Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene.
Lesley J. BruceDiane L. CopeGraham K. JonesAnn E. SchofieldMari‐Wyn BurleySue PoveyRobert J. UnwinAlbert OngM J A Tanner
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Abstract:
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. The mutation Arg589--> His was present in two families, while Arg589--> Cys and Ser613--> Phe changes were found in the other families. Linkage studies confirmed the co-segregation of the disease with a genetic marker close to AE1. The affected individuals with the Arg589 mutations had reduced red cell sulfate transport and altered glycosylation of the red cell band 3 N-glycan chain. The red cells of individuals with the Ser613--> Phe mutation had markedly increased red cell sulfate transport but almost normal red cell iodide transport. The erythroid and kidney isoforms of the mutant band 3 proteins were expressed in Xenopus oocytes and all showed significant chloride transport activity. We conclude that dominantly inherited dRTA is associated with mutations in band 3; but both the disease and its autosomal dominant inheritance are not related simply to the anion transport activity of the mutant proteins.Keywords:
Band 3
Renal tubular acidosis
Red Cell
A 62-year-old woman with Sjögren's syndrome, distal renal tubular acidosis and hypokalemic muscle paralysis is described. The sicca syndrome was nearly subclinical and went unrecognized for several years. The main and first manifestation to be expressed was that of hypokalemic muscle paralysis secondary to renal tubular acidosis. In the last decade several reports have appeared indicating that renal tubular acidosis is associated with Sjögren's syndrome. The data in this report support the view that adult onset distal renal tubular acidosis is often a disorder of an autoimmune disease, frequently that of Sjögren's syndrome. The complications to renal tubular acidosis such as hypokalemic muscle paralysis or chronic muscle weakness, nephrolithiasis, and osteomalacia can be avoided if the diagnosis of renal tubular acidosis is made and corrective alkali therapy is maintained.
Renal tubular acidosis
Hypokalemic periodic paralysis
Subclinical infection
Periodic paralysis
Sicca syndrome
Muscle weakness
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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.
Band 3
Compound heterozygosity
Renal tubular acidosis
Red Cell
Glycophorin
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▪ Abstract The primary or hereditary form of distal renal tubular acidosis (dRTA), although rare, has received increased attention recently because of dramatic advances in the understanding of its genetic basis. The final regulation of renal acid excretion is effected by various acid/base transporters localized in specialized cells in the cortical collecting and outer medullary collecting tubules. Inherited defects in two of the key acid/base transporters involved in distal acidification, as well as mutations in the cytosolic carbonic anhydrase gene, can cause dRTA. The syndrome is inherited in both autosomal dominant and recessive patterns; patients with recessive dRTA present with either acute illness or growth failure at a young age, sometimes accompanied by deafness, whereas dominant dRTA is usually a milder disease and involves no hearing loss. The AE1 gene encodes two Cl − /HCO 3 − exchangers that are expressed in the erythrocyte and in the acid-secreting intercalated cells of the kidney. AE1 contributes to urinary acidification by providing the major exit route for HCO 3 − across the basolateral membrane. Several mutations in the AE1 gene cosegregate with dominant dRTA. The modest degree of hypofunction exhibited in vitro by these mutations, however, does not explain the abnormal distal acidification phenotype. Other AE1 mutations have been linked to a recessive syndrome of dRTA and hemolytic anemia in which hypofunction can be discerned by in vitro studies. Several mutations in the carbonic anyhdrase II gene are associated with the autosomal recessive syndrome of osteopetrosis, renal tubular acidosis, and cerebral calcification. Some of these individuals present with deafness of the conductive type. By contrast, more recent studies have shown that mutations in ATP6B1, encoding the B-subtype unit of the apical H + ATPase, are responsible for a group of patients with autosomal recessive dRTA associated with sensorineural deafness. Thus, the presence of deafness and the type provide an important clue to the genetic lesion underlying hereditary dRTA.
Renal tubular acidosis
Tubulopathy
Distal convoluted tubule
Compound heterozygosity
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In distal renal tubular acidosis (dRTA) the tubular secretion of hydrogen ion in the distal nephron is impaired, leading to the development of metabolic acidosis, frequently accompanied by hypokalemia, nephrocalcinosis, and metabolic bone disease. The condition can be familial, when it is usually inherited as an autosomal dominant, though there is a rarer autosomal recessive form associated with nerve deafness. It has been shown that the autosomal dominant form of dRTA is associated with a defect in the anion exchanger (AE1) of the renal collecting duct intercalated cell. This transporter is a product of the same gene (AE1) as the erythrocyte anion exchanger, band 3. In this review we will look at the evidence for this association. Studies of genomic DNA from families with this disorder have shown, both by genetic linkage studies and by DNA sequencing, that affected individuals are heterozygous for mutations in the AE1 gene whilst unaffected family members have a normal band 3 sequence. Mutations have been found in the region of proposed helices 6 and 7 of the membrane domain of band 3 and involve amino acids Arg-589 and Ser-613, and in the COOH-terminal domain of band 3. Studies of red cell band 3 from these families have provided information on the effect these mutations have on the structure and function of erythrocyte band 3. Expression studies of the erythroid and kidney isoforms of the mutant AE1 proteins, in Xenopus laevis oocytes, have shown that they retained chloride transport activity, suggesting that the disease in the dRTA families is not related simply to the anion transport activity of the mutated proteins. A possible explanation for the dominant effect of these mutant AE1 proteins in the kidney cell is that these mutations affect the targeting of AE1 from the basolateral to the apical membrane of the alpha-intercalated cell.Key words: erythrocyte, kidney, acidosis.
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Intercalated Cell
Positional cloning
Renal tubular acidosis
Nephrocalcinosis
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We describe a mutation in human erythrocyte band 3 (anion exchanger 1; SLC4A1) causing both hereditary spherocytosis and distal renal tubular acidosis. The proband developed a transfusion-dependent, hemolytic anemia following birth. Immunoblotting showed band 3 was reduced to approximately 35% of wildtype; other proteins of the band 3/Rh macrocomplex were also reduced. DNA sequence analysis revealed a novel homozygous mutation, c.2000C>T, leading to the amino acid substitution Ser667Phe. The parents were heterozygous for the same mutation. Sulfate influx in the patient's erythrocytes was approximately 40% wild type. The mutant band 3 produced very little chloride influx when expressed in Xenopus oocytes. Influx was partially rescued by coexpression of glycophorin A and also rescued by coexpression of wild-type band 3. At 2 years of age, an ammonium chloride challenge showed the child has incomplete distal renal tubular acidosis (dRTA). Stable expression of mutant kidney band 3 in both nonpolarized and polarized Madin-Darby canine kidney cells showed that most of the mutant protein was retained in the endoplasmic reticulum. Overall our results suggest that the Ser667Phe does not affect the anion transport function of band 3, but causes a trafficking defect in both erythrocytes and kidney cells.
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Glycophorin
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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.
Band 3
Glycophorin
Renal tubular acidosis
Spherocytosis
Hereditary spherocytosis
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BACKGROUND: Band 3 (anion exchanger 1, AE1) is one of the most abundant proteins of the erythrocyte membrane. We have previously characterized twenty AE1 gene defects underlying spherocytic haemolytic anaemia with band 3 deficiency. Since AE1 is also expressed in the intercalated cells of renal cortical collecting ducts where it is thought to participate in urine acidification, we asked whether the spherocytogenic AE1 mutations also affect the regulation of urine acidity. METHODS: We examined 10 patients from seven unrelated families with hereditary spherocytosis with band 3 deficiency using the short urine acidification test with CaCl2 administration at a dose of 0.2 g/kg b.w. To asses the ability of the nephron to secrete protons, 400 ml of NaHCO3 were infused over a period of 2 h. RESULTS: While we detected no significant abnormalities in eight patients, we have diagnosed incomplete distal renal tubular acidosis (dRTA) in two patients from one family whose urinary pH 5 h after CaCl2 administration were 6.56 and 6.89. Administration of bicarbonate in these two patients resulted in high urinary HCO3- concentration. The patients carry the previously characterized mutation band 3PRIBRAM that encodes a C-terminally truncated band 3 containing only the cytoplasmic domain and the first three putative transmembrane segments. CONCLUSIONS: This finding shows an association of a band 3 defect with abnormal urinary acidification perhaps secondary to Cl-/HCO3- exchange in the basolateral membrane of alpha-intercalated cells of cortical collecting ducts.
Band 3
Renal tubular acidosis
Bicarbonate
Hereditary spherocytosis
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Citations (52)
In distal renal tubular acidosis (dRTA) the tubular secretion of hydrogen ion in the distal nephron is impaired, leading to the development of metabolic acidosis, frequently accompanied by hypokalemia, nephrocalcinosis, and metabolic bone disease. The condition can be familial, when it is usually inherited as an autosomal dominant, though there is a rarer autosomal recessive form associated with nerve deafness. It has been shown that the autosomal dominant form of dRTA is associated with a defect in the anion exchanger (AE1) of the renal collecting duct intercalated cell. This transporter is a product of the same gene (AE1) as the erythrocyte anion exchanger, band 3. In this review we will look at the evidence for this association. Studies of genomic DNA from families with this disorder have shown, both by genetic linkage studies and by DNA sequencing, that affected individuals are heterozygous for mutations in the AE1 gene whilst unaffected family members have a normal band 3 sequence. Mutations have been found in the region of proposed helices 6 and 7 of the membrane domain of band 3 and involve amino acids Arg-589 and Ser-613, and in the COOH-terminal domain of band 3. Studies of red cell band 3 from these families have provided information on the effect these mutations have on the structure and function of erythrocyte band 3. Expression studies of the erythroid and kidney isoforms of the mutant AE1 proteins, in Xenopus laevis oocytes, have shown that they retained chloride transport activity, suggesting that the disease in the dRTA families is not related simply to the anion transport activity of the mutated proteins. A possible explanation for the dominant effect of these mutant AE1 proteins in the kidney cell is that these mutations affect the targeting of AE1 from the basolateral to the apical membrane of the alpha-intercalated cell.
Band 3
Intercalated Cell
Positional cloning
Renal tubular acidosis
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Citations (21)
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). The mutationsA858D and DeltaV850 are novel; all three mutations seem to berestricted to South-East Asian populations. South-East Asianovalocytosis (SAO), resulting from the band 3 deletion of residues400-408, occurred in many of the families but did not itselfresult in dRTA. Compound heterozygotes of each of the dRTA mutationswith SAO all had dRTA, evidence of haemolytic anaemia and abnormal red-cell properties. The A858D mutation showed dominant inheritance and therecessive DeltaV850 and G701D mutations showed a pseudo-dominantphenotype when the transport-inactive SAO allele was also present. Red-cell and Xenopus oocyte expression studies showed that theDeltaV850 and A858D mutant proteins have greatly decreased aniontransport when present as compound heterozygotes (DeltaV850/A858D,DeltaV850/SAO or A858D/SAO). Red cells with A858D/SAO had only 3% ofthe SO(4)(2-) efflux of normal cells, thelowest anion transport activity so far reported for human red cells. The results suggest dRTA might arise by a different mechanism for eachmutation. We confirm that the G701D mutant protein has an absoluterequirement for glycophorin A for movement to the cell surface. Wesuggest that the dominant A858D mutant protein is possibly mis-targetedto an inappropriate plasma membrane domain in the renal tubular cell,and that the recessive DeltaV850 mutation might give dRTA because ofits decreased anion transport activity.
Band 3
Compound heterozygosity
Renal tubular acidosis
Red Cell
Glycophorin
Hereditary spherocytosis
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Citations (169)