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Novel Nonsense Mutation in the Na⁺/HCO₃^- Cotransporter Gene (SLC4A4) in a Patient with Permanent Isolated Proximal Renal Tubular Acidosis and Bilateral Glaucoma

TAKASHI IGARASHI^*, JUN INATOMI, TAKASHI SEKINE^*, GEORGE SEKI, MITSUNOBU SHIMADZU^§, FUMIKO TOZAWA^§, YASUHIRO TAKESHIMA^||, TORU TAKUMI^||, TOSHIKAZU TAKAHASHI^||, NORISHIGE YOSHIKAWA^||, HAJIME NAKAMURA^|| and HITOSHI ENDOU

^* Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo
Department of Nephrology and Endocrinology, Faculty of Medicine, University of Tokyo, Tokyo
Department of Pharmacology and Toxicology, Kyourin University School of Medicine, Tokyo
^§ Department of Genetics, Mitsubishi Yuka Bio-clinical Laboratories, Inc., Tokyo
^|| Department of Pediatrics, Faculty of Medicine, Kobe University, Kobe, Japan.

Correspondence to Dr. Takashi Igarashi, Department of Pediatrics, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-0-3-5800-8821; Fax: 81-0-3-5800-8822; E-mail: iga7400{at}mxq.mesh.ne.jp

	Abstract

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Abstract. Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease involving short stature, isolated pRTA, mental retardation, and ocular abnormalities. Kidney Na⁺/HCO₃^- cotransporter (kNBC1) cDNA from peripheral lymphocytes from a patient with permanent isolated pRTA and bilateral glaucoma was screened, and a novel homozygous mutation, namely a cytosine-to-thymine transition at nucleotide 234, which resulted in the formation of a stop codon at codon 29, was identified. This homozygous mutation, Q29X, was identified in the unique 5'-end of the kNBC1 gene (SLC4A4) of the patient. Cosegregation of this Q29X mutation with the disease and heterozygosity in the parents of the affected patient were observed. The absence of this mutation in 156 alleles from 78 Japanese individuals indicates that this mutation is directly related to the disease and is not a common DNA sequence polymorphism. This nonsense mutation predicts a truncated kNBC1 protein that lacks the 1007 amino acids of the carboxyl-terminus, and the effect on kNBC1 cotransport activity is likely to be a loss of function. In contrast, the pancreatic Na⁺/HCO₃^- cotransporter of the patient is not likely to be affected by this nonsense mutation. These results have implications for understanding the role of kNBC1 in the pathophysiologic processes of pRTA associated with ocular abnormalities and mental retardation.

	Introduction

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Proximal renal tubular acidosis (pRTA) (type II renal tubular acidosis) results from an impairment of bicarbonate (HCO₃^-) reabsorption in the proximal renal tubules, which is characterized by a decreased renal HCO₃^- threshold (1). pRTA commonly occurs as one manifestation of a generalized defect in proximal tubule function. Patients with this abnormality, which is termed the Fanconi syndrome, usually exhibit glycosuria, aminoaciduria, citraturia, and phosphaturia (2). However, pRTA may also occur as an isolated phenomenon (isolated pRTA). Primary isolated pRTA is usually transient in infants or young children (3,4); the permanent isolated type is extremely rare. Permanent isolated pRTA is divided into two categories according to the clinical features, i.e., (1) stunted growth as the predominant clinical feature, with no other abnormalities (5), and (2) stunted growth, mental retardation, and ocular abnormalities such as band keratopathy, cataracts, and glaucoma (6,7,8,9).

More than 85% of the filtered load of HCO₃^- is reabsorbed in the proximal renal tubules (10,11). This transepithelial flux is accomplished via the coordinated function of an apical membrane Na⁺/H⁺ exchanger, a basolateral Na⁺/HCO₃^- co-transporter (NBC), and apical membrane and intracellular carbonic anhydrases (10,11). Recently, we reported missense mutations in the kidney NBC (kNBC1) gene (SLC4A4), which significantly reduced the activity of kNBC1, causing permanent isolated pRTA with ocular abnormalities (12).

kNBC1 mRNA, which is expressed in the kidney, encodes a protein of 1035 amino acid residues (13). In contrast, the pancreatic NBC (pNBC1), which is expressed predominantly in the pancreas, with lower levels of expression in the kidney, brain, liver, prostate gland, colon, stomach, thyroid gland, and spinal cord, encodes a 1079-residue polypeptide (14). pNBC1 is similar to kNBC1 but has a unique 5'-end that includes 85 amino acids of the open reading frame and replaces the first 41 amino acids of kNBC1, which are transcribed from an alternative promoter in intron 3 of the pNBC1 gene (SLC4A4) (15). In this study, we report the identification of a novel nonsense mutation in the unique 5'-end of SLC4A4, in a patient with permanent isolated pRTA and bilateral glaucoma.

	Materials and Methods

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Description of the Patient
The patient was a 12-yr-old girl who manifested short stature (116.0 cm, -5.6 SD), pRTA, mental retardation, and bilateral glaucoma. She did not manifest cataracts or band keratopathy. She is a child of consanguineous parents with normal stature and normal blood pH and bicarbonate levels. The pH of early-morning urine samples from the parents was 5.0. The parents are second cousins. A trabeculotomy was performed to treat the glaucoma, but it was not effective. Serum analysis revealed the following levels: Na⁺, 137 mEq/L; K⁺, 3.4 mEq/L; Cl^-, 118 mEq/L; blood urea nitrogen, 16 mg/dl; creatinine, 0.6 mg/dl. Blood gas analysis revealed a pH of 7.200, HCO₃^- concentration of 9.4 mM, and Pco₂ of 32 mmHg. When the blood pH and HCO₃^- concentration were 7.120 and 10.2 mM, the urine pH (measured with a pH meter) and HCO₃^- concentration were 4.500 and 0.3 mM, respectively. When sufficient alkali therapy was administered to bring the blood HCO₃^- level to 20 mM, the fractional excretion of HCO₃^- was 40.4%. These results suggested that the patient could acidify the urine but the threshold to reabsorb HCO₃^- was decreased, indicating that this patient had pRTA. Urinalysis revealed a pH of 4.5, no protein, no glucose, no blood, 0 to 1 red blood cells/ high-power field, and 0 to 1 white blood cells/high-power field. The urinary excretion of amino acids was normal, and the urinary ß2-microglobulin level was 110 µg/L (normal, <240 µg/L). An abdominal ultrasound examination revealed no nephrocalcinosis. Large amounts of bicarbonate (10 mmol/kg per d) and potassium (5 mEq/kg per d) are essential to keep the blood pH above 7.250 and the serum K⁺ level above 3.5 mEq/L. The patient is now 24 yr of age and still manifests short stature (137 cm, -4.3 SD), pRTA, mental retardation, and bilateral glaucoma. Informed consent for participation in the study was obtained from the patient, her brother, and her parents, after the purpose, nature, and potential risks of the study were explained to them.

PCR Amplification and DNA Sequence Analysis of kNBC1 cDNA from Peripheral Lymphocyte RNA from the Patient
RNA was extracted from peripheral blood cells from the patient using acid guanidinium thiocyanate-phenol-chloroform methods (16). cDNA was constructed using a first-strand cDNA synthesis kit (Life Science, FL), following the protocol provided by the manufacturer. kNBC1 cDNA was constructed using 10 pM levels of pairs of kNBC1-specific primers (Table 1 and Figure 1) in a 40-µl reaction mixture containing 1 µg of first-strand cDNA, 8 nM levels of each dNTP, 1 x reaction buffer (10 mM Tris-HCl, pH 8.3, 50 mM KCl, 1.5 mM MgCl₂, 0.01%, wt/vol, gelatin), and 1 U of LA Taq DNA polymerase (Takara Shuzou, Kyoto, Japan) (17). Thirty-five amplifications were performed in a thermal cycler (Perkin Elmer 2400; Perkin Elmer Japan Applied Biosystems Division, Tokyo, Japan). Each cycle consisted of 30 s of denaturation at 95°C, 30 s of annealing at 58°C, and 120 s of primer extension at 60°C. All primers for PCR in this study were synthesized with a model 394 synthesizer (Perkin Elmer Japan Applied Biosystems Division). The DNA sequence of each PCR product was determined using the Taq polymerase DNA-sequencing method, with kNBC1-specific primers (Table 2 and Figure 1), in a model 373A automated DNA sequencer (Perkin Elmer Japan Applied Biosystems Division).

View larger version (12K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Schematic presentation of PCR products and DNA sequencing strategy for kidney Na+/HCO3- cotransporter (kNBC1) cDNA. The solid lines indicate the alignment of the PCR products of the partial kNBC1 cDNA that were amplified using kNBC1-specific primers (Table 1), as indicated by the arrows. kNBC1 cDNA was sequenced using specific primers, as indicated by the arrows (Table 2).

PCR Amplification and DNA Sequence Analysis of SLC4A4 Segments from the Control Subject and the Family Members
Genomic DNA was extracted from the peripheral leukocytes of the patient, her brother, her parents, and the control subject. PCR was performed using 25 pM levels of the kNBC1-specific forward primer (5'-CTTTAGATTGGGGATTTGGGAGGC) (F16), which corresponded to the kNBC1 sequence at positions 133 to 137, and reverse primer (5'-CCATCTCCTGCCCATCCACGGCCA) (R19), which corresponded to the sequence at positions 387 to 361 (Table 2 and Figure 1), in a 40-µl reaction mixture containing 100 ng of genomic DNA, 8 nM levels of each dNTP, 1 x reaction buffer (10 mM Tris-HCl, pH 8.3, 50 mM KCl, 1.5 mM MgCl₂, 0.01%, wt/vol, gelatin), and 1 U of Taq DNA polymerase (17). Forty-five amplifications were performed in a thermal cycler (Perkin Elmer 2400; Perkin Elmer Japan Applied Biosystems Division). Each cycle consisted of 30 s of denaturation at 95°C, 30 s of annealing at 60°C, and 120 s of primer extension at 60°C.

The DNA sequence of each PCR product was determined using the Taq polymerase DNA-sequencing method, with primer F16 or R19, in a model 373A automated DNA sequencer (Perkin Elmer Japan Applied Biosystems Division).

Detection of the Mutation by Restriction Enzyme Analysis
DNA sequence abnormalities were confirmed by restriction endonuclease analysis of the genomic PCR products obtained using the forward primer F16 and the reverse primer R19 (Table 2). The corresponding genomic DNA sequences from 78 unrelated healthy Japanese individuals (23 male and 55 female subjects) were also analyzed.

	Results

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PCR Amplification and DNA Sequence Analysis of kNBC1 cDNA from Peripheral Lymphocyte mRNA from the Control Subject and the Patient
PCR amplification of kNBC1 cDNA from peripheral lymphocyte RNA from the control subject and the patient and DNA sequence analysis revealed homozygous cytosine-to-thymine transitions at nucleotide 234 of kNBC1 cDNA in the patient (Figure 2). This substitution is predicted to convert a glutamine to a stop codon at amino acid 29 in the kNBC1 protein of the patient.

View larger version (28K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. DNA sequence analysis of kNBC1 cDNA from the affected patient, revealing homozygous cytosine-to-thymine transitions at nucleotide 234 (codon 29). These transitions altered the wild-type sequence CAG, which encodes a glutamine (Q), to the mutant sequence TAG, which encodes a stop codon (X).

PCR Amplification and DNA Sequence Analysis of SLC4A4 Segments from the Control Subject and the Family Members
PCR amplification and DNA sequence analysis of SLC4A4 segments from the family revealed that (1) the patient had cytosine-to-thymine transitions at nucleotide 234 that affected both alleles, (2) both parents had a cytosine-to-thymine transition at nucleotide 234 in one allele, with one normal allele, and (3) the brother had no cytosine-to-thymine transition in either allele (data not shown).

Detection of a Mutation at Nucleotide 234 by Restriction Enzyme Analysis
DNA sequence analysis of DNA from the patient revealed a cytosine-to-thymine transition at codon 29 in both alleles. This transition changed the wild-type sequence CAG, which encodes a glutamine (Q), to the mutant sequence TAG, which is a stop codon (X). This nonsense mutation, Q29X, also resulted in the gain of a MaeI restriction enzyme site (C/TAG). PCR amplification and MaeI digestion would result in two products (154 and 120 bp) from the mutant sequence but only one product (274 bp) from the normal sequence, as illustrated in the restriction map (Figure 3). Cosegregation of this Q29X mutation with the disease and its heterozygosity were confirmed for the parents of the affected patient. The absence of this Q29X mutation in 156 alleles from 78 unrelated Japanese individuals (23 male and 55 female subjects) indicates that it is not a common DNA sequence polymorphism.

View larger version (11K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Detection of the mutation in SLC4A4 in the family by restriction enzyme analysis. DNA sequence analysis of the affected female patient II. 1 revealed cytosine-to-thymine transitions at codon 29 (A). These transitions changed the wild-type sequence CAG, which encodes a glutamine, to the mutant sequence TAG, which encodes a stop codon. This nonsense mutation (Q29X) also resulted in the gain of a MaeI digestion site (C/TAG). PCR amplification and MaeI digestion (B) would result in only one product (274 bp) from the normal sequence (N) but two products (154 and 120 bp) from the mutant sequence (I.1 and I.2), as illustrated in the restriction map (C). The father (I.1) and the mother (I.2) are heterozygous for the normal and mutant alleles. The brother (II.2) is homozygous for the wild-type allele. Therefore, the mutation (Q29X) cosegregates with the disease. In addition, this Q29X mutation was not present in 78 unrelated normal Japanese individuals (23 male and 55 female subjects), indicating that it is not a common DNA sequence polymorphism. Individuals shown are male (square) or female (circle) and unaffected (open symbols), carrier (half-filled symbols), or affected (filled symbols). Standard size markers, in the form of HaeII-digested X174 (M1) and a 50-bp ladder (M2), are indicated.

	Discussion

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This report demonstrates that the novel nonsense mutation Q29X in the unique 5'-end of SLC4A4 is related to permanent isolated pRTA with mental retardation and bilateral glaucoma. pNBC1 is similar to kNBC1 except that pNBC1 has a unique 5'-end that includes 85 amino acids of the open reading frame and replaces the first 41 amino acids of kNBC1, which are transcribed from an alternative promoter in intron 3 of the pNBC1 gene (SLC4A4) (15). The Q29X mutation is predicted to yield a truncated kNBC1 protein that lacks 1007 amino acids, and the effect on the kNBC1 protein is likely to be complete loss of function. This phenomenon may readily explain the severe pRTA observed in our patient. However, the parents of the patient, each of whom has only one normal kNBC1 allele, do not suffer from pRTA. Although the exact reason for this phenomenon is not clear, one possible explanation is that pNBC1, which is not likely to be affected by the Q29X mutation, can compensate for the partial loss of kNBC1 activity in the parents. Most investigators generally accept that kNBC1 mediates the efflux of HCO₃^- from the proximal renal tubules into the peritubular plasma (18). In addition, the expression of pNBC1 in the kidney has been confirmed (14). We previously reported that two missense mutations, i.e., R298S and R510S, in SLC4A4 cause the same disorder (12). Functional analysis of R298S and R510S mutant proteins revealed that kNBC1 activity was reduced to 55 and 57% of wild-type activity, respectively (12). Because these two mutations are present in the common coding region for kNBC1 and pNBC1, the effect is likely to be inactivation of both kNBC1 and pNBC1 functions. Our data also demonstrated that all three of the patients with permanent isolated pRTA and ocular abnormalities whom we studied exhibited homozygous mutations in SLC4A4.

The corneal endothelium transports fluids, Na⁺, and HCO₃^- from the corneal stroma into the aqueous humor. This process is considered to be essential for maintaining corneal hydration and transparency. A recent study (19) confirmed that human corneal endothelial cells have NBC activity, as previously suggested (20), and express both kNBC1 and pNBC1 mRNA. Therefore, we can speculate that inactivation of both kNBC1 and pNBC1 functions (12) may increase the HCO₃^- concentration in the corneal stroma, facilitating the deposition of Ca²⁺ in the corneal stroma and leading to band keratopathy. In contrast, little is known regarding the role of kNBC1 and pNBC1 in the pathogenesis of cataracts. The patient manifests neither band keratopathy nor cataracts. Our observations suggest that the complete loss of kNBC1 function alone may not lead to band keratopathy and cataracts. However, the patient manifested bilateral glaucoma. Although the exact relationship between impaired NBC functions and glaucoma remains unclear, it should be noted that the human ciliary muscle, which is involved in regulating aqueous humor outflow, expresses NBC activity (21).

Finally, a recent study confirmed that kNBC1 and pNBC1 are expressed in the brain (22). This NBC expression is widespread throughout the cerebellum, cortex, olfactory bulb, and subcortical structures. In addition, the expression profile suggests that NBC activity may be critical during the later stages of brain development. A malfunction in these activities could be related to the mental retardation that accompanies pRTA, which may be caused by the R298S mutation (12) or the Q29X mutation described here. Our clinical observation suggests that normally functioning pNBC1 may not prevent mental retardation when kNBC1 does not function in the brain.

	Acknowledgments

 
Support for this study was provided by the Ministry of Education, Science, and Culture of Japan (Grant 11670741), the Ministry of Health and Welfare (Grant H10-Kodomo-025), and a grant from Pharmacia. We are grateful to the patient and her family for their participation.

	References

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