative but should be undertaken only after careful assessment of the risks and benefits.
Differentiating erythroblasts execute a dynamic alternative splicing program shown here to include extensive and diverse intron retention (IR) events. Cluster analysis revealed hundreds of ...developmentally-dynamic introns that exhibit increased IR in mature erythroblasts, and are enriched in functions related to RNA processing such as SF3B1 spliceosomal factor. Distinct, developmentally-stable IR clusters are enriched in metal-ion binding functions and include mitoferrin genes SLC25A37 and SLC25A28 that are critical for iron homeostasis. Some IR transcripts are abundant, e.g. comprising ∼50% of highly-expressed SLC25A37 and SF3B1 transcripts in late erythroblasts, and thereby limiting functional mRNA levels. IR transcripts tested were predominantly nuclear-localized. Splice site strength correlated with IR among stable but not dynamic intron clusters, indicating distinct regulation of dynamically-increased IR in late erythroblasts. Retained introns were preferentially associated with alternative exons with premature termination codons (PTCs). High IR was observed in disease-causing genes including SF3B1 and the RNA binding protein FUS. Comparative studies demonstrated that the intron retention program in erythroblasts shares features with other tissues but ultimately is unique to erythropoiesis. We conclude that IR is a multi-dimensional set of processes that post-transcriptionally regulate diverse gene groups during normal erythropoiesis, misregulation of which could be responsible for human disease.
Malaria is a major world health problem. It results from infection of parasites belonging to the genus Plasmodium. Plasmodium falciparum and Plasmodium vivax cause the major human malarias, with P ...falciparum being the more virulent. During their blood stages of infection, both P falciparum and P vivax induce anemia. Severe malarial anemia caused by P falciparum is responsible for approximately a third of the deaths associated with disease. Malarial anemia appears to be multi-factorial. It involves increased removal of circulating erythrocytes as well as decreased production of erythrocytes in the bone marrow. The molecular mechanisms underlying malarial anemia are largely unknown. Over the last five years, malaria parasite ligands have been investigated for their remodeling of erythrocytes and possible roles in destruction of mature erythrocytes. Polymorphisms in cytokines have been associated with susceptibility to severe malarial anemia: these cytokines and malaria "toxins" likely function by perturbing erythropoiesis. Finally a number of co-infections increase susceptibility to malarial anemia, likely because they exacerbate inflammation caused by malaria. Because of the complexities involved, the study of severe malarial anemia may need a "systems approach" to yield comprehensive understanding of defects in both erythropoiesis and immunity associated with disease. New and emerging tools such as (i) mathematical modeling of the dynamics of host control of malarial infection, (ii) ex vivo perfusion of human spleen to measure both infected and uninfected erythrocyte retention, and (iii) in vitro development of erythroid progenitors to dissect responsiveness to cytokine imbalance or malaria toxins, may be especially useful to develop integrated mechanistic insights and therapies to control this major and fatal disease pathology.
PDF
