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British Journal of Haematology May 2008Studies during the last three decades have enabled the development of detailed molecular insights into the structural basis of altered function in various inherited red... (Review)
Review
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.
Topics: Anemia, Hemolytic, Congenital; Elliptocytosis, Hereditary; Erythrocyte Membrane; Erythrocytes, Abnormal; Humans; Spherocytosis, Hereditary
PubMed: 18341630
DOI: 10.1111/j.1365-2141.2008.07091.x -
BMC Genomics Jun 2023Hereditary spherocytosis (HS) is a common inherited hemolytic anemia, caused by mutations in five genes that encode erythrocyte membrane skeleton proteins. The red blood...
BACKGROUND
Hereditary spherocytosis (HS) is a common inherited hemolytic anemia, caused by mutations in five genes that encode erythrocyte membrane skeleton proteins. The red blood cell (RBC) lifespan could directly reflect the degree of hemolysis. In the present cohort of 23 patients with HS, we performed next-generation sequencing (NGS) and Levitt's carbon monoxide (CO) breath test to investigate the potential genotype-degree of hemolysis correlation.
RESULTS
In the present cohort, we identified 8 ANK1,9 SPTB,5 SLC4A1 and 1 SPTA1 mutations in 23 patients with HS, and the median RBC lifespan was 14(8-48) days. The median RBC lifespan of patients with ANK1, SPTB and SLC4A1 mutations was 13 (8-23), 13 (8-48) and 14 (12-39) days, respectively, with no statistically significant difference (P = 0.618). The median RBC lifespan of patients with missense, splice and nonsense/insertion/deletion mutations was 16.5 (8-48), 14 (11-40) and 13 (8-20) days, respectively, with no significant difference (P = 0.514). Similarly, we found no significant difference in the RBC lifespan of patients with mutations located in the spectrin-binding domain and the nonspectrin-binding domain [14 (8-18) vs. 12.5 (8-48) days, P = 0.959]. In terms of the composition of mutated genes, 25% of patients with mild hemolysis carried ANK1 or SPTA1 mutations, while 75% of patients with mild hemolysis carried SPTB or SLC4A1 mutations. In contrast, 46.7% of patients with severe hemolysis had ANK1 or SPTA1 mutations and 53.3% of patients with severe hemolysis had SPTB or SLC4A1 mutations. However, there was no statistically significant difference in the distribution of mutated genes between the two groups (P = 0.400).
CONCLUSION
The present study is the first to investigate the potential association between genotype and degree of hemolysis in HS. The present findings indicated that there is no significant correlation between genotype and degree of hemolysis in HS.
Topics: Humans; Hemolysis; Ankyrins; Spectrin; Spherocytosis, Hereditary; Cytoskeletal Proteins; Membrane Proteins; Mutation; Genotype
PubMed: 37280519
DOI: 10.1186/s12864-023-09364-8 -
Annals of Translational Medicine Sep 2018Hereditary spherocytosis (HS) belongs to the group of congenital hemolytic anemias resulting from plasma membrane protein deficiency. When diagnosed too late, HS bares... (Review)
Review
Hereditary spherocytosis (HS) belongs to the group of congenital hemolytic anemias resulting from plasma membrane protein deficiency. When diagnosed too late, HS bares the risk of long-term complications including gall stones and severe anemia. Here, there are discussed advances in HS screening and diagnostics, with a particular focus on methodologies, most of which are available in clinical laboratories worldwide.
PubMed: 30306078
DOI: 10.21037/atm.2018.07.35 -
The Journal of Clinical Investigation Oct 2020During hemolysis, macrophages in the liver phagocytose damaged erythrocytes to prevent the toxic effects of cell-free hemoglobin and heme. It remains unclear how this...
During hemolysis, macrophages in the liver phagocytose damaged erythrocytes to prevent the toxic effects of cell-free hemoglobin and heme. It remains unclear how this homeostatic process modulates phagocyte functions in inflammatory diseases. Using a genetic mouse model of spherocytosis and single-cell RNA sequencing, we found that erythrophagocytosis skewed liver macrophages into an antiinflammatory phenotype that we defined as MarcohiHmoxhiMHC class IIlo erythrophagocytes. This phenotype transformation profoundly mitigated disease expression in a model of an anti-CD40-induced hyperinflammatory syndrome with necrotic hepatitis and in a nonalcoholic steatohepatitis model, representing 2 macrophage-driven sterile inflammatory diseases. We reproduced the antiinflammatory erythrophagocyte transformation in vitro by heme exposure of mouse and human macrophages, yielding a distinctive transcriptional signature that segregated heme-polarized from M1- and M2-polarized cells. Mapping transposase-accessible chromatin in single cells by sequencing defined the transcription factor NFE2L2/NRF2 as a critical driver of erythrophagocytes, and Nfe2l2/Nrf2 deficiency restored heme-suppressed inflammation. Our findings point to a pathway that regulates macrophage functions to link erythrocyte homeostasis with innate immunity.
Topics: Animals; Disease Models, Animal; Female; Heme; Hemolysis; Humans; In Vitro Techniques; Inflammation; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; NF-E2-Related Factor 2; Non-alcoholic Fatty Liver Disease; Phagocytes; Phagocytosis; Phenotype; RNA-Seq; Single-Cell Analysis; Spherocytosis, Hereditary
PubMed: 32663195
DOI: 10.1172/JCI137282 -
British Journal of Haematology Oct 2019Hereditary erythrocyte membrane disorders are caused by mutations in genes encoding various transmembrane or cytoskeletal proteins of red blood cells. The main... (Review)
Review
Hereditary erythrocyte membrane disorders are caused by mutations in genes encoding various transmembrane or cytoskeletal proteins of red blood cells. The main consequences of these genetic alterations are decreased cell deformability and shortened erythrocyte survival. Red blood cell membrane defects encompass a heterogeneous group of haemolytic anaemias caused by either (i) altered membrane structural organisation (hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis and Southeast Asian ovalocytosis) or (ii) altered membrane transport function (overhydrated hereditary stomatocytosis, dehydrated hereditary stomatocytosis or xerocytosis, familial pseudohyperkalaemia and cryohydrocytosis). Herein we provide a comprehensive review of the recent literature on the molecular genetics of erythrocyte membrane defects and their reported clinical consequences. We also describe the effect of low-expression genetic variants on the high inter- and intra-familial phenotype variability of erythrocyte structural defects.
Topics: Alleles; Anemia, Hemolytic, Congenital; Elliptocytosis, Hereditary; Erythrocyte Membrane; Erythrocytes, Abnormal; Humans; Membrane Proteins; Spherocytosis, Hereditary
PubMed: 31364155
DOI: 10.1111/bjh.16126 -
Journal of Biosciences 2020Ankyrins are ubiquitously expressed proteins that play a critical role in the integrity of cytoskeleton and cellular signalling. Their presence in metazoans and... (Review)
Review
Ankyrins are ubiquitously expressed proteins that play a critical role in the integrity of cytoskeleton and cellular signalling. Their presence in metazoans and evolutionary conserved protein primary sequence indicates their functional significance. Tissue-specific isoforms and an array of transcript variants make this protein one of the indispensable cellular components. Membrane-binding domains consist of ankyrin repeats that bind with several functional membrane proteins that enable maintaining cellular integrity. Cytosolic ankyrins help in cellular signal transduction. Linkage studies and recent genome-wide association studies uncovered the pathogenic roles of ankyrins (ankyrin-R, ankyrin-B and ankyrin-G) in several diseases, such as hereditary spherocytosis, long QT syndrome, intellectual disability, and CRASH syndrome, among several others. Identification of in celiac disease may potentially explain the link between neuronal health and immunity. It is thus warranted to investigate the role of neuronal factors in immune diseases and vice versa. In this review, we briefly discussed the contribution of ankyrin genes to human diseases.
Topics: Ankyrins; Celiac Disease; Genetic Diseases, X-Linked; Genome-Wide Association Study; Humans; Intellectual Disability; Long QT Syndrome; Signal Transduction; Spastic Paraplegia, Hereditary; Spherocytosis, Hereditary
PubMed: 33410423
DOI: No ID Found -
Pediatrics Jun 2015Newborn infants who have hereditary spherocytosis (HS) can develop anemia and hyperbilirubinemia. Bilirubin-induced neurologic dysfunction is less likely in these... (Review)
Review
Newborn infants who have hereditary spherocytosis (HS) can develop anemia and hyperbilirubinemia. Bilirubin-induced neurologic dysfunction is less likely in these neonates if the diagnosis of HS is recognized and appropriate treatment provided. Among neonates listed in the USA Kernicterus Registry, HS was the third most common underlying hemolytic condition after glucose-6-phosphate dehydrogenase deficiency and ABO hemolytic disease. HS is the leading cause of direct antiglobulin test (direct Coombs) negative hemolytic anemia requiring erythrocyte transfusion in the first months of life. We anticipate that as physicians become more familiar with diagnosing HS in the newborn period, fewer neonates with HS will develop hazardous hyperbilirubinemia or present to emergency departments with unanticipated symptomatic anemia. We predict that early suspicion, prompt diagnosis and treatment, and anticipatory guidance will prevent adverse outcomes in neonates with HS. The purpose of this article was to review the neonatal presentation of HS and to provide practical and up-to-date means of diagnosing and treating HS in neonates.
Topics: Ankyrins; Decision Trees; Humans; Infant, Newborn; Pediatrics; Practice Guidelines as Topic; Spherocytosis, Hereditary
PubMed: 26009624
DOI: 10.1542/peds.2014-3516 -
Orphanet Journal of Rare Diseases Oct 2021Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of... (Review)
Review
Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis. These rare and heterogeneous conditions may generate several difficulties from the diagnostic point of view. Membrane defects include hereditary spherocytosis and elliptocytosis, and the group of hereditary stomatocytosis; glucose-6-phosphate dehydrogenase and pyruvate kinase, are the most common enzyme deficiencies. Among ultra-rare forms, it is worth reminding other enzyme defects (glucosephosphate isomerase, phosphofructokinase, adenylate kinase, triosephosphate isomerase, phosphoglycerate kinase, hexokinase, and pyrimidine 5'-nucleotidase), and congenital dyserythropoietic anemias. Family history, clinical findings (anemia, hemolysis, splenomegaly, gallstones, and iron overload), red cells morphology, and biochemical tests are well recognized diagnostic tools. Molecular findings are increasingly used, particularly in recessive and de novo cases, and may be fundamental in unraveling the diagnosis. Notably, several confounders may further challenge the diagnostic workup, including concomitant blood loss, nutrients deficiency, alterations of hemolytic markers due to other causes (alloimmunization, infectious agents, rare metabolic disorders), coexistence of other hemolytic disorders (autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc.). Additional factors to be considered are the possible association with bone marrow, renal or hepatic diseases, other causes of iron overload (hereditary hemochromatosis, hemoglobinopathies, metabolic diseases), and the presence of extra-hematological signs/symptoms. In this review we provide some instructive clinical vignettes that highlight the difficulties and confounders encountered in the diagnosis and clinical management of CHAs.
Topics: Anemia, Hemolytic, Congenital; Erythrocytes; Hemoglobinopathies; Humans; Pyruvate Kinase; Spherocytosis, Hereditary
PubMed: 34627331
DOI: 10.1186/s13023-021-02036-4 -
Biochimica Et Biophysica Acta Jul 2016The crystal structure of the dimeric membrane domain of human Band 3(1), the red cell chloride/bicarbonate anion exchanger 1 (AE1, SLC4A1), provides a structural context... (Review)
Review
The crystal structure of the dimeric membrane domain of human Band 3(1), the red cell chloride/bicarbonate anion exchanger 1 (AE1, SLC4A1), provides a structural context for over four decades of studies into this historic and important membrane glycoprotein. In this review, we highlight the key structural features responsible for anion binding and translocation and have integrated the following topological markers within the Band 3 structure: blood group antigens, N-glycosylation site, protease cleavage sites, inhibitor and chemical labeling sites, and the results of scanning cysteine and N-glycosylation mutagenesis. Locations of mutations linked to human disease, including those responsible for Southeast Asian ovalocytosis, hereditary stomatocytosis, hereditary spherocytosis, and distal renal tubular acidosis, provide molecular insights into their effect on Band 3 folding. Finally, molecular dynamics simulations of phosphatidylcholine self-assembled around Band 3 provide a view of this membrane protein within a lipid bilayer.
Topics: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Acid-Base Imbalance; Acidosis, Renal Tubular; Anemia, Hemolytic, Congenital; Anion Exchange Protein 1, Erythrocyte; Bicarbonates; Elliptocytosis, Hereditary; Erythrocytes; Erythrocytes, Abnormal; Gene Expression; Glycosylation; Humans; Ligands; Metabolism, Inborn Errors; Mutation; Protein Binding; Spherocytosis, Hereditary
PubMed: 27058983
DOI: 10.1016/j.bbamem.2016.03.030 -
JCI Insight Oct 2023Hereditary spherocytosis (HS) is the most common, nonimmune, hereditary, chronic hemolytic anemia after hemoglobinopathies. The genetic defects in membrane function...
Hereditary spherocytosis (HS) is the most common, nonimmune, hereditary, chronic hemolytic anemia after hemoglobinopathies. The genetic defects in membrane function causing HS lead to perturbation of the RBC metabolome, with altered glycolysis. In mice genetically lacking protein 4.2 (4.2-/-; Epb42), a murine model of HS, we showed increased expression of pyruvate kinase (PK) isoforms in whole and fractioned RBCs in conjunction with abnormalities in the glycolytic pathway and in the glutathione (GSH) system. Mitapivat, a PK activator, metabolically reprogrammed 4.2-/- mouse RBCs with amelioration of glycolysis and the GSH cycle. This resulted in improved osmotic fragility, reduced phosphatidylserine positivity, amelioration of RBC cation content, reduction of Na/K/Cl cotransport and Na/H-exchange overactivation, and decrease in erythroid vesicles release in vitro. Mitapivat treatment significantly decreased erythrophagocytosis and beneficially affected iron homeostasis. In mild-to-moderate HS, the beneficial effect of splenectomy is still controversial. Here, we showed that splenectomy improves anemia in 4.2-/- mice and that mitapivat is noninferior to splenectomy. An additional benefit of mitapivat treatment was lower expression of markers of inflammatory vasculopathy in 4.2-/- mice with or without splenectomy, indicating a multisystemic action of mitapivat. These findings support the notion that mitapivat treatment should be considered for symptomatic HS.
Topics: Animals; Mice; Disease Models, Animal; Spherocytosis, Hereditary; Erythrocytes; Anemia, Hemolytic
PubMed: 37676741
DOI: 10.1172/jci.insight.172656