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
Lesley J. BruceOliver WrongAshley M. ToyeMark T. YoungGraham D. OgleZulkifli ISMAILAshim K. SINHAPaddy MCMASTERIlomo HWAIHWANJEGerard B. NASHSarah HartEvelyn LAVURonald PALMERAinoon OTHMANRobert J. UnwinMinna Tanner
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Abstract:
We describe three mutations of the red-cell anion exchanger band 3 (AE1, SLC4A1) gene associated with distal renal tubular acidosis (dRTA) in families from Malaysia and Papua New Guinea: Gly701 → Asp (G701D), Ala858 → Asp (A858D) and deletion of Val850 (δV850). The mutations A858D and ∆V850 are novel; all three mutations seem to be restricted to South-East Asian populations. South-East Asian ovalocytosis (SAO), resulting from the band 3 deletion of residues 400–408, occurred in many of the families but did not itself result in dRTA. Compound heterozygotes of each of the dRTA mutations with SAO all had dRTA, evidence of haemolytic anaemia and abnormal red-cell properties. The A858D mutation showed dominant inheritance and the recessive ∆V850 and G701D mutations showed a pseudo-dominant phenotype when the transport-inactive SAO allele was also present. Red-cell and Xenopus oocyte expression studies showed that the ∆V850 and A858D mutant proteins have greatly decreased anion transport when present as compound heterozygotes (∆V850/A858D, ∆V850/SAO or A858D/SAO). Red cells with A858D/SAO had only 3% of the SO42- efflux of normal cells, the lowest anion transport activity so far reported for human red cells. The results suggest dRTA might arise by a different mechanism for each mutation. We confirm that the G701D mutant protein has an absolute requirement for glycophorin A for movement to the cell surface. We suggest that the dominant A858D mutant protein is possibly mis-targeted to an inappropriate plasma membrane domain in the renal tubular cell, and that the recessive ∆V850 mutation might give dRTA because of its decreased anion transport activity.Keywords:
Band 3
Compound heterozygosity
Renal tubular acidosis
Red Cell
Glycophorin
Band 3
Glycophorin
Hereditary spherocytosis
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Glycophorin
Band 3
Sialoglycoproteins
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Objective. The anion exchanger gene (AE1) or band 3 encodes a chloride-bicarbonate (Cl−/HCO3−) exchanger expressed in the erythrocyte and in the renal α-intercalated cells involved in urine acidification. The purpose of the present study was to screen for mutations in the AE1 gene in 2 brothers (10 and 15 years of age) with familial distal renal tubular acidosis (dRTA), nephrocalcinosis, and failure to thrive. Methods. AE1 mutations were screened by single-strand conformation polymorphism, cloning, and sequencing. Results. A complete form of dRTA was confirmed in the 2 affected brothers and an incomplete form in their father. All 3 were heterozygous for a novel 20-bp deletion in exon 20 of the AE1 gene. This deletion resulted in 1 mutation in codon 888 (Ala-888→Leu) followed by a premature termination codon at position 889, truncating the protein by 23 amino acids. As band 3 deficiency might lead to spherocytic hemolytic anemia or ovalocytosis, erythrocyte abnormalities were also investigated, but no morphologic changes in erythrocyte membrane were found and the osmotic fragility test was normal. Conclusions. A novel mutation in the AE1 gene was identified in association with autosomal dominant dRTA. We suggest that RTA be considered a diagnostic possibility in all children with failure to thrive and nephrocalcinosis.
Band 3
Renal tubular acidosis
Nephrocalcinosis
Anion gap
Failure to Thrive
Tubulopathy
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The AE1 gene encodes band 3 Cl-/HCO3- exchangers that are expressed both in the erythrocyte and in the acid-secreting, type A intercalated cells of the kidney. Kidney AE1 contributes to urinary acidification by providing the major exit route for HCO3- across the basolateral membrane. Several AE1 mutations cosegregate with dominantly transmitted nonsyndromic renal tubular acidosis (dRTA). However, the modest degree of in vitro hypofunction exhibited by these dRTA-associated mutations fails to explain the disease phenotype in light of the normal urinary acidification associated with the complete loss-of-function exhibited by AE1 mutations linked to dominant spherocytosis. We report here novel AE1 mutations linked to a recessive syndrome of dRTA and hemolytic anemia in which red cell anion transport is normal. Both affected individuals were triply homozygous for two benign mutations M31T and K56E and for the loss-of-function mutation, G701D. AE1 G701D loss-of-function was accompanied by impaired trafficking to the Xenopus oocyte surface. Coexpression with AE1 G701D of the erythroid AE1 chaperonin, glycophorin A, rescued both AE1-mediated Cl- transport and AE1 surface expression in oocytes. The genetic and functional data both suggest that the homozygous AE1 G701D mutation causes recessively transmitted dRTA in this kindred with apparently normal erythroid anion transport.
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Glycophorin
Renal tubular acidosis
Spherocytosis
Hereditary spherocytosis
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Abstract Originally published in: Cell Membrane. Yoshihito Yawata. Copyright © 2003 Wiley‐VCH Verlag GmbH & Co. KGaA Weinheim. Print ISBN: 3‐527‐30463‐9 The sections in this article are Band 3 Structure of Band 3 Functions of Band 3 Membrane Protein Binding by the Cytoplasmic Domain of Band 3 Binding to Glycolytic Enzymes by the Cytoplasmic Domain of Band 3 Binding to Hemoglobin by the Cytoplasmic Domain of Band 3 Anion Exchange Channel by the Transmembrane Domain of Band 3 Lateral and Rotational Mobility of Band 3 Blood Type Antigens and Band 3 Band 3 in Nonerythyroid Cells Glycophorins Glycophorins A , B , and E Glycophorin A ( GPA ) Glycophorin B ( GPB ) Glycophorin E ( GPE ) Gylcophorins C and D Glycophorin C ( GPC ) Glycophorin D ( GPD ) Blood Group Antigens ABO Blood Group R h Blood Group P Blood Group L utheran Blood Group K ell Blood Group L ewis Blood Group D uffy Blood Group K idd Blood Group LW Blood Group Ii Blood Group The D iego and W right Blood Group Antigens on Band 3 Other Minor Blood Group Antigens Glycosyl Phoshatidylinositol ( GPI ) Anchor Proteins
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTBand 3-glycophorin A association in erythrocyte membranes demonstrated by combining protein diffusion measurements with antibody-induced cross-linkingErich A. Nigg, Claude Bron, Marc Girardet, and Richard J. CherryCite this: Biochemistry 1980, 19, 9, 1887–1893Publication Date (Print):April 1, 1980Publication History Published online1 May 2002Published inissue 1 April 1980https://doi.org/10.1021/bi00550a024RIGHTS & PERMISSIONSArticle Views78Altmetric-Citations109LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (2 MB) Get e-Alerts Get e-Alerts
Glycophorin
Band 3
Association (psychology)
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Band 3
Glycophorin
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We have studied the properties of band 3 in different glycophorin A (GPA)-deficient red cells. These red cells lack either both GPA and glycophorin B (GPB) (M(k)M(k) cells) or GPA (En(a-) cells) or contain a hybrid of GPA and GPB (MiV cells). Sulfate transport was reduced in all three red cell types to approximately 60% of that in normal control red cells as a result of an increased apparent K(m) for sulfate. Transport of the monovalent anions iodide and chloride was also reduced. The reduced iodide transport resulted from a reduction in the V(max) for iodide transport. The anion transport site was investigated by measuring iodide fluorescence quenching of eosin-5-maleimide (EMA)-labeled band 3. The GPA-deficient cells had a normal K(d) for iodide binding, in agreement with the unchanged K(m) found in transport studies. However, the apparent diffusion quenching constant (K(q)) was increased, and the fluorescence polarization of band 3-bound EMA decreased in the variant cells, suggesting increased flexibility of the protein in the region of the EMA-binding site. This increased flexibility is probably associated with the decrease in V(max) observed for iodide transport. Our results suggest that band 3 in the red cell can take up two different structures: one with high anion transport activity when GPA is present and one with lower anion transport activity when GPA is absent.
Glycophorin
Band 3
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Band 3
Glycophorin
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Band 3
Glycophorin
Hereditary spherocytosis
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