We will consider an array of genetic disorders of the red cell membrane. Some affect well-known genes. The mutations of most cases of hereditary spherocytosis (HS) are located in the following genes: ANK1, SPTB, SLC4A1, EPB42 and SPTA1, which encode ankyrin, spectrin β-chain, the anion exchanger 1 (band 3), protein 4.2 and spectrin α-chain, respectively. A dominant form of distal renal tubular acidosis also stems from distinct mutations in the SLC4A1 gene. The mutations responsible for hereditary elliptocytosis (HE) and its aggravated form, poikilocytosis (HP), lie in the SPTA1 and SPTB gene, already mentioned, and in the EPB41 gene encoding protein 4.1. Whereas in HS, the SPTA1 and SPTB gene mutations tend to abolish the synthesis of the corresponding chains, in HE/HP, they hinder spectrin tetramerization. Allele αLELY is a common polymorphic allele which plays the role of an aggravating factor when it occurs in trans of an elliptocytogenic allele of the SPTA1 gene. Southeast Asian ovalocytosis results from a 27- nucleotide deletion in the SLC4A1 gene. Besides these conditions in which the mutations were reached from known alterations in the proteins, other conditions required a positional cloning approach. Such are the genetic disorders of membrane permeability to monovalent cations. Knowledge is the most advanced as regards dehydrated hereditary stomatocytois (DHS). DHS was shown to belong to a pleiotropic syndrome: DHS + fetal edema + pseudohyperkalemia, which maps to 16q23–24. Concerning DHS and another disease of the same class, overhydrated hereditary stomatocytosis, splenectomy almost certainly appears to elicit thromboembolic accidents.

1.
Gallagher PG, Forget BG: Hematologically important mutations: Spectrin and ankyrin variants in hereditary spherocytosis. Blood Cells Mol Dis 1998;24:539–543.
2.
Gallagher PG, Forget B: Hematologically important mutations: Band 3 and protein 4.2 in hereditary spherocytosis. Blood Cells Mol Dis 1997;23:417–421.
3.
Peters LL, Shivdasani RA, Liu SC, Hanspal M, John KM, Gonzalez JM, Brugnara C, Gwynn B, Mohandas N, Alper SL, Orkin SH, Lux SE: Anion exchanger 1 (band 3) is required to prevent erythrocyte surface loss but not to form the membrane skeleton. Cell 1996;86:917–927.
4.
Southgate CD, Chishti AH, Mitchell B, Yi SJ, Palek J: Targeted disruption of the murine erythroid band 3 gene results in spherocytosis and severe haemolytic anaemia despite a normal membrane skeleton. Nat Genet 1996;14:227–230.
5.
Hassoun H, Wang Y, Vassiliadis J, Lutchman M, Palek J, Aish L, Aish IS, Liu SC, Chishti AH: Targeted inactivation of murine band 3 (AE1) gene produces a hypercoagulable state causing widespread thrombosis in vivo. Blood 1998;92:1785–1792.
6.
Alloisio N, Maillet P, Carré G, Texier P, Vallier A, Baklouti F, Philippe N, Delaunay J: 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;88:1062–1069.
7.
Alloisio N, Texier P, Vallier A, Ribeiro ML, Morlé L, Bozon M, Bursaux E, Maillet P, Goncalves P, Tanner MJ, Tamagnini G, Delaunay J: Modulation of clinical expression and 3 deficiency in hereditary spherocytosis. Blood 1997;90:414–420.
8.
Ribeiro L, Alloisio N, Almeida H, Gomes C, Texier P, Lemos C, Mimoso G, Morlé L, Bey-Cabet F, Rudigoz RC, Delaunay J, Tamagnini G: Near lethal hereditary spherocytosis and distal tubular acidosis associated with the total absence of band 3. Blood 2000;96:1602–1604.
9.
Bruce LJ, Cope DL, Jones GK, Schofield AE, Burley M, Povey S, Unwin RJ, Wrong O, Tanner MJ: Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (band 3, AE1) gene. J Clin Invest 1997;100:1693–1707.
10.
Jarolim P, Shayakul C, Prabakaran D, Jiang L, Stuart-Tilley A, Rubin HL, Simova S, Zavadil J, Herrin JT, Brouillette J, Somers MJG, Seemanova E, Brugnara C, Guay-Woodford LM, Alper SL: Autosomal dominant distal renal tubular acidosis is associated in three families with heterozygosity for the R589H mutation in the AE1 (band 3) Cl/CO3 exchanger. J Biol Chem 1998;273:6380–6388.
11.
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;98:2300–2307.
12.
Alloisio N, Morlé L, Maréchal J, Roux AF, Ducluzeau MT, Guetarni D, Pothier B, Baklouti F, Ghanem A, Kastally R, Delaunay J: SpαV/41: A common spectrin polymorphism at the αIV-αV domain junction. Relevance to the expression level of hereditary elliptocytosis due to α-spectrin variants located in trans. J Clin Invest 1991;87:2169–2177.
13.
Wilmotte R, Maréchal J, Morlé L, Baklouti F, Philippe N, Kastally R, Kotula L, Delaunay J, Alloisio N: Low expression allele αLELY of red cell spectrin is associated with mutations in exon 40 (αV/41 polymorphism) and intron 45 and with partial skipping of exon 46. J Clin Invest 1993;91:2091–2096.
14.
Jarolim P, Palek J, Amato D, Hassan K, Sapak P, Nurse GT, Rubin HL, Zhai S, Sahr KE, Liu SC: Deletion of erythrocyte band 3 gene in malaria-resistant Southeast Asian ovalocytosis. Proc Natl Acad Sci USA 1991;88:11022–11026.
15.
Schofield AE, Tanner MJA, Pinder JC, Clough B, Bayley PM, Nash GB, Dluzewski AR, Reardon DM, Cox TM, Wilson RJM, Gratzer WB: Basis of unique red cell membrane properties in hereditary ovalocytosis. J Mol Biol 1992;223:949–958.
16.
Stewart GW, Amess JAL, Eber SW, Kingswood C, Lane PA, Smith BD, Mentzer WC: Thrombo-embolic disease after splenectomy for hereditary stomatocytosis. Br J Haematol 1996;93:303–310.
17.
Zhu Y, Paszty C, Turetsky T, Tsai S, Kuypers FA, Lee G, Cooper P, Gallagher PG, Stevens ME, Rubin E, Mohandas N, Mentzer WC: Stomatocytosis is absent in ‘stomatin’-deficient murine red blood cells. Blood 1999;93:2404–2410.
18.
Salzer U, Prohaska R: Stomatin, flotillin-1 and flotillin-2 are major integral proteins of erythrocyte lipids rafts. Blood 2001;97:1141–1143.
19.
Iolascon A, Stewart G, Ajetunmobi JF, Perrotta S, Delaunay J, Carella M, Zelante L, Gasparini P: Familial pseudohyperkalemia maps to the same locus as dehydrated hereditary stomatocytosis (hereditary xerocytosis). Blood 1999;93:3120–3123.
20.
Carella M, Stewart G, Ajetunmobi JF, Perrotta S, Grootenboer S, Tchernia G, Delaunay J, Totaro A, Zelante L, Gasparini P, Iolascon A: Genomewide search for dehydrated hereditary stomatocytosis (hereditary xerocytosis): Mapping of locus to chromosome 16 (16q23-qter). Am J Hum Genet 1998;63:810–816.
21.
Grootenboer S, Schischmanoff PO, Laurendeau I, Cynober T, Tchernia G, Dommergues JP, Dhermy D, Bost M, Varet B, Snyder M, Ballas SK, Ducot B, Babron MC, Stewart GW, Gasparini P, Iolascon A, Delaunay J: Pleiotropic syndrome of dehydrated hereditary stomatocytosis, pseudohyperkalemia and perinatal edema maps to 16q23-q24. Blood 2000;96:2599–2605.
22.
Coles SE, Ho MH, Chetty MC, Nicolaou A, Stewart GW: A variant of hereditary stomatocytosis with marked pseudohyperkalaemia. Br J Haematol 1999;104:275–283.
23.
Carella M, Stewart G, Ajetunmobi JF, Schettini F Jr, Delaunay J, Iolascon A: Genetic heterogeneity of hereditary stomatocytosis syndrome showing pseudohyperkalaemia (correspondence). Haematologica 1999;84:862–864.
24.
Haines PG, Jarvis HG, King S, Noormohamed FH, Chetty MC, Fisher J, Hill P, Nicolaou A, Stewart GW: Two further British families with the ‘cryohydrocytosis’ form of hereditary stomatocytosis. Br J Haematol 2001;113:932–937.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.