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PEDIATRICS Vol. 112 No. 6 December 2003, pp. 1361-1367

A Novel Mutation in the Anion Exchanger 1 Gene Is Associated With Familial Distal Renal Tubular Acidosis and Nephrocalcinosis

Lara Cheidde, MD, MSc*, Teresa Cristina Vieira, MD, PhD{ddagger}, Paulo Roberto Moura Lima, PhD§, Sara Teresinha Ollala Saad, MD, PhD§ and Ita Pfeferman Heilberg, MD, PhD*

* Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
{ddagger} Endocrinology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
§ Hemocentro, Faculdade de Ciências Médicas de Campinas, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. The anion exchanger gene (AE1) or band 3 encodes a chloride-bicarbonate (Cl–/HCO3–) exchanger expressed in the erythrocyte and in the renal {alpha}-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.

Key Words: distal renal tubular acidosis • nephrocalcinosis • anion exchanger 1 • band 3

Abbreviations: NC, nephrocalcinosis • dRTA, distal renal tubular acidosis • CA II, cytoplasmic carbonic anhydrase II • uRBP, urinary retinol binding protein • SSCP, single-strand conformation polymorphism • PCR, polymerase chain reaction

Nephrocalcinosis (NC) is defined by calcium deposition within the renal parenchyma. NC can be divided into medullary and cortical forms, the former being the most common one. The main causes of NC in pediatric patients are long-term furosemide treatment in neonates1,2 and renal tubular acidosis during childhood.3 Distal renal tubular acidosis (dRTA) is a clinical syndrome identified by hyperchloremic metabolic acidosis secondary to a selective defect in distal renal acidification and characterized by inappropriately high urine pH, hypokalemia, and reduced net acid excretion. Rare cases of hereditary dRTA have been described.4–10 Primary hereditary forms of dRTA are predominantly seen as autosomal dominant traits.4,5,11–13 An autosomal recessive mode of inheritance has also been described in association or not with sensorineural deafness.9,10,13 Some patients with autosomal dominant dRTA remain asymptomatic until adolescence or adulthood, whereas others and those with recessive disease may be severely affected in infancy, with impaired growth and early NC eventually leading to renal insufficiency.4,13

The physiology of distal tubular function is complex, and different hypotheses explaining the occurrence of dRTA have been proposed.5,9,10,13–15 Cytoplasmic carbonic anhydrase II (CA II) catalyzes the hydration of carbon dioxide to carbonic acid, which dissociates to form bicarbonate (HCO3–) and hydrogen ions (H+), the latter being secreted into the tubule through the action of H+-ATPase or H+/K+-ATPase on the apical membrane of the {alpha}-intercalated cells in the renal collecting duct. The HCO3– generated by this process is transported across the basolateral membrane through the anion exchanger 1 (AE1), a HCO3–/Cl– anion exchanger. Hypotheses for the occurrence of dRTA are depicted in Fig 1. One of the possible defects resulting in dRTA may affect the anion exchanger, vital to tubular acid secretion because loss of its function in the presence of continuing H+ secretion by the luminal proton pumps would lead to excessive accumulation of HCO3– within the cell, with a consequent reduction in the dissociation of CA II and hence reduced availability of protons for secretion into the tubular lumen.


Figure 1
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  		Fig 1. Hypotheses involved in dRTA. Defects in either H+/ATPase (1) or H+/K+-ATPase (2) on the apical membrane of the H+-secreting intercalated cells of the collecting duct, or an increased permeability of this membrane causing excessive back-diffusion of secreted H+ (3), besides defects in carbonic anhydrase II (4) or AE1 (5) resulting in failure to establish or maintain a cell-to-lumen hydrogen ion gradient resulting in abnormal renal acidification.

 
The members of the AE gene family are widely distributed in tissues, where they are involved in the regulation of intracellular pH and cell volume and in the transcellular transport of acid and base across epithelial cells.16,17 There are at least 4 members of the AE gene family,18 and the very abundant form present in red cells (AE1 or band 3) has been studied.11,16,19

Band 3 protein is a 911 amino acid membrane protein encoded by the anion exchanger erythroid isoform (AE1) gene located on chromosome 17q21-qter20 presenting 20 exons21,22 and 3 distinct functional domains: 2 cytoplasm tails (N-terminal and C-terminal) and the central integral membrane domain that has 12 to 14 membrane-spanning regions. The C-terminal tail binds to CA II,23 essential for the anion exchange. The renal isoform of band 3, truncated at the N-terminus, described as kidney AE1 (kAE1) lacking erythroid exons 1 to 3, could be predicted to initiate translation at Met 66.19 This kAE1 is localized in the basolateral membrane of the collecting duct in {alpha}-intercalated cell.

Several AE1 mutations have been characterized in association with hereditary spherocytosis14,22,24–28 and Southeast Asian ovalocytosis.6,8,11 Most of the studies in the literature have not focused on investigating abnormalities in renal acidification because only after 1997 were autosomal dominant and recessive forms of dRTA reported to present mutations in the AE1 gene.4,5,10,11,14,15,29 To date, the associations between dRTA and red blood cell disorders such as spherocytosis or Southeast Asian ovalocytosis have been reported only in the recessive form of dRTA.8,11,14

In the present investigation, we report 2 related patients with hereditary dRTA who were screened for mutations in the AE1 gene. A novel 20-bp deletion in exon 20 of the AE1 gene was identified.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
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Patient Characteristics
Two brothers, 10 and 15 years of age (probands III 2 and III 3 in Fig 2), were referred to the outpatient Renal Stone Clinic of the Nephrology Division, Universidade Federal de São Paulo, because of NC and calculus voiding. The mother reported that medical advice was sought for the children at age 3 and 6 years because of failure to thrive. Suspicion of hypophosphatemic rickets was raised, and calcium, phosphorus, and vitamin D supplementation was started at that time for both children. After 4 years of treatment, a plain radiography showed severe NC. At the present admission, in view of the similar signs and symptoms shared by the 2 brothers, a possible hereditary renal disease was considered and a search for a familial disease was started. Written informed consent was obtained from all individuals of the family participating in the study, which was approved by the Ethics Committee of the Universidade Federal de São Paulo. Complete metabolic evaluation was performed in the affected brothers and their parents only. Complete dRTA was diagnosed in 2 brothers, and incomplete dRTA was diagnosed in their father.


Figure 2
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  		Fig 2. Pedigree of the Brazilian family under study. Family tree of the dRTA patients examined in this study. Complete dRTA was diagnosed in 2 brothers (III 2 and III 3) indicated by filled symbols and incomplete dRTA in their father (II 3) indicated by half-filled symbol. Urinary acidification studies were performed in patients II 2, II 3, III 2, and III 3.

 
Metabolic Evaluation
The diagnosis of complete dRTA was based on an alkaline pH after an overnight 12-hour fast in the presence of acidosis. Complete dRTA is characterized by the inability to lower urinary pH below 5.5 under the stimulus of spontaneous systemic acidemia, whereas in the incomplete form of dRTA despite a high urinary pH, acidemia is lacking as a result of a mechanism of arterial pH compensation. Both forms of dRTA may be clinically indistinguishable. In individuals with incomplete dRTA, an acute acid challenge test is necessary to induce a metabolic acidosis and disclose the failure of lowering urinary pH. The acidification tests, nicely reviewed recently,30 can be divided into 3 types: acid loading (ammonium chloride [NH4Cl], calcium chloride, or arginine hydrochloride), maneuvers that increase the distal delivery of sodium (sodium sulfate infusion and furosemide test), and buffer loading (bicarbonate titration, urine partial pressure of carbon dioxide with urinary alkalinization, and urine partial pressure of carbon dioxide with phosphate infusion). In the present study, the NH4Cl loading (0.1 g or 1.9 mEq/kg body weight), the most common test, was used. Urine was collected for a period of 3 hours after NH4Cl ingestion, and pH and net acid excretion were determined.31 A 2-fold increase in ammonium excretion and a 3-fold increase in titratable acidity are considered to be an adequate response to the acid load, but the most important and diagnostic parameter was the reduction of urinary pH to <5.5 after the load.

The family pedigree is presented in Fig 2. Biochemical analysis was performed only in the affected patients (III 2 and III 3) and their parents (II 2 and II 3) and consisted of the determination of serum calcium, uric acid, creatinine, sodium, potassium, phosphorus, chloride, bicarbonate, 25(OH)D3, 1,25 (OH)2D3, and blood smear analysis as well as urinary oxalate, potassium, sodium, calcium, uric acid, citrate, chloride, creatinine, phosphorus, and magnesium determination. Creatinine clearance was also determined and urinary retinol binding protein (uRBP) was measured in spot urine.

Because of the presence of hypercalciuria, NC, and rickets, we suspected a mutation in the chloride channel (CLCN5)32,33 and thus performed determinations of uRBP as a screening for CLCN5 mutation. Abnormal uRBP excretion was present in both children and their father but not in their mother. Because CLCN5 mutation is a familial tubular syndrome whose inheritance is X-linked recessive, with no instances of male-to-male transmission33 and the pattern of inheritance suggested dominant autosomal dRTA transmitted by the father, the possibility of a CLCN5 mutation was excluded and the AE1 gene was elected as a candidate gene.

DNA Analysis and Polymerase Chain Reaction
Single-strand conformation polymorphism (SSCP) analysis of genomic DNA was performed as previously described.24 DNA was extracted from peripheral blood leukocytes obtained from blood samples using the Puregene DNA Isolation kit (Gentra Systems, Minneapolis, MN). Exons 2 to 20 of the AE1 gene were amplified by polymerase chain reaction (PCR) using primers located on intronic boundaries, as described elsewhere.24 The PCR product of the exon that showed a mobility shift was analyzed by automatic DNA sequencing. The PCR product was subcloned in MAX Efficiency DH5{alpha} Competent Cells (GIBCO-BRL, Rockville, MD) using the Original TA Cloning kit (Invitrogen, Groningen, The Netherlands). The plasmid DNA from positive colonies was isolated using the QIAprep Spin Miniprep kit (QIAGEN, Hilden, Germany). For identifying the mutation in the exons of the AE1 gene observed in the PCR-SSCP analysis, the product was sequenced by automatic DNA sequencing using the Big Dye reaction in the ABI PRISM Model 377 apparatus (Applied Biosystem, Foster City, CA).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
On the occasion of the present admission, the diagnosis of complete dRTA was established for both children (III 2 and III 3) by the detection of inappropriately alkaline urinary pH in the presence of spontaneous metabolic acidosis, as shown in Table 1. The mother (II 2) presented a normal response to the NH4Cl test. Conversely, the father (II 3) maintained an alkaline urinary pH (6.6) and presented a slight but inadequate increase in ammonium excretion and titratable acidity, characterizing an incomplete form of dRTA. Both children had normal renal function, hypokalemia, hypercalciuria, hypocitraturia, hyperuricosuria, and hyperchloremia, as shown in Table 2. Because serum levels of 25(OH)D3 and 1,25 (OH)2D3 were within normal limits, vitamin D supplementation was then withdrawn. The reason for an increase in uRBP in both children and their father remains unclear. Nevertheless, it has already been reported by other investigators in a dRTA setting.34


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  		TABLE 1. Acidification Parameters Under Basal Conditions and After the NH4Cl Load Test

 

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  		TABLE 2. Serum and Urinary Parameters in the Patients and Their Parents

 
NC was confirmed by hyperechogenicity of renal pyramids and calcifications in renal ultrasonography as well as parenchymal calcifications by helical computed tomography. Pelvicaliceal calcifications were also observed in computed tomography, indicating the association with nephrolithiasis. Potassium citrate supplementation was started soon after the diagnosis of dRTA was established. Control of metabolic acidosis was then achieved, and an improvement in growth rate was observed in both children (>7 cm/child after 14 months of treatment). Renal calcification has not got worsen; neither did renal function deteriorate during the same period.

The father presented a normal ultrasound but reported a history of previous stone voiding and submission to 4 extracorporeal shock wave lithotripsy procedures. The half-sister and the half-brother (probands III 4 and III 1 in Fig 2, respectively) had normal urinary pH (data not shown). The mother had no nephrolithiasis or NC despite the presence of hypercalciuria (Table 2). All members of the family presented normal renal function, as assessed by serum creatinine levels (data not shown).

Because of hematologic diseases linked to mutations in the AE1 gene, a hematologic investigation was initiated. The peripheral blood smears and the osmotic fragility test were normal, indicating no spherocytosis or ovalocytosis. The blood counts in both affected brothers were normal, with the following values: hematocrit, 45.2% and 42.2%; hemoglobin, 15.7 and 14.9 g/dL; mean corpuscular volume, 88 and 90; mean corpuscular hemoglobin concentration, 35.0 and 35.3 g/dL; and reticulocyte count, 1.4% and 1.5%, proband III 2 and III 3, respectively.

Genetic Investigation
SSCP analysis revealed a mobility shift in exon 20 of the AE1 gene in proband III 3 and his father (II 3), as seen in Fig 3. Except for this mobility shift of exon 20, the PCR-SSCP patterns of all other exons, including intron 3, were normal (data not shown). The 3% agarose gel electrophoresis performed in the entire family (Fig 4) showed a single band of 267 bp in relatives without dRTA and 2 bands (267 bp and 247 bp) in the patients with dRTA (III 2, III 3) and their father (II 3). The smaller band suggested the presence of a deletion in exon 20 of these patients. The PCR product of patient III 3 was subcloned in pCR 2.1, and the product was then sequenced. A 20-bp sequence starting from the third base in codon 887 was deleted, identifying the AE1 mutation (Fig 5). This deletion did not alter the protein encoded by codon 887 but 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. Because we evaluated 3 generations and the double band was lacking in the grandparents, we had to confirm parenthood using DNA fingerprinting through a technique based on the variable number of tandem repeats, VNTR (Profile Kit, Perkin Elmer, Boston, MA). Parenthood was confirmed, hence suggesting that the deletion resulted from a de novo mutation (Fig 4). We named this mutation Dourados (Band 3 Dourados) in reference to the area of origin of the children.


Figure 3
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  		Fig 3. Screening of mutations in exon 20 of the AE1 gene in patients with dRTA by PCR-SSCP analysis. From left to right, patient III 2 with complete dRTA and NC; his father II 3 with incomplete dRTA and nephrolithiasis; control (C). Arrows indicate band shifts in exon 20.

 

Figure 4
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  		Fig 4. AE1 Mutations in dRTA. Agarose gel electrophoresis of exon 20 in the entire family showing a double band (267 and 247 bp) only in patients with dRTA (III 2 and III 3) and their father (patient II 3).

 

Figure 5
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  		Fig 5. DNA sequence changes. Automatic sequencing showed a 20-bp deletion in exon 20. The result leads to mutation in codon 888 (Ala->Asp) and premature termination at codon 889, truncating the protein by 23 amino acids.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Familial forms of distal RTA have been described since 1968,35 but it was only after 1997 that both dominant4,5,29 and recessive7,8,11 autosomal forms were associated with AE1 mutations. In the present investigation, complete dRTA and NC were detected in 2 brothers and incomplete dRTA with nephrolithiasis in their father. The similar clinical course observed in the 2 brothers led us to hypothesize that a genetic cause of the disorder should be sought.

In the present study, the affected brothers and their father shared a 20-bp deletion in exon 20 of the AE1 gene or Band 3 (Band 3 Dourados), resulting in a premature termination codon at position 889, truncating the protein by 23 amino acids. The deletion at the C-terminal tail was responsible for the double band evidenced by agarose gel electrophoresis of the exon 20 PCR product of the brothers and their father, 1 with 267 and 1 with 247 bp (without 20 bp) instead of the single 267-bp band.

The structure and function of the short C-terminal cytoplasmic tail (33 residues) of band 3 have not been well characterized. Recent studies have proposed that CA II binds to AE1 through the C-terminal tail, catalyzing CO2 hydration and favoring HCO3– reabsorption and H+ secretion.23,34,36,37

There are only 3 reported mutations in this C-terminal tail, specifically in exon 20.4,15,38 Karet et al4 were the first to identify an intragenic 13-bp duplication in tandem that resulted in a premature termination codon at position 901, truncating the protein in the last 11 amino acids in association with dRTA. Another mutation was Band 3 Vesuvio,18 characterized by a frameshift deletion in codon 894 resulting in a reading frame for 133 extra codons (instead of 18) before the new stop codon at position 1027, associated with hereditary spherocytosis but not with dRTA. More recently, Toye et al15 reported the presence of dRTA and NC in 2 brothers who shared the same mutation described by Karet et al4 and an additional deletion of 9 bp over the sequence that would have coded for amino acids Tyr904-Glu906 of normal band 3, named band 3 Walton.

In the present study, the deletion of 23 amino acids in the mutant AE1 protein probably did not interfere with band 3 insertion into the red cell membrane because no hematologic diseases were diagnosed. However, it is possible that the mutant protein may be targeted differently in erythrocytes and kidney cells as already described for other mutations in this region.15 The presence of such mutation in children who present with dRTA suggests that the extreme C-terminal tail of the band 3 protein must play an important role in anion transport and renal acidification in the renal tubular cells. Another disturbed mechanism caused by the expression of the mutant band 3 in collecting duct cells may be the lack of proper CA II binding, disturbing the cell capacity for bicarbonate transport, or a decrease in the production/rapid degradation of mutant mRNA38 coding for AE1 leading to the absence or decrease of net acid movement across renal tubular cells.

Despite that the father and 2 children had the same genetic defect, a minor expressivity resulting in an incomplete form of dRTA was diagnosed in the father. The incomplete form of the disease probably rendered a milder clinical presentation without hypercalciuria or bone loss as a result of the lack of persistent systemic acidosis. Besides the phenotypic variation, it is unclear why some patients with dRTA present with stones but no overt NC whereas others display the opposite, as already stated by Karet.13The possibility that vitamin D treatment, as well as calcium and phosphorus supplementation, before the establishment of the dRTA diagnosis might have contributed to aggravate the renal calcifications in the children cannot be excluded.39–41 Nevertheless, as already mentioned earlier, the finding of similar clinical signs and symptoms shared by the 2 brothers suggests that a secondary NC could not represent the single entity presented by these children. The proper control of metabolic acidosis with potassium citrate after the diagnosis of dRTA was established led to an important improvement in growth rate. We suggest that RTA should be considered as a diagnostic possibility in all children with failure to thrive and NC.


   FOOTNOTES
 
Received for publication Sep 18, 2002; Accepted Mar 16, 2003.

Reprint requests to (I.P.H.) Rua Botucatu, 740 Vila Clementino, São Paulo SP, Brazil, CEP 04023–900, Nephrology Division/ Universidade Federal de São Paulo. E-mail: ipheilberg{at}nefro.epm.br


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 METHODS
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 DISCUSSION
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A. C. Fry and F. E. Karet
Inherited Renal Acidoses
Physiology, June 1, 2007; 22(3): 202 - 211.
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 Am. J. Physiol. Renal Physiol.Home page
A. Pushkin and I. Kurtz
SLC4 base (HCO3-, CO32-) transporters: classification, function, structure, genetic diseases, and knockout models
Am J Physiol Renal Physiol, March 1, 2006; 290(3): F580 - F599.
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S. Kittanakom, E. Cordat, V. Akkarapatumwong, P.-t. Yenchitsomanus, and R. A. F. Reithmeier
Trafficking Defects of a Novel Autosomal Recessive Distal Renal Tubular Acidosis Mutant (S773P) of the Human Kidney Anion Exchanger (kAE1)
J. Biol. Chem., September 24, 2004; 279(39): 40960 - 40971.
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N. Rungroj, M. A. J. Devonald, A. W. Cuthbert, F. Reimann, V. Akkarapatumwong, P.-t. Yenchitsomanus, W. M. Bennett, and F. E. Karet
A Novel Missense Mutation in AE1 Causing Autosomal Dominant Distal Renal Tubular Acidosis Retains Normal Transport Function but Is Mistargeted in Polarized Epithelial Cells
J. Biol. Chem., April 2, 2004; 279(14): 13833 - 13838.
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