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Atypical Bartter Syndrome with Sensorineural Deafness with G47R Mutation of the ß-Subunit for ClC-Ka and ClC-Kb Chloride Channels, Barttin

Department of Metabolic Medicine, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan

Address all correspondence and requests for reprints to: Eiichi Araki, M.D., Ph.D., Department of Metabolic Medicine, Kumamoto University School of Medicine, 1-1-1, Honjo Kumamoto, 860-8556, Japan. E-mail: earaki{at}kaiju.medic.kumamoto-u.ac.jp.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Bartter syndrome comprises several related renal tubular disorders including classic Bartter, infantile Bartter (IBS), and Gitelman syndrome. A new distinct group in Bartter syndrome accompanied by sensorineural deafness (BSND) has been identified among the IBS patients. Recently a gene encoding an essential ß-subunit for ClC chloride channels, named barttin, with several mutations of the gene as the cause of BSND, has been described. We have observed a male who had not been diagnosed as Bartter syndrome until 28 yr because of a mild clinical manifestation. The patient was affected with congenital deafness, which urged us to analyze his gene for barttin, and a mutation G47R, which was previously reported, has been identified. However, the clinical feature in the patient lacking the characteristic symptoms of IBS such as polyhydramnios, premature labor, or severe salt loss in neonatal period contrasts with that of the typical BSND patients described so far in the literature. This might be due to a less severe loss of function of barttin induced by G47R mutation, compared with others, and our observation seems to suggest a possibility of the prevalence of mild form BSND with various levels of barttin dysfunction among patients with congenital deafness of unknown origin.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
BARTTER SYNDROME (1) COMPRISES several closely related renal tubular disorders that can be grouped into at least three clinical phenotypes: infantile variant of Bartter syndrome (IBS), classic Bartter syndrome, and Gitelman syndrome (2). Recently a clinically distinct group of patients with infantile Bartter syndrome with sensorineural deafness (BSND) has been recognized among those with IBS (3, 4, 5). The molecular basis of Bartter syndrome had been elucidated that there are at least four genetically distinct abnormalities resulted from mutations in the genes encoding renal electrolyte transporters and channels: the Na-K-2Cl cotransporter (NKCC2) (6), the outwardly rectifying potassium channel (ROMK) (7), a chloride channel ClC-Kb (CLCNKB) (8), and the thiazide-sensitive sodium-chloride transporter (NCCT) (9). And the correspondences between responsible gene and phenotype include NKCC or ROMK to IBS, CLCNKB to classic Bartter syndrome, and NCCT to Gitelman syndrome.

IBS has been reported in a previous 1985 study by Seyberth et al. (10), and inbred Bedouin kindred with IBS with sensorineural deafness (the first description for BSND) were reported by Landau et al. in 1995 (11). In a report of patients with neonatal Bartter-like syndrome from Costa Rica, 8 of 20 patients described were with sensorineural deafness (3). Linkage of BSND to chromosome 1p has been demonstrated (4, 12), and a clinical analysis of eight patients from six families in Lebanon and Turkey has revealed that BSND represents genetically and clinically a disease entity distinct from IBS (5). In 2001, a gene (named BSND) encoding a new membranous protein has been identified by positional cloning as the cause of BSND, and the gene product has been termed barttin (13, 14). Barttin acts as an essential ß-subunit for ClC-Ka and ClC-Kb chloride channels, with which it colocalizes in basolateral membranes of renal tubules and of potassium-secreting epithelia of the inner ear (14, 15). Thus, a new disease entity (the fifth gene to the fourth phenotype, or BSND to BSND) of Bartter’s syndrome has just been established.

We report herein a male affected with BSND of whom the BSND gene has been analyzed. This is the first case report for BSND from Japan, in which the Japanese patient’s clinical pictures might discriminate himself from the BSND patients reported so far from several countries and ethnics.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Case reports

A 28-yr-old man was referred and admitted to our hospital in 1994. He had visited a hospital with his parents in 1990, complaining of fatigue, numbness and weakness of both legs, and polydipsia. Clinical findings were impaired glucose tolerance, fatty liver, congenital deafness, and hypokalemia. Potassium supplement was commenced, leading to very little improvement of the symptoms. Four years later the parents consulted another physician, who referred him to us with suspicion of renal tubular acidosis.

The patient’s family history was not notable. However, the pedigree showed that he is an offspring of a consanguineous union (Fig 1). His history that was taken from his parents was: he had been born by vaginal delivery at 40 wk gestation to a 22-yr-old mother. Polyhydramnios had not been pointed out through the gestation period. The neonate was in normal length but extremely thin (his birth weight was 2500 g, length 50 cm). During the postnatal period, the parents had noticed that their son had hearing loss, polydipsia, and polyuria. At 10 months of age, sensorineural deafness was diagnosed at a hospital. Although the birth length was in the normal range, failure to thrive was observed thereafter (Fig 2). Polydipsia with polyuria also persisted. He attended school for deaf-mutes, at which his class teacher noticed his unique characteristics with intellectual brightness, emotional instability, physical clumsiness, and muscle weakness among deaf-mute children. His intelligence quotient was estimated to be within normal range, although an accurate intelligence test was not performed. Otherwise, he had been well without receiving any treatment. His height reached 166.5 cm (-0.48 SD) with growth acceleration after 14 yr of age (Fig. 2). After graduation from high school, he obtained a clerking job. About that time he began to complain of fatigue and numbness and weakness of both legs.

View larger version (13K): [in this window] [in a new window]   Figure 1. Abbreviated pedigree of the kindred. The solid square indicates the patient. Consanguineous parents (indicated by half-closed symbols) did not manifest any clinical symptoms of Bartter syndrome. Auditory acuity is also normal in both parents. Other members of the pedigree are not examined, but no Bartter-like syndrome or deafness has been noted.

View larger version (12K): [in this window] [in a new window]   Figure 2. Growth curve of the patient. Solid circles indicate patient’s height. Solid curves represent longitudinal growth of Japanese male (mean ± 2 SD).

Neither parent manifested any clinical symptoms of Bartter syndrome. Audiogram tests were preformed for both parents, which revealed a dip-shaped hearing loss at the frequency of 5000 Hz (a threshold level of 55 dB) in the father and a hearing loss at high frequency zone (8000 Hz, 60 dB) in the mother. However, these data suggested that their hearing acuity matched for their age, 63 yr and 58 yr, respectively.

These studies were approved by local ethics committees and informed consents were obtained from the patient and the parents.

In vitro study

BSND gene analysis. Genomic DNA was extracted from peripheral blood from the patient and his parents using a commercial kit (blood genomic DNA extraction system Maxiprep, ViogeneBiotek Corp., Sunnyvale, CA) according to the manufacturer’s instruction. The entire sequences of exons 1–4 of the BNSD gene of the patient were directly sequenced using DNA fragments amplified by PCR. Exon-flanking primers used for the analysis were designed based on the published sequence of BSND gene (GenBank accession no. AY034632): exon 1, 5'-TCCCTCGCTCAGATTCACAC-3'/5'-ATGGATGGATGGGACAGACG-3'; exon 2, 5'-TTCACTCCTT GCTGCTCCTA-3'/5'-CCCTCCCTC TCACTCTCCTC-3'; exon 3, 5'-CTTGTGAGGT GAGGGGAGAC3'/5'-CCCACTCCTCTCCTTTTTA-3'; exon 4,5'-CTAGCGGCTGGAATGTGGAC-3'/5'-TTGGGGGAAGGTGGAAAATG-3'.

PCR amplification consisted of a 12-min start at 95 C, followed by 40 cycles at 94 C for 1 min and 62 C for 1 min, and a final cycle at 72 C for 10 min. All purified PCR fragments were directly sequenced with either forward or reverse primers using Big Dye Terminator kit (Applied Biosystems Japan, Chiba, Japan) and resolved by capillary electrophoresis on a CEQ 2000XL DNA analysis system (Beckman Coulter, Inc., Fullerton, CA).

PCR-restriction fragment length polymorphism

A DNA fragment of 642 bp containing exon 1 amplified by PCR using a primer set described above was digested with Bcl I (New England Bio Labs Inc., Beverly, MA) at 50 C for 2 h, and the sample was size separated in 0.8% agarose gel containing ethidium bromide. The PCR samples were from the patient, his parents, and a normal control.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
BSND gene analysis

One base substitution of A for G was identified at 139 nucleic acid position in the barttin cDNA, which lies in the exon 1 of BSND (13). This base change was present in the homozygous state in the patient and in the heterozygous state in both of parents (Fig. 3A). The point mutation predicts an amino acid substitution of arginine for glycine at 47 amino acid position (G47R mutation), which has been suggested to be in the second putative transmembrane -helix (Fig. 4) (13).

View larger version (32K): [in this window] [in a new window]   Figure 3. A, A mutation at exon 1 of BSND. The G139A transversion indicated by an asterisk leads to a G47R amino acid change. This base change was present in the homozygous state in the patient and in the heterozygous state in both of parents. It creates a Bcl I restriction site (i.e. TGATCG to TGATCA). B, Restriction fragment length polymorphism analysis. Lanes 1 and 4, patient; lanes 2 and 5, father; lanes 3 and 6, mother. Bcl I digestion of PCR-amplified DNA fragment of 642-bp length containing exon 1 yielded two distinct bands of 432 and 210 bp in the patient and three bands of 642, 432, and 210 bp in both of parents (lanes 4–6).

View larger version (36K): [in this window] [in a new window]   Figure 4. Putative topology of barttin (13 ). G47R mutation is presumed to be located in the second transmembrane -helix. Point mutations R8W, R8L, and G10S, which have previously been reported (13 ), are also indicated by arrows. Mutations that cause large deletions (loss of START codon, loss of exons 3 and 4, and a 41-bp deletion including 21 bp of exon 1 and 20 bp of intron 1) have also been reported (13 ).

The nucleotide substitution of the family at nucleic acid position 139 creates a novel Bcl I restriction site (i.e. TGATCG to TGATCA). Bcl I digestion of PCR-amplified DNA fragment of 642-bp length containing exon 1 yielded two distinct bands of 432 and 210 bp in the patient and three bands of 642, 432, and 210 bp in both of parents (Fig. 3B), whereas only single 642 bp band in a normal control (data not shown).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Here we have reported a Japanese case with BNSD. This seems to be the first case report from Japan. Probably because it has not been long since BSND was recognized as a new disease entity and because of rareness of the disease, there are only a few reports in the literature on BSND available in the world (3, 11, 12, 13, 14, 15). The clinical pictures of our patient, first, did not seem to allow the definite diagnosis of BNSD. It is because all of the BNSD patients reported so far were born prematurely and presented with prenatal maternal polyhydramnios, whereas this patient was born by full-term vaginal delivery and did not present with remarkable polyhydramnios. None of other phenotypes [IBS (16), classic Bartter syndrome (17), or Gitelman syndrome], however, appeared to be consistent with the patient’s symptoms (Table 1).

In our case, Bartter’s syndrome had not been diagnosed until the patient visited our hospital at 28 yr of age. Although the absence of medical records before 24 yr of age makes his clinical history rather unclear, his clinical form has been obviously mild, compared with typical BSND or IBS patients. The symptoms observed in the patient seemed rather compatible with those of most patients with classic [so-called type III (18)] Bartter’s syndrome, except for deafness and nephrocalcinosis. Nephrocalcinosis is uncommon in the classic form and, if present, is regularly accompanied with hypercalciuria (17). However, the patient’s urinary calcium excretion was within normal range. Classic Bartter syndrome has been elucidated to be caused by mutations in CLCNKB with a highly variable phenotype, ranging from a severe perinatal course to patients who were almost symptom free and diagnosed only by accidental detection of hypokalemia (17). However, sensorineural deafness has never accompanied this disorder.

The most striking feature that characterizes him includes the absence of marked fetal polyhydramnios, premature labor, preterm delivery, or severe renal loss of salt and water during the neonatal period (Table 1). Because the mother remembered that she had been told during the delivery about her larger amount of amnionic fluid than usual, there might have been mild polyhydramnios. The gestational age and body weight at birth of eight patients with BSND with barttin abnormality have been described to be 30 ± 1.85 wk and 1470 ± 277 g, respectively (5). In another study, 8 of 20 cases with Bartter-like syndrome in Costa Rica revealed to be with sensorineural deafness, and the age of gestation at birth of the group was 31.4 ± 2.26 wk (3). Proesmans (20) described nine patients with neonatal variant of Bartter syndrome (i.e. IBS, with no mention of complicated deafness made in the literature), of whom the gestational age and body weight at birth were 31.2 ± 2.9 wk and 1873 ± 451 g, respectively. Vargas-Poussou et al. (21) reported that the average gestational age of type I was 32 wk. The longest gestational age at birth among all of these patients with possible BSND and/or IBS was 35 wk. In addition, all of these patients were noted with marked polyhydramnios. These findings contrast with those in our patient, who had been born by vaginal delivery at 40 wk gestation without notable polyhydramnios.

In the study cloning of a new gene BSND, the authors (13) identified seven mutations of the gene, three point mutations resulting in amino acid substitutions (G10S, R8W, R8L) and four other mutations resulting in loss of START codon or large deletions (Fig. 4). Recently we have analyzed our patient’s BSND gene and identified a homozygous point mutation of G47R (a nucleotide change of G139A). It was present in the heterozygous state in his parents (Fig. 3, A and B). Because we have not analyzed the function of the product with G47R mutation, it seems questionable to assert that the mutation is responsible for the patient’s syndrome. However, the function of G47R has recently been reported (14). In the study, the authors demonstrated the mechanism accounting for pathophysiology of BSND, that BSND gene product, designated barttin, acts as an essential ß-subunit for at least two of the ClC chloride channels. In their functional analysis, G47R mutation of barttin (clinical data were not shown) has been proved to abolish the stimulatory effect on ClC-Ka when cotransfected into Xenopus oocytes (14). This confirms that the G47R mutation of the gene for barttin in our patient is responsible for BSND.

The extraordinary clinical characteristics for BSND of our G47R patient such as absence of polyhydramnios, normal physical and mental developments, and full-term delivery may be due to milder functional abnormality of the ClC-Kb-barttin complex with G47R mutation, compared with other BSND patients (Table 1). A similarity of the phenotype between our patient with BSND and those with classic form may result from a similar dysfunction of the ClC-Kb-barttin complex, the former with G47R mutation of barttin and the latter with various mutations of ClC-Kb itself (17). Functional analysis of the ClC-Kb-barttin complex with G47R mutation has not been successful in vitro (14). There also remains the possibility that channels other than ClC-Ka or Kb also work with barttin as complexes modifying the pathophysiology of BSND. These questions should be addressed.

Another problem is nephrocalcinosis without hypercalciuria observed in the patient. Most of IBS patients have hypercalciuria and nephrocalcinosis, but both symptoms are regularly absent in those with classic Bartter syndrome (Table 1). In BSND patients, only transitory hypercalciuria were observed, and they had no signs of nephrocalcinosis (5). The patients were also affected with severe renal failure of unknown origin (5). A speculation for the nephrocalcinosis in view of the normocalciuria in our patient with BSND may be that he had the preceding hypercalciuria before developing nephrocalcinosis. Along with the decrease of glomerular filtration rate, filtered load of calcium might have decreased to a level that can be absorbed sufficiently by pathways other than voltage-driven paracellular absorption of calcium in the thick ascending limb. Mechanism of the impairment of the patient’s glomerular function is unknown. Jeck et al. (5) showed that only 1 of 32 IBS patients affected by mutations in either NKCC2 or ROMK had a GFR <60 ml/min per 1.73 m². However, lower glomerular filtration rate and lower urinary calcium excretion in our patient, compared with IBS patients, might point to his age and nephrocalcinosis that might be of long standing because most of the described patients with IBS are considered to be younger than our patient.

We have described the first distinct BSND patient of Asian origin and the clinical manifestation of a patient with G47R mutation for the first time in the world. The incidence of Bartter syndrome in Japan is unknown because there has been so far no epidemiological investigation for this disorder. In 1979 Sasaki (22) had accumulated 79 case reports of Bartter syndrome from the United States, European countries, and Japan. Twenty-one of them were from Japan, suggesting the prevalence of the syndrome in Japan is considerably high or almost equal to the world. It is of interest that G47R mutation was detected in a Japanese patient because all the BSND patients reported so far have been from the Middle and Near East, Europe, or North Africa; the origin of the previous G47R patient has not been described in the literature (14). It might be possible that G47R is a hot spot for the barttin mutation across the race. Prevalence of the G47R mutation should be determined, and PCR-RFLP analysis using a restriction enzyme Bcl I may benefit the screening for the carrier of this mutation.

Approximately 1 in 1,000 children are born with bilateral sensorineural deafness, and over 60% are inherited. Of those disorders, 75% are nonsyndromic, with most inherited as autosomal recessive traits (23). The milder clinical picture of our G47R patient concerning renal tubular salt loss than those of severe form of BSND suggests a possibility of the presence of mild form BSND with less severe loss of function of barttin among patients with congenital deafness of unknown origin. The prevalence of IBS is estimated to be about 1:50,000 to 1:100,000 (3, 17). That of BSND is now unknown; however, it may be higher than expected including patients with congenital deafness and inconspicuous renal tubular salt loss, resulting from a mild case of the barttin dysfunction.

	Acknowledgments

 
We thank Misako Takahashi for assistance with DNA preparation and sequencing.

	Footnotes

 
N.M. and K.M. equally contributed to this study.

Abbreviations: BSND, Bartter syndrome with sensorineural deafness; IBS, infantile variant of Bartter syndrome.

Received September 5, 2002.

Accepted November 3, 2002.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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