The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

SLC4A1  -  solute carrier family 4 (anion exchanger),...

Homo sapiens

Synonyms: AE 1, AE1, Anion exchange protein 1, Anion exchanger 1, BND3, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of SLC4A1

  • All affected patients in four families with autosomal dominant familial renal tubular acidosis (dRTA) were heterozygous for mutations in their red cell HCO3-/Cl- exchanger, band 3 (AE1, SLC4A1) genes, and these mutations were not found in any of the nine normal family members studied [1].
  • We describe three mutations of the red-cell anion exchangerband 3 (AE1, SLC4A1) gene associated with distalrenal tubular acidosis (dRTA) in families from Malaysia and Papua NewGuinea: Gly(701)-->Asp (G701D), Ala(858)-->Asp(A858D) and deletion of Val(850) (DeltaV850) [2].
  • These mutations comprise a group almost entirely distinct from the SLC4A1 mutations that underlie the familial hemolytic anemia of hereditary spherocytosis [3].
  • 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 [4].
  • We also investigated methylation profiles in peripheral blood mononuclear cells from patients with red cell membrane diseases, such as complete protein 4.2 deficiency due to ELB42 mutations, hereditary spherocytosis with EPB3 mutations, and hereditary elliptocytosis with SPTB mutations [5].

Psychiatry related information on SLC4A1

  • Whereas the western-type diet (WD) is representative of the usual dietary habits, the normal mixed diet (ND) and the ovo-lacto-vegetarian diet (VD) were calculated according to the requirements [6].

High impact information on SLC4A1

  • Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate exchanger, AE1 [7].
  • Autosomal dominant distal renal tubular acidosis (ddRTA) is caused by mutations in SLC4A1, which encodes the polytopic chloride-bicarbonate exchanger AE1 that is normally expressed at the basolateral surface of alpha-intercalated cells in the distal nephron [8].
  • The identification of this symptom-modulating RNA as a co-linear deletion mutant of the helper virus genome establishes it as the first definitive defective interfering RNA (DI RNA) to be identified in association with a plant virus [9].
  • Here we show that in human erythrocytes haemoglobin-derived S-nitrosothiol (SNO), generated from imported NO, is associated predominantly with the red blood cell membrane, and principally with cysteine residues in the haemoglobin-binding cytoplasmic domain of the anion exchanger AE1 [10].
  • Anion exchange chromatography separated from normal neutrophil cytosol a 47-kilodalton neutrophil cytosol factor, NCF-1, that restored activity to defective neutrophil cytosol from most patients with autosomally inherited CGD in a cell-free O2.--generating system [11].

Chemical compound and disease context of SLC4A1


Biological context of SLC4A1

  • MATERIALS AND METHODS: DNA from the members of three unrelated kindreds whose red cells type as Sw(a+) was isolated and analyzed for variation in SLC4A1 (solute carrier family, anion exchanger member 1 gene) by single-strand conformational polymorphism (SSCP) and DNA sequence analyses [17].
  • Molecular demonstration of SLC4A1 gene deletion in two Mexican patients with Southeast Asian ovalocytosis [18].
  • The SLC4A1 gene was screened, analyzed, and confirmed for mutations by molecular genetic techniques [19].
  • In this study, we have used cell-free binding assays to investigate the interaction of anion exchangers with an Ank1 fragment, R13-H, that contains the AE1 binding site [20].
  • The AE1 binding domain of ankyrin consists of 24 tandem repeats of a 33-amino acid motif that is present on a wide variety of otherwise unrelated proteins [21].

Anatomical context of SLC4A1

  • The erythrocyte membrane provides the best studied example of how the spectrin-actin based membrane cytoskeleton is linked via two proteins, ankyrin and protein 4.1, to the anion exchanger (anion exchanger 1, AE1) [22].
  • The major anion exchanger in type A intercalated cells of the cortical and medullary collecting ducts of the human kidney is a truncated isoform of erythrocyte band 3 (AE1) that lacks the N-terminal 65 residues [23].
  • The major kidney isoform of AE1 (kAE1), a protein that is otherwise identical to erythroid AE1 but lacks the NH2-terminal 79 amino acids, is localized to the basolateral plasma membrane of acid-secreting (alpha-type) intercalated cells of distal nephron [20].
  • Human red cell glycophorin A (GPA) enhances the expression of band 3 anion transport activity at the cell surface of Xenopus oocytes [24].
  • The interaction of the endoplasmic reticulum chaperone calnexin with N-glycosylation mutants of a polytopic membrane glycoprotein, the human erythrocyte anion exchanger (AE1), was characterized by cell-free translation and in transfected HEK293 cells, followed by co-immunoprecipitation using anti-calnexin antibody [25].

Associations of SLC4A1 with chemical compounds


Physical interactions of SLC4A1

  • The extracellular component of a transport metabolon. Extracellular loop 4 of the human AE1 Cl-/HCO3- exchanger binds carbonic anhydrase IV [28].
  • Monoclonal antibodies (MAbs) to cytokeratins included MAb KA 1, which binds to polypeptide 5 in a complex with polypeptide 14 and recognizes preferentially myoepithelial cells; MAb KA4, which binds to polypeptides 14, 15, 16 and 19; individual MAbs to polypeptides 7, 13, and 16, 17, 18, and 19, and the MAb mixture AE1/AE3 [29].

Regulatory relationships of SLC4A1

  • AE2 is a widely expressed anion exchanger and has a homologous Ct region with 60% sequence identity to AE1 [30].
  • AE1 activity was maximally inhibited 61 +/- 4% in the presence of V143Y CAII [31].
  • Anion-exchange chromatography of culture supernatant from cells expressing a soluble truncated form of human furin resulted in a greatly enriched preparation of the endoprotease (approximately 70% pure as determined by protein staining) [32].

Other interactions of SLC4A1

  • This effect of GPA could occur in two ways, enhancement of band 3 anion transport function or enhancement of band 3 trafficking to the cell surface [24].
  • To determine whether cell surface-anchored carbonic anhydrase IV (CAIV) interacts with AE proteins to accelerate the bicarbonate transport rate, AE1-mediated bicarbonate transport was monitored in transfected HEK293 cells [28].
  • The binding of the basic amino-terminal region of CAII to an acidic Ct in AE1 provides a structural basis for linking bicarbonate transport across the cell membrane to intracellular bicarbonate metabolism [33].
  • The homologous isoform CAI does not bind AE1, despite having 60% sequence identity to CAII [33].
  • In search of sequence motifs involved in binding of integral membrane proteins to components of the cytoskeleton we found that the binding interface of AE1 to protein 4.1 (an actin and spectrin cross-linking protein) consists of a cluster of five amino acid residues, namely IRRRY in AE1 and LEEDY on protein 4 [34].

Analytical, diagnostic and therapeutic context of SLC4A1

  • AE1, AE1 R589H, and kAE1 were present at the cell surface, whereas kAE1 R589H was located primarily intracellularly as shown by immunofluorescence, cell surface biotinylation, N-glycosylation, and anion transport assays [35].
  • EPB3 has previously been mapped to 17q21-qter by in situ hybridization, and linkage analysis showed that EPB3 is tightly linked to the gene for the nerve growth factor receptor (NGFR) [36].
  • AE1 and vH(+)-ATPase polypeptides in kidney tissue from an AE1 R589H patient were examined by immunocytochemistry for the first time [37].
  • DNA was extracted, amplified by PCR using intronic primer sets flanking exons 11-20 of SLC4A1, and screened by single-strand conformation polymorphism (SSCP) analysis [38].
  • Using size exclusion chromatography, both AE1 and AE1C- were found to associate as a mixture of dimers and high molecular mass complexes [39].


  1. Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene. Bruce, L.J., Cope, D.L., Jones, G.K., Schofield, A.E., Burley, M., Povey, S., Unwin, R.J., Wrong, O., Tanner, M.J. J. Clin. Invest. (1997) [Pubmed]
  2. Band 3 mutations, renal tubular acidosis and South-East Asian ovalocytosis in Malaysia and Papua New Guinea: loss of up to 95% band 3 transport in red cells. Bruce, L.J., Wrong, O., Toye, A.M., Young, M.T., Ogle, G., Ismail, Z., Sinha, A.K., McMaster, P., Hwaihwanje, I., Nash, G.B., Hart, S., Lavu, E., Palmer, R., Othman, A., Unwin, R.J., Tanner, M.J. Biochem. J. (2000) [Pubmed]
  3. Defects in processing and trafficking of the AE1 Cl-/HCO3- exchanger associated with inherited distal renal tubular acidosis. Shayakul, C., Alper, S.L. Clin. Exp. Nephrol. (2004) [Pubmed]
  4. 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. Miraglia del Giudice, E., Vallier, A., Maillet, P., Perrotta, S., Cutillo, S., Iolascon, A., Tanner, M.J., Delaunay, J., Alloisio, N. Br. J. Haematol. (1997) [Pubmed]
  5. DNA methylation in promoter regions of red cell membrane protein genes in healthy individuals and patients with hereditary membrane disorders. Remus, R., Kanzaki, A., Yawata, A., Nakanishi, H., Wada, H., Sugihara, T., Zeschnigk, M., Zuther, I., Schmitz, B., Naumann, F., Doerfler, W., Yawata, Y. Int. J. Hematol. (2005) [Pubmed]
  6. The effect of different diets on urine composition and the risk of calcium oxalate crystallisation in healthy subjects. Siener, R., Hesse, A. Eur. Urol. (2002) [Pubmed]
  7. Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate exchanger, AE1. Bruce, L.J., Robinson, H.C., Guizouarn, H., Borgese, F., Harrison, P., King, M.J., Goede, J.S., Coles, S.E., Gore, D.M., Lutz, H.U., Ficarella, R., Layton, D.M., Iolascon, A., Ellory, J.C., Stewart, G.W. Nat. Genet. (2005) [Pubmed]
  8. Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis. Devonald, M.A., Smith, A.N., Poon, J.P., Ihrke, G., Karet, F.E. Nat. Genet. (2003) [Pubmed]
  9. A defective interfering RNA that contains a mosaic of a plant virus genome. Hillman, B.I., Carrington, J.C., Morris, T.J. Cell (1987) [Pubmed]
  10. Export by red blood cells of nitric oxide bioactivity. Pawloski, J.R., Hess, D.T., Stamler, J.S. Nature (2001) [Pubmed]
  11. Two forms of autosomal chronic granulomatous disease lack distinct neutrophil cytosol factors. Nunoi, H., Rotrosen, D., Gallin, J.I., Malech, H.L. Science (1988) [Pubmed]
  12. A novel missense mutation in AE1 causing autosomal dominant distal renal tubular acidosis retains normal transport function but is mistargeted in polarized epithelial cells. Rungroj, N., Devonald, M.A., Cuthbert, A.W., Reimann, F., Akkarapatumwong, V., Yenchitsomanus, P.T., Bennett, W.M., Karet, F.E. J. Biol. Chem. (2004) [Pubmed]
  13. Trafficking defects of a novel autosomal recessive distal renal tubular acidosis mutant (S773P) of the human kidney anion exchanger (kAE1). Kittanakom, S., Cordat, E., Akkarapatumwong, V., Yenchitsomanus, P.T., Reithmeier, R.A. J. Biol. Chem. (2004) [Pubmed]
  14. Anion exchanger 1 in human kidney and oncocytoma differs from erythroid AE1 in its NH2 terminus. Kollert-Jöns, A., Wagner, S., Hübner, S., Appelhans, H., Drenckhahn, D. Am. J. Physiol. (1993) [Pubmed]
  15. Paratracheal lymph node metastasis is associated with cervical lymph node metastasis in patients with thoracic esophageal squamous cell carcinoma. Sato, F., Shimada, Y., Li, Z., Kano, M., Watanabe, G., Maeda, M., Kawabe, A., Kaganoi, J., Itami, A., Nagatani, S., Imamura, M. Ann. Surg. Oncol. (2002) [Pubmed]
  16. Distal renal tubular acidosis and the potassium enigma. Batlle, D., Moorthi, K.M., Schlueter, W., Kurtzman, N. Semin. Nephrol. (2006) [Pubmed]
  17. Distinctive Swann blood group genotypes: molecular investigations. Zelinski, T., Rusnak, A., McManus, K., Coghlan, G. Vox Sang. (2000) [Pubmed]
  18. Molecular demonstration of SLC4A1 gene deletion in two Mexican patients with Southeast Asian ovalocytosis. Ramos-Kuri, M., Carrillo Farga, J., Zúñiga, J., Amador Guerrero, M.T., Granados, J., Estrada, F.J. Hum. Biol. (2005) [Pubmed]
  19. Novel compound heterozygous SLC4A1 mutations in Thai patients with autosomal recessive distal renal tubular acidosis. Sritippayawan, S., Sumboonnanonda, A., Vasuvattakul, S., Keskanokwong, T., Sawasdee, N., Paemanee, A., Thuwajit, P., Wilairat, P., Nimmannit, S., Malasit, P., Yenchitsomanus, P.T. Am. J. Kidney Dis. (2004) [Pubmed]
  20. The major kidney AE1 isoform does not bind ankyrin (Ank1) in vitro. An essential role for the 79 NH2-terminal amino acid residues of band 3. Ding, Y., Casey, J.R., Kopito, R.R. J. Biol. Chem. (1994) [Pubmed]
  21. Mapping of ankyrin binding determinants on the erythroid anion exchanger, AE1. Ding, Y., Kobayashi, S., Kopito, R. J. Biol. Chem. (1996) [Pubmed]
  22. Identification of the binding interface involved in linkage of cytoskeletal protein 4.1 to the erythrocyte anion exchanger. Jöns, T., Drenckhahn, D. EMBO J. (1992) [Pubmed]
  23. Partial characterization of the cytoplasmic domain of human kidney band 3. Wang, C.C., Moriyama, R., Lombardo, C.R., Low, P.S. J. Biol. Chem. (1995) [Pubmed]
  24. Distinct regions of human glycophorin A enhance human red cell anion exchanger (band 3; AE1) transport function and surface trafficking. Young, M.T., Tanner, M.J. J. Biol. Chem. (2003) [Pubmed]
  25. Calnexin interaction with N-glycosylation mutants of a polytopic membrane glycoprotein, the human erythrocyte anion exchanger 1 (band 3). Popov, M., Reithmeier, R.A. J. Biol. Chem. (1999) [Pubmed]
  26. Increased rotational mobility and extractability of band 3 from protein 4.2-deficient erythrocyte membranes: evidence of a role for protein 4.2 in strengthening the band 3-cytoskeleton linkage. Rybicki, A.C., Schwartz, R.S., Hustedt, E.J., Cobb, C.E. Blood (1996) [Pubmed]
  27. Effect of human carbonic anhydrase II on the activity of the human electrogenic Na/HCO3 cotransporter NBCe1-A in Xenopus oocytes. Lu, J., Daly, C.M., Parker, M.D., Gill, H.S., Piermarini, P.M., Pelletier, M.F., Boron, W.F. J. Biol. Chem. (2006) [Pubmed]
  28. The extracellular component of a transport metabolon. Extracellular loop 4 of the human AE1 Cl-/HCO3- exchanger binds carbonic anhydrase IV. Sterling, D., Alvarez, B.V., Casey, J.R. J. Biol. Chem. (2002) [Pubmed]
  29. Coexpression patterns of vimentin and glial filament protein with cytokeratins in the normal, hyperplastic, and neoplastic breast. Gould, V.E., Koukoulis, G.K., Jansson, D.S., Nagle, R.B., Franke, W.W., Moll, R. Am. J. Pathol. (1990) [Pubmed]
  30. Identification of the carbonic anhydrase II binding site in the Cl(-)/HCO(3)(-) anion exchanger AE1. Vince, J.W., Reithmeier, R.A. Biochemistry (2000) [Pubmed]
  31. A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers. Sterling, D., Reithmeier, R.A., Casey, J.R. J. Biol. Chem. (2001) [Pubmed]
  32. Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves anthrax toxin protective antigen. Molloy, S.S., Bresnahan, P.A., Leppla, S.H., Klimpel, K.R., Thomas, G. J. Biol. Chem. (1992) [Pubmed]
  33. Localization of the Cl-/HCO3- anion exchanger binding site to the amino-terminal region of carbonic anhydrase II. Vince, J.W., Carlsson, U., Reithmeier, R.A. Biochemistry (2000) [Pubmed]
  34. Cytoskeleton and epithelial polarity. Drenckhahn, D., Jöns, T., Kollert-Jöns, A., Koob, R., Kraemer, D., Wagner, S. Renal physiology and biochemistry. (1993) [Pubmed]
  35. Impaired trafficking of distal renal tubular acidosis mutants of the human kidney anion exchanger kAE1. Quilty, J.A., Li, J., Reithmeier, R.A. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  36. A PstI polymorphism for the human erythrocyte surface protein band 3 (EPB3) demonstrates close linkage of EPB3 to the nerve growth factor receptor. Stewart, E.A., Kopito, R., Bowcock, A.M. Genomics (1989) [Pubmed]
  37. Characterization of a highly polymorphic marker adjacent to the SLC4A1 gene and of kidney immunostaining in a family with distal renal tubular acidosis. Shayakul, C., Jarolim, P., Zachlederova, M., Prabakaran, D., Cortez-Campeao, D., Kalabova, D., Stuart-Tilley, A.K., Ideguchi, H., Haller, C., Alper, S.L. Nephrol. Dial. Transplant. (2004) [Pubmed]
  38. An amino acid substitution in the putative second extracellular loop of RBC band 3 accounts for the Froese blood group polymorphism. McManus, K., Lupe, K., Coghlan, G., Zelinski, T. Transfusion (2000) [Pubmed]
  39. The role of cysteine residues in the erythrocyte plasma membrane anion exchange protein, AE1. Casey, J.R., Ding, Y., Kopito, R.R. J. Biol. Chem. (1995) [Pubmed]
WikiGenes - Universities