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

• Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger AE1, cause distal renal tubular acidosis (dRTA), a disease of defective urinary acidification by the distal nephron [12].
• Autosomal dominant and recessive distal renal tubular acidosis (dRTA) can be caused by mutations in the anion exchanger 1 (AE1 or SLC4A1) gene, which encodes the erythroid chloride/bicarbonate anion exchanger membrane glycoprotein (eAE1) and a truncated kidney isoform (kAE1) [13].
• Anion exchanger 1 in human kidney and oncocytoma differs from erythroid AE1 in its NH2 terminus [14].
• RESULTS: Hematoxylin and eosin-positive and AE1/AE3-positive lymph node metastases were found in 59% and 77% of patients, respectively [15].
• The degree of hypokalemia varies depending on whether the disease is autosomal autosomal-recessive or dominant, but, interestingly, it occurs in defects caused by mutations in genes encoding the AE-1 exchanger, the carbonic anhydrase II gene, and genes encoding different subunits of the H+ adenosine triphosphatase [16].

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

• P4.2 deficiency does not affect band 3 anion transport activity, since uptake of radiolabeled sulfate was similar for control and P4.2-deficient RBCs [26].
• The results show that the interaction of calnexin with the polytopic membrane glycoprotein AE1 was dependent on the presence but not the location of the oligosaccharide [25].
• Others report that carbonic anhydrase II (CA II) binds to the C termini of the anion exchanger AE1 and the electrogenic Na/HCO3 cotransporter NBCe1-A, enhancing transport [27].
• Glutathione S-transferase pull-down assays revealed that the interaction between CAIV and AE1 occurs on the large fourth extracellular loop of AE1 [28].
• An association of calnexin with truncated versions of N-glycosylated AE1 was detected after release of the nascent chains from ribosomes with puromycin [25].

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].

References