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Hereditary spherocytosis: Mechanism of hemolysis and pathogenesis

William C Mentzer, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Jennifer S Tirnauer, MD


Hereditary spherocytosis (HS) is the most common hemolytic anemia due to a red cell membrane defect. This topic will review the determinants of hemolysis and the molecular pathogenesis and genetics of HS. The clinical presentation, diagnosis, and treatment of HS are discussed separately. (See "Hereditary spherocytosis: Clinical features, diagnosis, and treatment".)


Overview — Hereditary spherocytosis (HS) is a result of heterogeneous alterations in genes that encode for proteins involved in the vertical associations that tie the red cell's inner membrane skeleton to its outer lipid bilayer (figure 1). The resistance and elastic deformability of red cells are due to a cytoskeleton that underlies the lipid bilayer and to proteins that provide vertical association of the cytoskeleton with the bilayer. A number of interconnected proteins are involved in the coupling of the cytoskeleton to the lipid bilayer. (See "Red blood cell membrane dynamics and organization".)

Spectrin (composed of alpha, beta heterodimers)


Band 4.2 (previously called pallidin)


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Literature review current through: Sep 2016. | This topic last updated: Aug 25, 2016.
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  1. Agre P, Orringer EP, Bennett V. Deficient red-cell spectrin in severe, recessively inherited spherocytosis. N Engl J Med 1982; 306:1155.
  2. Bolton-Maggs PH, Stevens RF, Dodd NJ, et al. Guidelines for the diagnosis and management of hereditary spherocytosis. Br J Haematol 2004; 126:455.
  3. An X, Mohandas N. Disorders of red cell membrane. Br J Haematol 2008; 141:367.
  4. Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet 2008; 372:1411.
  5. Salomao M, Chen K, Villalobos J, et al. Hereditary spherocytosis and hereditary elliptocytosis: aberrant protein sorting during erythroblast enucleation. Blood 2010; 116:267.
  6. Da Costa L, Mohandas N, Sorette M, et al. Temporal differences in membrane loss lead to distinct reticulocyte features in hereditary spherocytosis and in immune hemolytic anemia. Blood 2001; 98:2894.
  7. Lux SE, Palek J. Disorders of the red cell membrane. In: Blood. Principles and Practice of Hematology, Handin RI, Lux SE, Stossel TP (Eds), Lippincott, Philadelphia 1995. p.1701.
  8. Reliene R, Mariani M, Zanella A, et al. Splenectomy prolongs in vivo survival of erythrocytes differently in spectrin/ankyrin- and band 3-deficient hereditary spherocytosis. Blood 2002; 100:2208.
  9. De Franceschi L, Olivieri O, Miraglia del Giudice E, et al. Membrane cation and anion transport activities in erythrocytes of hereditary spherocytosis: effects of different membrane protein defects. Am J Hematol 1997; 55:121.
  10. Joiner CH, Franco RS, Jiang M, et al. Increased cation permeability in mutant mouse red blood cells with defective membrane skeletons. Blood 1995; 86:4307.
  11. De Franceschi L, Rivera A, Fleming MD, et al. Evidence for a protective role of the Gardos channel against hemolysis in murine spherocytosis. Blood 2005; 106:1454.
  12. Safeukui I, Buffet PA, Deplaine G, et al. Quantitative assessment of sensing and sequestration of spherocytic erythrocytes by the human spleen. Blood 2012; 120:424.
  13. Schrier SL. What does the spleen see? Blood 2012; 120:242.
  14. Ingrosso D, D'Angelo S, Perrotta S, et al. Cytoskeletal behaviour in spectrin and in band 3 deficient spherocytic red cells: evidence for differentiated splenic conditioning role. Br J Haematol 1996; 93:38.
  15. Peters LL, Shivdasani RA, Liu SC, et al. Anion exchanger 1 (band 3) is required to prevent erythrocyte membrane surface loss but not to form the membrane skeleton. Cell 1996; 86:917.
  16. Southgate CD, Chishti AH, Mitchell B, et al. Targeted disruption of the murine erythroid band 3 gene results in spherocytosis and severe haemolytic anaemia despite a normal membrane skeleton. Nat Genet 1996; 14:227.
  17. Peters LL, Jindel HK, Gwynn B, et al. Mild spherocytosis and altered red cell ion transport in protein 4. 2-null mice. J Clin Invest 1999; 103:1527.
  18. Peters LL, Lux SE. Ankyrins: structure and function in normal cells and hereditary spherocytes. Semin Hematol 1993; 30:85.
  19. Inaba M, Yawata A, Koshino I, et al. Defective anion transport and marked spherocytosis with membrane instability caused by hereditary total deficiency of red cell band 3 in cattle due to a nonsense mutation. J Clin Invest 1996; 97:1804.
  20. Robledo RF, Lambert AJ, Birkenmeier CS, et al. Analysis of novel sph (spherocytosis) alleles in mice reveals allele-specific loss of band 3 and adducin in alpha-spectrin-deficient red cells. Blood 2010; 115:1804.
  21. Tchernia G, Mohandas N, Shohet SB. Deficiency of skeletal membrane protein band 4.1 in homozygous hereditary elliptocytosis. Implications for erythrocyte membrane stability. J Clin Invest 1981; 68:454.
  22. Takakuwa Y, Tchernia G, Rossi M, et al. Restoration of normal membrane stability to unstable protein 4.1-deficient erythrocyte membranes by incorporation of purified protein 4.1. J Clin Invest 1986; 78:80.
  23. White RA, Sokolovsky IV, Britt MI, et al. Hematologic characterization and chromosomal localization of the novel dominantly inherited mouse hemolytic anemia, neonatal anemia (Nan). Blood Cells Mol Dis 2009; 43:141.
  24. Heruth DP, Hawkins T, Logsdon DP, et al. Mutation in erythroid specific transcription factor KLF1 causes Hereditary Spherocytosis in the Nan hemolytic anemia mouse model. Genomics 2010; 96:303.
  25. Randon J, Miraglia del Giudice E, Bozon M, et al. Frequent de novo mutations of the ANK1 gene mimic a recessive mode of transmission in hereditary spherocytosis: three new ANK1 variants: ankyrins Bari, Napoli II and Anzio. Br J Haematol 1997; 96:500.
  26. del Giudice EM, Hayette S, Bozon M, et al. Ankyrin Napoli: a de novo deletional frameshift mutation in exon 16 of ankyrin gene (ANK1) associated with spherocytosis. Br J Haematol 1996; 93:828.
  27. Morlé L, Bozon M, Alloisio N, et al. Ankyrin Bugey: a de novo deletional frameshift variant in exon 6 of the ankyrin gene associated with spherocytosis. Am J Hematol 1997; 54:242.
  28. Miraglia del Giudice E, Francese M, Nobili B, et al. High frequency of de novo mutations in ankyrin gene (ANK1) in children with hereditary spherocytosis. J Pediatr 1998; 132:117.
  29. Miraglia del Giudice E, Lombardi C, Francese M, et al. Frequent de novo monoallelic expression of beta-spectrin gene (SPTB) in children with hereditary spherocytosis and isolated spectrin deficiency. Br J Haematol 1998; 101:251.
  30. Miraglia del Giudice E, Nobili B, Francese M, et al. Clinical and molecular evaluation of non-dominant hereditary spherocytosis. Br J Haematol 2001; 112:42.
  31. Jarolim P, Murray JL, Rubin HL, et al. Characterization of 13 novel band 3 gene defects in hereditary spherocytosis with band 3 deficiency. Blood 1996; 88:4366.
  32. Miraglia del Giudice E, Iolascon A, Pinto L, et al. Erythrocyte membrane protein alterations underlying clinical heterogeneity in hereditary spherocytosis. Br J Haematol 1994; 88:52.
  33. Eber SW, Gonzalez JM, Lux ML, et al. Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis. Nat Genet 1996; 13:214.
  34. Dhermy D, Galand C, Bournier O, et al. Heterogenous band 3 deficiency in hereditary spherocytosis related to different band 3 gene defects. Br J Haematol 1997; 98:32.
  35. Mariani M, Barcellini W, Vercellati C, et al. Clinical and hematologic features of 300 patients affected by hereditary spherocytosis grouped according to the type of the membrane protein defect. Haematologica 2008; 93:1310.
  36. Rocha S, Costa E, Rocha-Pereira P, et al. Erythrocyte membrane protein destabilization versus clinical outcome in 160 Portuguese Hereditary Spherocytosis patients. Br J Haematol 2010; 149:785.
  37. Jarolim P, Rubin HL, Brabec V, Palek J. Comparison of the ankyrin (AC)n microsatellites in genomic DNA and mRNA reveals absence of one ankyrin mRNA allele in 20% of patients with hereditary spherocytosis. Blood 1995; 85:3278.
  38. Gallagher PG, Ferreira JD, Costa FF, et al. A recurrent frameshift mutation of the ankyrin gene associated with severe hereditary spherocytosis. Br J Haematol 2000; 111:1190.
  39. Okamoto N, Wada Y, Nakamura Y, et al. Hereditary spherocytic anemia with deletion of the short arm of chromosome 8. Am J Med Genet 1995; 58:225.
  40. Jarolim P, Rubin HL, Brabec V, et al. Abnormal alternative splicing of erythroid ankyrin mRNA in two kindred with hereditary spherocytosis (ankyrin Prague and ankyrin Rakovnik). Blood 1993; 82(Suppl 1):5a.
  41. Hayette S, Carré G, Bozon M, et al. Two distinct truncated variants of ankyrin associated with hereditary spherocytosis. Am J Hematol 1998; 58:36.
  42. Gallagher PG, Steiner LA, Liem RI, et al. Mutation of a barrier insulator in the human ankyrin-1 gene is associated with hereditary spherocytosis. J Clin Invest 2010; 120:4453.
  43. Gallagher PG. Hematologically important mutations: ankyrin variants in hereditary spherocytosis. Blood Cells Mol Dis 2005; 35:345.
  44. Bogusławska DM, Heger E, Listowski M, et al. A novel L1340P mutation in the ANK1 gene is associated with hereditary spherocytosis? Br J Haematol 2014; 167:269.
  45. Tanner MJ. The structure and function of band 3 (AE1): recent developments (review). Mol Membr Biol 1997; 14:155.
  46. Jarolim P, Rubin HL, Brabec V, et al. Mutations of conserved arginines in the membrane domain of erythroid band 3 lead to a decrease in membrane-associated band 3 and to the phenotype of hereditary spherocytosis. Blood 1995; 85:634.
  47. Jarolim P, Palek J, Amato D, et al. Deletion in erythrocyte band 3 gene in malaria-resistant Southeast Asian ovalocytosis. Proc Natl Acad Sci U S A 1991; 88:11022.
  48. Bruce LJ, Cope DL, Jones GK, et al. Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene. J Clin Invest 1997; 100:1693.
  49. Karet FE, Gainza FJ, Györy AZ, et al. Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis. Proc Natl Acad Sci U S A 1998; 95:6337.
  50. Jarolim P, Shayakul C, Prabakaran D, et al. Autosomal dominant distal renal tubular acidosis is associated in three families with heterozygosity for the R589H mutation in the AE1 (band 3) Cl-/HCO3- exchanger. J Biol Chem 1998; 273:6380.
  51. Lima PR, Gontijo JA, Lopes de Faria JB, et al. Band 3 Campinas: a novel splicing mutation in the band 3 gene (AE1) associated with hereditary spherocytosis, hyperactivity of Na+/Li+ countertransport and an abnormal renal bicarbonate handling. Blood 1997; 90:2810.
  52. Ribeiro ML, Alloisio N, Almeida H, et al. Severe hereditary spherocytosis and distal renal tubular acidosis associated with the total absence of band 3. Blood 2000; 96:1602.
  53. Toye AM, Williamson RC, Khanfar M, et al. Band 3 Courcouronnes (Ser667Phe): a trafficking mutant differentially rescued by wild-type band 3 and glycophorin A. Blood 2008; 111:5380.
  54. Chu C, Woods N, Sawasdee N, et al. Band 3 Edmonton I, a novel mutant of the anion exchanger 1 causing spherocytosis and distal renal tubular acidosis. Biochem J 2010; 426:379.
  55. Chang YH, Shaw CF, Jian SH, et al. Compound mutations in human anion exchanger 1 are associated with complete distal renal tubular acidosis and hereditary spherocytosis. Kidney Int 2009; 76:774.
  56. Jenkins PB, Abou-Alfa GK, Dhermy D, et al. A nonsense mutation in the erythrocyte band 3 gene associated with decreased mRNA accumulation in a kindred with dominant hereditary spherocytosis. J Clin Invest 1996; 97:373.
  57. Miraglia del Giudice E, Vallier A, Maillet P, et al. Novel band 3 variants (bands 3 Foggia, Napoli I and Napoli II) associated with hereditary spherocytosis and band 3 deficiency: status of the D38A polymorphism within the EPB3 locus. Br J Haematol 1997; 96:70.
  58. Maillet P, Vallier A, Reinhart WH, et al. Band 3 Chur: a variant associated with band 3-deficient hereditary spherocytosis and substitution in a highly conserved position of transmembrane segment 11. Br J Haematol 1995; 91:804.
  59. Bianchi P, Zanella A, Alloisio N, et al. A variant of the EPB3 gene of the anti-Lepore type in hereditary spherocytosis. Br J Haematol 1997; 98:283.
  60. Alloisio N, Texier P, Vallier A, et al. Modulation of clinical expression and band 3 deficiency in hereditary spherocytosis. Blood 1997; 90:414.
  61. Alloisio N, Maillet P, Carré G, et al. Hereditary spherocytosis with band 3 deficiency. Association with a nonsense mutation of the band 3 gene (allele Lyon), and aggravation by a low-expression allele occurring in trans (allele Genas). Blood 1996; 88:1062.
  62. van Zwieten R, van Oirschot BA, Veldthuis M, et al. Partial pyruvate kinase deficiency aggravates the phenotypic expression of band 3 deficiency in a family with hereditary spherocytosis. Am J Hematol 2015; 90:E35.
  63. Hassoun H, Vassiliadis JN, Murray J, et al. Characterization of the underlying molecular defect in hereditary spherocytosis associated with spectrin deficiency. Blood 1997; 90:398.
  64. Dhermy D, Galand C, Bournier O, et al. Hereditary spherocytosis with spectrin deficiency related to null mutations of the beta-spectrin gene. Blood Cells Mol Dis 1998; 24:251.
  65. Garbarz M, Galand C, Bibas D, et al. A 5' splice region G-->C mutation in exon 3 of the human beta-spectrin gene leads to decreased levels of beta-spectrin mRNA and is responsible for dominant hereditary spherocytosis (spectrin Guemene-Penfao). Br J Haematol 1998; 100:90.
  66. Becker PS, Tse WT, Lux SE, Forget BG. Beta spectrin kissimmee: a spectrin variant associated with autosomal dominant hereditary spherocytosis and defective binding to protein 4.1. J Clin Invest 1993; 92:612.
  67. Hassoun H, Vassiliadis JN, Murray J, et al. Molecular basis of spectrin deficiency in beta spectrin Durham. A deletion within beta spectrin adjacent to the ankyrin-binding site precludes spectrin attachment to the membrane in hereditary spherocytosis. J Clin Invest 1995; 96:2623.
  68. Hassoun H, Vassiliadis JN, Murray J, et al. Hereditary spherocytosis with spectrin deficiency due to an unstable truncated beta spectrin. Blood 1996; 87:2538.
  69. Maciag M, Płochocka D, Adamowicz-Salach A, Burzyńska B. Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA. Br J Haematol 2009; 146:326.
  70. Tse WT, Gallagher PG, Jenkins PB, et al. Amino-acid substitution in alpha-spectrin commonly coinherited with nondominant hereditary spherocytosis. Am J Hematol 1997; 54:233.
  71. Bogardus H, Schulz VP, Maksimova Y, et al. Severe nondominant hereditary spherocytosis due to uniparental isodisomy at the SPTA1 locus. Haematologica 2014; 99:e168.
  72. Wichterle H, Hanspal M, Palek J, Jarolim P. Combination of two mutant alpha spectrin alleles underlies a severe spherocytic hemolytic anemia. J Clin Invest 1996; 98:2300.
  73. Yawata Y, Yawata A, Kanzaki A, et al. Electron microscopic evidence of impaired intramembrane particles and instability of the cytoskeletal network in band 4.2 deficiency in human red cells. Cell Motil Cytoskeleton 1996; 33:95.
  74. Bouhassira EE, Schwartz RS, Yawata Y, et al. An alanine-to-threonine substitution in protein 4.2 cDNA is associated with a Japanese form of hereditary hemolytic anemia (protein 4.2NIPPON). Blood 1992; 79:1846.
  75. Takaoka Y, Ideguchi H, Matsuda M, et al. A novel mutation in the erythrocyte protein 4.2 gene of Japanese patients with hereditary spherocytosis (protein 4.2 Fukuoka). Br J Haematol 1994; 88:527.
  76. Kanzaki A, Yasunaga M, Okamoto N, et al. Band 4.2 Shiga: 317 CGC-->TGC in compound heterozygotes with 142 GCT-->ACT results in band 4.2 deficiency and microspherocytosis. Br J Haematol 1995; 91:333.
  77. Matsuda M, Hatano N, Ideguchi H, et al. A novel mutation causing an aberrant splicing in the protein 4.2 gene associated with hereditary spherocytosis (protein 4.2Notame). Hum Mol Genet 1995; 4:1187.
  78. van den Akker E, Satchwell TJ, Pellegrin S, et al. Investigating the key membrane protein changes during in vitro erythropoiesis of protein 4.2 (-) cells (mutations Chartres 1 and 2). Haematologica 2010; 95:1278.
  79. Jarolim P, Palek J, Rubin HL, et al. Band 3 Tuscaloosa: Pro327----Arg327 substitution in the cytoplasmic domain of erythrocyte band 3 protein associated with spherocytic hemolytic anemia and partial deficiency of protein 4.2. Blood 1992; 80:523.
  80. Rybicki AC, Qiu JJ, Musto S, et al. Human erythrocyte protein 4.2 deficiency associated with hemolytic anemia and a homozygous 40glutamic acid-->lysine substitution in the cytoplasmic domain of band 3 (band 3Montefiore). Blood 1993; 81:2155.
  81. Inoue T, Kanzaki A, Kaku M, et al. Homozygous missense mutation (band 3 Fukuoka: G130R): a mild form of hereditary spherocytosis with near-normal band 3 content and minimal changes of membrane ultrastructure despite moderate protein 4.2 deficiency. Br J Haematol 1998; 102:932.
  82. Kanzaki A, Hayette S, Morlé L, et al. Total absence of protein 4.2 and partial deficiency of band 3 in hereditary spherocytosis. Br J Haematol 1997; 99:522.
  83. Bustos SP, Reithmeier RA. Structure and stability of hereditary spherocytosis mutants of the cytosolic domain of the erythrocyte anion exchanger 1 protein. Biochemistry 2006; 45:1026.
  84. Nicolas V, Le Van Kim C, Gane P, et al. Rh-RhAG/ankyrin-R, a new interaction site between the membrane bilayer and the red cell skeleton, is impaired by Rh(null)-associated mutation. J Biol Chem 2003; 278:25526.
  85. Lopez C, Métral S, Eladari D, et al. The ammonium transporter RhBG: requirement of a tyrosine-based signal and ankyrin-G for basolateral targeting and membrane anchorage in polarized kidney epithelial cells. J Biol Chem 2005; 280:8221.