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Gene Review

SLC4A3  -  solute carrier family 4 (anion exchanger),...

Homo sapiens

Synonyms: AE 3, AE3, Anion exchange protein 3, Anion exchanger 3, CAE3/BAE3, ...
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Disease relevance of SLC4A3

  • In order to study the potential role of AE3 in human neurological disease, we characterized AE3 genomic structure and performed mutational analysis on patients with an episodic movement disorder that maps to the same genetic locus [1].
  • Human SLC4A3/AE3 polymorphisms have been associated with seizure disorder [2].
  • In contrast, amyloids in lichen amyloidosus and macular amyloidosis were stained strongly with EKH4 but only weakly or not at all with AE1, AE2, AE3, and EKH1 [3].
  • Cytoid bodies in lichen planus (LP) and discoid lupus erythematosus (DLE) were strongly stained with AE1, AE3, EKH4, and EKH1 antibodies but were negative with AE2 [3].
  • BM aspirates from 920 patients with primary breast cancer were analyzed for tumor cells by standardized direct immunocytochemical analysis (ICC) of 2 x 10(6) mononuclear cells (MNCs) using anticytokeratin monoclonal antibody (AE1/AE3) [4].

High impact information on SLC4A3

  • Characterization of an AE3 mutant lacking the NH2-terminal 645 amino acids demonstrates that the COOH-terminal half of the polypeptide is both necessary and sufficient for correct insertion into the plasma membrane and for anion exchange activity [5].
  • Expression of AE3 cDNA in COS cells leads to chronic cytoplasmic acidification and to chloride- and bicarbonate-dependent changes in intracellular pH, confirming that this gene product is an anion exchanger [5].
  • Through extensive longitudinal analyses of human factor IX gene expression in transgenic mice, two essential age-regulatory elements, AE5' and AE3', have been identified [6].
  • Keratin proteins of both the acidic (AE1-reactive, type I) and the basic (AE3-reactive, type II) subfamilies were present throughout development [7].
  • Specifically, a 50-kilodalton (kd) (AE1-positive) and a 58-kd (AE3-positive) keratin are present in all diseases, supporting the concept that they represent "permanent" markers for keratinocytes [8].

Chemical compound and disease context of SLC4A3

  • RESULTS: Hematoxylin and eosin-positive and AE1/AE3-positive lymph node metastases were found in 59% and 77% of patients, respectively [9].
  • RESULTS--The luminal epithelium in all fibroadenomas and all cases of fibrocystic disease, as well as tumour cells in most carcinomas, reacted with the specific antibodies to cytokeratins 7, 8, 18, and 19 and to antibodies which included these cytokeratins in their specificities (Cam 5.2, AE1, AE3, RCK102, and LP34) [10].
  • Paraffin blocks of all axillary lymph nodes from 97 patients with an initial histologic diagnosis of infiltrating ductal carcinoma and negative axillary nodes were recut and stained with two monoclonal antibodies, AE/AE3 (antikeratin) and DF3 (developed against breast cancer cells and reactive with a glycoprotein tumor-associated antigen) [11].

Biological context of SLC4A3

  • Polymorphic tandem repeats within the candidate genes CHRND (delta polypeptide of the nicotinic acetylcholine receptor) and SLC4A3 were examined yielding LOD scores of -7.68 and 6.08, respectively, at a recombination fraction of 0 [12].
  • Injection into Xenopus oocytes of cRNAs encoding either cAE3 or bAE3 produced increased 36Cl- uptake into the oocytes, confirming the ability of both AE3 isoforms to transport Cl-. The human AE3 gene was localized to chromosome 2 [13].
  • A polymorphic dinucleotide (GT/CA)n repeat marker was developed from sequences in the AE3 cosmid and typed on a subset of the CEPH families [14].
  • Fractional length measurements were made, and AE3 mapped at high resolution to the cytogenetic band 2q36 [14].
  • AE3 genomic organization, including the nucleotide sequence of the 5'-untranslated region and intron/ exon boundaries, is highly conserved between humans and homologs from mouse and rat [1].

Anatomical context of SLC4A3

  • Oligonucleotide primers based on this sequence were used in a polymerase chain reaction to specifically amplify a segment of the human gene from a panel of human-rodent somatic cell hybrids, allowing the assignment of AE3 to chromosome 2 [14].
  • We conclude that following Ang II stimulation of cells, PKCepsilon phosphorylates serine 67 of the AE3 cytoplasmic domain, inducing the Ang II-induced increase in anion transport observed in the hypertrophic myocardium [15].
  • To determine whether these keratin classes can serve as markers for identifying epithelial cells in culture, we analyzed cytoskeletal proteins from various cultured human cells by the immunoblot technique using AE1 and AE3 monoclonal antikeratin antibodies [16].
  • AE3 mainly stained Mallory bodies and normal hepatocytes, but also stained bile duct epithelium weakly [17].
  • Monoclonal antibodies AE1 (which stains the basal cell layer in normal human epidermis), AE2 (suprabasal layers), AE3 (whole epidermis), EKH4 (lower 2-3 layers), and EKH1 (recognizes all classes of intermediate filaments) were used to stain frozen skin sections by the indirect immunofluorescent or indirect immunoperoxidase technique [3].

Associations of SLC4A3 with chemical compounds

  • Anion exchanger isoform 3 (AE3) is prominently expressed in the brain and performs an electroneutral exchange of chloride and bicarbonate ions [1].
  • Mutation of serine 67 of AE3 prevented the PMA-induced increase of anion transport activity [15].
  • METHODS: Five additional levels from formalin-fixed, paraffin-embedded nodes were examined at 150-microns intervals with H&E staining and a cocktail of antikeratin antibodies (AE1/AE3) recognizing low molecular weight acidic keratins [18].
  • None of the immunostains for individual K showed positivity comparable to that obtained with AE1/AE3 CK [19].
  • They were diagnosed as clear lymph nodes by hematoxylin and eosin stain and then examined immunohistochemically with cytokeratins (AE1/AE3) for evidence of micrometastases [20].

Physical interactions of SLC4A3

  • The wider reactivity of AE1/AE3, lu-5, and MFN 116, which includes cytokeratins 8,18 (Moll's catalogue) expressed in simple epithelia and their tumours, as well as cytokeratins expressed in complex stratified squamous epithelia, permits identification of a wider range of epithelial derived tumours [21].

Other interactions of SLC4A3

  • Association of the brain anion exchanger, AE3, with the repeat domain of ankyrin [22].
  • The most extensively studied among them are the Na+-independent anion exchangers AE1, AE2, and AE3 [23].
  • Naturally occurring mutations in the human AE2 and AE3 genes have not been detected [24].
  • Widespread reactivity for keratin AE1/AE3 corresponds closely to the pattern of GFAP staining [25].
  • Cl(-)-HCO(3)(-) and Cl(-)-OH(-) exchange activity of SLC26A6 and AE3 were investigated in transfected HEK293 cells, using intracellular fluorescence measurements of 2',7'-bis (2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF), to monitor intracellular pH (pH(i)) [26].

Analytical, diagnostic and therapeutic context of SLC4A3


  1. Genomic structure of human anion exchanger 3 and its potential role in hereditary neurological disease. Einum, D.D., Zhang, J., Arneson, P.J., Menon, A.G., Ptacek, L.J. Neurogenetics (1998) [Pubmed]
  2. Molecular physiology of SLC4 anion exchangers. Alper, S.L. Exp. Physiol. (2006) [Pubmed]
  3. Differential staining of cytoid bodies and skin-limited amyloids with monoclonal anti-keratin antibodies. Eto, H., Hashimoto, K., Kobayashi, H., Fukaya, T., Matsumoto, M., Sun, T.T. Am. J. Pathol. (1984) [Pubmed]
  4. Detection of isolated tumor cells in bone marrow in early-stage breast carcinoma patients: comparison with preoperative clinical parameters and primary tumor characteristics. Naume, B., Borgen, E., Kvalheim, G., Kåresen, R., Qvist, H., Sauer, T., Kumar, T., Nesland, J.M. Clin. Cancer Res. (2001) [Pubmed]
  5. Regulation of intracellular pH by a neuronal homolog of the erythrocyte anion exchanger. Kopito, R.R., Lee, B.S., Simmons, D.M., Lindsey, A.E., Morgans, C.W., Schneider, K. Cell (1989) [Pubmed]
  6. Genetic mechanisms of age regulation of human blood coagulation factor IX. Kurachi, S., Deyashiki, Y., Takeshita, J., Kurachi, K. Science (1999) [Pubmed]
  7. Expression of epidermal keratins and filaggrin during human fetal skin development. Dale, B.A., Holbrook, K.A., Kimball, J.R., Hoff, M., Sun, T.T. J. Cell Biol. (1985) [Pubmed]
  8. Monoclonal antibody analysis of keratin expression in epidermal diseases: a 48- and 56-kdalton keratin as molecular markers for hyperproliferative keratinocytes. Weiss, R.A., Eichner, R., Sun, T.T. J. Cell Biol. (1984) [Pubmed]
  9. 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]
  10. Cytokeratin intermediate filament expression in benign and malignant breast disease. Heatley, M., Maxwell, P., Whiteside, C., Toner, P. J. Clin. Pathol. (1995) [Pubmed]
  11. Immunohistochemical detection and significance of axillary lymph node micrometastases in breast carcinoma. A study of 97 cases. Elson, C.E., Kufe, D., Johnston, W.W. Anal. Quant. Cytol. Histol. (1993) [Pubmed]
  12. Paroxysmal dystonic choreoathetosis. Genetic linkage studies in a British family. Jarman, P.R., Davis, M.B., Hodgson, S.V., Marsden, C.D., Wood, N.W. Brain (1997) [Pubmed]
  13. Molecular cloning, expression, and chromosomal localization of two isoforms of the AE3 anion exchanger from human heart. Yannoukakos, D., Stuart-Tilley, A., Fernandez, H.A., Fey, P., Duyk, G., Alper, S.L. Circ. Res. (1994) [Pubmed]
  14. Molecular cloning and physical and genetic mapping of the human anion exchanger isoform 3 (SLC2C) gene to chromosome 2q36. Su, Y.R., Klanke, C.A., Houseal, T.W., Linn, S.C., Burk, S.E., Varvil, T.S., Otterud, B.E., Shull, G.E., Leppert, M.F., Menon, A.G. Genomics (1994) [Pubmed]
  15. Molecular basis for angiotensin II-induced increase of chloride/bicarbonate exchange in the myocardium. Alvarez, B.V., Fujinaga, J., Casey, J.R. Circ. Res. (2001) [Pubmed]
  16. The 50- and 58-kdalton keratin classes as molecular markers for stratified squamous epithelia: cell culture studies. Nelson, W.G., Sun, T.T. J. Cell Biol. (1983) [Pubmed]
  17. Changes in the cytokeratin intermediate filament cytoskeleton associated with Mallory body formation in mouse and human liver. Katsuma, Y., Swierenga, S.H., Khettry, U., Marceau, N., French, S.W. Hepatology (1987) [Pubmed]
  18. Prognostic significance of occult lymph node metastases in node-negative breast cancer. Clare, S.E., Sener, S.F., Wilkens, W., Goldschmidt, R., Merkel, D., Winchester, D.J. Ann. Surg. Oncol. (1997) [Pubmed]
  19. Keratin expression in schwannoma; a study of 115 retroperitoneal and 22 peripheral schwannomas. Fanburg-Smith, J.C., Majidi, M., Miettinen, M. Mod. Pathol. (2006) [Pubmed]
  20. Distribution of lymph node micrometastasis in pN0 well-differentiated thyroid carcinoma. Qubain, S.W., Nakano, S., Baba, M., Takao, S., Aikou, T. Surgery (2002) [Pubmed]
  21. Comparison of commercially available cytokeratin antibodies in normal and neoplastic adult epithelial and non-epithelial tissues. Goddard, M.J., Wilson, B., Grant, J.W. J. Clin. Pathol. (1991) [Pubmed]
  22. Association of the brain anion exchanger, AE3, with the repeat domain of ankyrin. Morgans, C.W., Kopito, R.R. J. Cell. Sci. (1993) [Pubmed]
  23. How pH regulates a pH regulator: a regulatory hot spot in the N-terminal cytoplasmic domain of the AE2 anion exchanger. Alper, S.L., Chernova, M.N., Stewart, A.K. Cell Biochem. Biophys. (2002) [Pubmed]
  24. Regulation of Na+-independent Cl-/HCO3- exchangers by pH. Alper, S.L., Chernova, M.N., Stewart, A.K. JOP (2001) [Pubmed]
  25. The immunophenotype of ependymomas. Vege, K.D., Giannini, C., Scheithauer, B.W. Appl. Immunohistochem. Mol. Morphol. (2000) [Pubmed]
  26. Slc26a6: a cardiac chloride-hydroxyl exchanger and predominant chloride-bicarbonate exchanger of the mouse heart. Alvarez, B.V., Kieller, D.M., Quon, A.L., Markovich, D., Casey, J.R. J. Physiol. (Lond.) (2004) [Pubmed]
  27. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. Wiedswang, G., Borgen, E., Kåresen, R., Kvalheim, G., Nesland, J.M., Qvist, H., Schlichting, E., Sauer, T., Janbu, J., Harbitz, T., Naume, B. J. Clin. Oncol. (2003) [Pubmed]
  28. Change in epithelial keratin expression during healing of rabbit corneal wounds. Jester, J.V., Rodrigues, M.M., Sun, T.T. Invest. Ophthalmol. Vis. Sci. (1985) [Pubmed]
  29. Transport activity of chimaeric AE2-AE3 chloride/bicarbonate anion exchange proteins. Fujinaga, J., Loiselle, F.B., Casey, J.R. Biochem. J. (2003) [Pubmed]
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