Skip to main content
SpringerLink
Log in

Molecular Genetics of Inherited Red Cell Membrane Disorders

  • Chapter
  • First Online:
Hematopathology

Abstract

Inherited red cell membrane disorders constitute a diverse group of disorders which are characterized by wide clinical and molecular heterogeneity. They are nonimmune hereditary hemolytic anemia, and patients present with variable degrees of pallor, episodic jaundice, splenomegaly, and elevated lactate dehydrogenase (LDH) levels. The underlying cause is the defects either in the organization of membrane structure or membrane transport function arising because of mutations in genes encoding erythrocyte membrane proteins essential for stable structure and function. The commonest disorder is hereditary spherocytosis (HS) followed by relatively uncommon conditions such as hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP). Disorders of alterations of hydration include hereditary stomatocytosis (HSt) where cation permeability in the red cell membrane is disturbed, leading to overhydrated HSt and hereditary xerocytosis with dehydrated HSt. Extensive biochemical, biophysical, and genetic studies of the red cell membrane in the decades have provided detailed molecular insights into the structural basis for normal red cell membrane function and for altered function in various inherited red cell membrane disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Lux SE, Wolfe LC. Inherited disorders of the red cell membrane skeleton. Pediatr Clin North Am. 1980;27:463–86.

    Article  CAS  Google Scholar 

  2. Bruce LJ, Guizouarn H, Burton NM, Gabillat N, Poole J, Flatt JF, et al. The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein. Blood. 2009;113:1350–7. http://www.ncbi.nlm.nih.gov/pubmed/18931342.

    Article  CAS  Google Scholar 

  3. Andolfo I, Russo R, Gambale A, Iolascon A. New insights on hereditary erythrocyte membrane defects. Haematologica. 2016;101:1284–94.

    Article  CAS  Google Scholar 

  4. Narla J, Mohandas N. Red cell membrane disorders. Int J Lab Hematol. 2017;39:47–52.

    Article  Google Scholar 

  5. Delaunay J, Stewart G, Iolascon A. Hereditary dehydrated and overhydrated stomatocytosis: recent advances. Curr Opin Hematol. 1999;6:110–4. http://www.ncbi.nlm.nih.gov/pubmed/10088641.

    Article  CAS  Google Scholar 

  6. Agarwal AM, Nussenzveig RH, Reading NS, Patel JL, Sangle N, Salama ME, et al. Clinical utility of next-generation sequencing in the diagnosis of hereditary haemolytic anaemias. Br J Haematol. 2016;174:806–14. https://doi.org/10.1111/bjh.14131.

    Article  CAS  PubMed  Google Scholar 

  7. Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet. 2008;372:1411–26. https://doi.org/10.1016/S0140-6736(08)61588-3.

    Article  CAS  PubMed  Google Scholar 

  8. Kedar P. Red cell membrane pathology in hereditary spherocytosis in India. Indian J Hematol Blood Transfus. 2013;29(4):245–6.

    Google Scholar 

  9. Karan AS, Saxena R, Choudhry VP. Autosomal non-dominant hereditary spherocytosis: does it occur in India? Am J Hematol. 2002;70:266–7.

    Article  Google Scholar 

  10. Das A, Bansal D, Das R, Trehan A, Marwaha RK. Hereditary spherocytosis in children: profile and post-splenectomy outcome. Indian Pediatr. 2014;51:139–41.

    Article  Google Scholar 

  11. Tse WT, Lux SE. Red blood cell membrane disorders. Br J Haematol. 1999;104:2–13.

    Article  CAS  Google Scholar 

  12. Eber SW, Gonzalez JM, Lux ML, Scarpa AL, Tse WT, Dornwell M, et al. Ankyrin–1 mutations are a major cause of dominant and recessive hereditary spherocytosis. Nat Genet. 1996;13:214–8. http://www.ncbi.nlm.nih.gov/pubmed/8640229.

    Article  CAS  Google Scholar 

  13. Del Giudice EM, Nobili B, Francese M, D’Urso L, Iolascon A, Eber S, et al. Clinical and molecular evaluation of non-dominant hereditary spherocytosis. Br J Haematol. 2001;112:42–7.

    Article  Google Scholar 

  14. del Giudice EM, Hayette S, Bozon M, Perrotta S, Alloisio N, Vallier A, et al. Ankyrin Napoli: a de novo deletional frameshift mutation in exon 16 of ankyrin gene (ANK1) associated with spherocytosis. Br J Haematol. 1996;93:828–34. http://www.ncbi.nlm.nih.gov/pubmed/8703812.

    Article  Google Scholar 

  15. Morlé L, Bozon M, Alloisio N, Vallier A, Hayette S, Pascal O, et al. Ankyrin Bugey: a de novo deletional frameshift variant in exon 6 of the ankyrin gene associated with spherocytosis. Am J Hematol. 1997;54:242–8. http://www.ncbi.nlm.nih.gov/pubmed/9067504.

    Article  Google Scholar 

  16. Hayette S, Carré G, Bozon M, Alloisio N, Maillet P, Wilmotte R, et al. Two distinct truncated variants of ankyrin associated with hereditary spherocytosis. Am J Hematol. 1998;58:36–41. http://www.ncbi.nlm.nih.gov/pubmed/9590147.

    Article  CAS  Google Scholar 

  17. Random J, Miraglia Del Giudice E, Bozon M, Perrotta S, De Vivo M, Iolascon A, 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;96:500–6.

    Article  Google Scholar 

  18. Iolascon A, Miraglia del Giudice E, Perrotta S, Alloisio N, Morlé L, Delaunay J. Hereditary spherocytosis: from clinical to molecular defects. Haematologica. 1998;83:240–57. http://www.ncbi.nlm.nih.gov/pubmed/9573679.

    CAS  PubMed  Google Scholar 

  19. Hamosh A, Scott AF, Amberger J, Valle D, McKusick VA. Online Mendelian inheritance in man (OMIM). Hum Mutat. 2000;15:57–61.

    Article  CAS  Google Scholar 

  20. Bianchi P, Fermo E, Vercellati C, Marcello AP, Porretti L, Cortelezzi A, et al. Diagnostic power of laboratory tests for hereditary spherocytosis: a comparison study in 150 patients grouped according to molecular and clinical characteristics. Haematologica. 2012;97:516–23. http://www.ncbi.nlm.nih.gov/pubmed/22058213.

    Article  CAS  Google Scholar 

  21. Kedar PS, Colah RB, Kulkarni S, Ghosh K, Mohanty D. Experience with eosin-5′-maleimide as a diagnostic tool for red cell membrane cytoskeleton disorders. Clin Lab Haematol. 2003;25:373–6.

    Article  CAS  Google Scholar 

  22. Kar R, Mishra P, Pati HP. Evaluation of eosin-5-maleimide flow cytometric test in diagnosis of hereditary spherocytosis. Int J Lab Hematol. 2010;32:8–16.

    Article  CAS  Google Scholar 

  23. Joshi P, Aggarwal A, Jamwal M, Sachdeva MUS, Bansal D, Malhotra P, et al. A comparative evaluation of Eosin-5′-maleimide flow cytometry reveals a high diagnostic efficacy for hereditary spherocytosis. Int J Lab Hematol. 2016;38:520–6.

    Article  CAS  Google Scholar 

  24. Bolton-Maggs PHB, Langer JC, Iolascon A, Tittensor P, King M-J. Guidelines for the diagnosis and management of hereditary spherocytosis - 2011 update. Br J Haematol [Internet]. 2012;156:37–49. https://doi.org/10.1111/j.1365-2141.2011.08921.x.

    Article  PubMed  Google Scholar 

  25. Alfinito F, Calabro V, Cappellini MD, Fiorelli G, Filosa S, Iolascon A, et al. Glucose 6-phosphate dehydrogenase deficiency and red cell membrane defects: additive or synergistic interaction in producing chronic haemolytic anaemia. Br J Haematol. 1994;87:148–52.

    Article  CAS  Google Scholar 

  26. del Giudice EM, Perrotta S, Nobili B, Specchia C, d’Urzo G, Iolascon A. Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis. Blood. 1999;94:2259–62.

    PubMed  Google Scholar 

  27. Li CK, Heung-Ling Ng M, Cheung KL, Lam TK, Ming-Kong SM. Interaction of hereditary spherocytosis and alpha thalassaemia: a family study. Acta Haematol. 1994;91:201–5.

    Article  CAS  Google Scholar 

  28. Sukumar S, Mukherjee MB, Colah RB, Mohanty D. Molecular basis of G6PD deficiency in India. Blood Cells Mol Dis. 2004;33:141–5.

    Article  CAS  Google Scholar 

  29. Lee HJ, Moon HS, Lee ES, Kim SH, Sung JK, Lee BS, et al. A case of concomitant Gilbert’s syndrome and hereditary spherocytosis. Korean J Hepatol. 2010;16:321–4. https://doi.org/10.3350/kjhep.2010.16.3.321.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Iijima S, Ohzeki T, Maruo Y. Hereditary spherocytosis coexisting with UDP-glucuronosyltransferase deficiency highly suggestive of Crigler-Najjar syndrome type II. Yonsei Med J. 2011;52:369–72.

    Article  CAS  Google Scholar 

  31. Rivet C, Caron N, Lachaux A, Morel B, Pracros JP, Francina A, et al. Association of a glucose-6-phosphate deficiency and a Gilbert syndrome as risk factors for a severe choledocholithiasis in a 2-month-old male infant. Pediatr Blood Cancer. 2012;58:316.

    Article  Google Scholar 

  32. Jamwal M, Aggarwal A, Kumar V, Sharma P, Sachdeva MUS, Bansal D, et al. Disease-modifying influences of coexistent G6PD-deficiency, Gilbert syndrome and deletional alpha thalassemia in hereditary spherocytosis: a report of three cases. Clin Chim Acta. 2016;458:51–4. http://linkinghub.elsevier.com/retrieve/pii/S0009898116301450.

    Article  CAS  Google Scholar 

  33. Heaton DC, Fellowes AP, George PM. Concurrence of hereditary spherocytosis and alpha thalassaemia. Aust NZ J Med. 1991;21:485–6.

    Article  CAS  Google Scholar 

  34. Gallagher PG. Hereditary elliptocytosis: spectrin and protein 4.1R. Semin Hematol. 2004;41:142–64.

    Article  CAS  Google Scholar 

  35. Zhang Z, Weed SA, Gallagher PG, Morrow JS. Dynamic molecular modeling of pathogenic mutations in the spectrin self-association domain. Blood. 2001;98:1645–53.

    Article  CAS  Google Scholar 

  36. Wrong O, Bruce LJ, Unwin RJ, Toye AM, Tanner MJA. Band 3 mutations, distal renal tubular acidosis, and Southeast Asian ovalocytosis. Kidney Int. 2002;62:10–9.

    Article  CAS  Google Scholar 

  37. Reardon DM, Seymour CA, Cox TM, Pinder JC, Schofield AE, Tanner MJA. Hereditary ovalocytosis with compensated haemolysis. Br J Haematol. 1993;85:197–9.

    Article  CAS  Google Scholar 

  38. Jarolim P, Palek J, Amato D, Hassan K, Sapak P, Nurse GT, et al. Deletion in erythrocyte band 3 gene in malaria-resistant Southeast Asian ovalocytosis. Proc Natl Acad Sci U S A. 1991;88:11022–6. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=53065&tool=pmcentrez&rendertype=abstract.

    Article  CAS  Google Scholar 

  39. Picard V, Proust A, Eveillard M, Flatt JF, Couec ML, Caillaux G, et al. Homozygous Southeast Asian ovalocytosis is a severe dyserythropoietic anemia associated with distal renal tubular acidosis. Blood. 2014;123:1963–5.

    Article  CAS  Google Scholar 

  40. Glogowska E, Gallagher PG. Disorders of erythrocyte volume homeostasis. Int J Lab Hematol. 2015;37:85–91.

    Article  Google Scholar 

  41. Manzoor F, Bhat S, Bashir N, Geelani S, Rasool J. Hereditary stomatocytosis: first case report from Valley of Kashmir. Med J Dr DY Patil Univ. 2015;8:347. http://www.mjdrdypu.org/text.asp?2015/8/3/347/157083.

    Article  Google Scholar 

  42. Jamwal M, Aggarwal A, Sachdeva MUS, Sharma P, Malhotra P, Maitra A, et al. Overhydrated stomatocytosis associated with a complex RHAG genotype including a novel de novo mutation. J Clin Pathol. 2018;71:648–52. https://doi.org/10.1136/jclinpath-2018-205018.

    Article  CAS  PubMed  Google Scholar 

  43. Stewart GW, Amess JA, Eber SW, Kingswood C, Lane PA, Smith BD, et al. Thrombo-embolic disease after splenectomy for hereditary stomatocytosis. Br J Haematol. 1996;93:303–10.

    Article  CAS  Google Scholar 

  44. Bruce LJ. Hereditary stomatocytosis and cation leaky red cells—recent developments. Blood Cells Mol Dis. 2009;42:216–22.

    Article  CAS  Google Scholar 

  45. Houston BL, Zelinski T, Israels SJ, Coghlan G, Chodirker BN, Gallagher PG, et al. Refinement of the hereditary xerocytosis locus on chromosome 16q in a large Canadian kindred. Blood Cells Mol Dis. 2011;47:226–31.

    Article  CAS  Google Scholar 

  46. Grootenboer S, Schischmanoff PO, Laurendeau I, Cynober T, Tchernia G, Dommergues JP, et al. Pleiotropic syndrome of dehydrated hereditary stomatocytosis, pseudohyperkalemia, and perinatal edema maps to 16q23-q24. Blood. 2000;96:2599–605. http://www.ncbi.nlm.nih.gov/pubmed/11001917.

    CAS  PubMed  Google Scholar 

  47. Andolfo I, Russo R, Manna F, Shmukler BE, Gambale A, Vitiello G, et al. Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis). Am J Hematol. 2015;90:921–6.

    Article  CAS  Google Scholar 

  48. Rapetti-Mauss R, Lacoste C, Picard V, Guitton C, Lombard E, Loosveld M, et al. A mutation in the Gardos channel is associated with hereditary xerocytosis. Blood. 2015;126:1273–80.

    Article  CAS  Google Scholar 

  49. Glogowska E, Lezon-Geyda K, Maksimova Y, Schulz VP, Gallagher PG. Mutations in the Gardos channel (KCNN4) are associated with hereditary xerocytosis. Blood. 2015;126:1281–4.

    Article  CAS  Google Scholar 

  50. Andolfo I, Alper SL, Delaunay J, Auriemma C, Russo R, Asci R, et al. Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia. Am J Hematol. 2013;88:66–72.

    Article  CAS  Google Scholar 

  51. Rees DC, Iolascon A, Carella M, O’Marcaigh AS, Kendra JR, Jowitt SN, et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol. 2005;130:297–309.

    Article  CAS  Google Scholar 

  52. Jamwal M, Aggarwal A, Maitra A, Sharma P, Bansal D, Trehan A, et al. First report of Mediterranean stomatocytosis/macrothrombocytopenia in an Indian family: a diagnostic dilemma. Pathology. 2017;49:811.

    Article  Google Scholar 

  53. Sun Y, Ruivenkamp CAL, Hoffer MJV, Vrijenhoek T, Kriek M, van Asperen CJ, et al. Next-generation diagnostics: gene panel, exome, or whole genome? Hum Mutat. 2015;36:648–55.

    Article  CAS  Google Scholar 

  54. Roy NBA, Wilson EA, Henderson S, Wray K, Babbs C, Okoli S, et al. A novel 33-gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias. Br J Haematol. 2016;175:318–30.

    Article  CAS  Google Scholar 

  55. Del Orbe BR, Arrizabalaga B, De la Hoz AB, García-Orad A, Tejada MI, Garcia-Ruiz JC, et al. Detection of new pathogenic mutations in patients with congenital haemolytic anaemia using next-generation sequencing. Int J Lab Hematol. 2016;38:629–38.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

    Anu Aggarwal, Manu Jamwal & Reena Das

Authors
  1. Anu Aggarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manu Jamwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reena Das
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reena Das .

Editor information

Editors and Affiliations

  1. Department of Hematology, All India Institute of Medical Sciences, New Delhi, India

    Renu Saxena

  2. Department of Hematology, All India Institute of Medical Sciences, New Delhi, India

    Hara Prasad Pati

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Aggarwal, A., Jamwal, M., Das, R. (2019). Molecular Genetics of Inherited Red Cell Membrane Disorders. In: Saxena, R., Pati, H. (eds) Hematopathology. Springer, Singapore. https://doi.org/10.1007/978-981-13-7713-6_5

Download citation

  • DOI: https://doi.org/10.1007/978-981-13-7713-6_5

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-13-7712-9

  • Online ISBN: 978-981-13-7713-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation