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Link to original content: https://omim.org/entry/602023
Alternative titles; symbols
HGNC Approved Gene Symbol: CLCNKB
SNOMEDCT: 700111000;
Cytogenetic location: 1p36.13 Genomic coordinates (GRCh38) : 1:16,043,782-16,057,326 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.13 | Bartter syndrome, type 3 | 607364 | Autosomal recessive | 3 |
| Bartter syndrome, type 4b, digenic | 613090 | Digenic recessive | 3 |
The CLCNKA and CLCNKB channels are members of the ClC family, which comprises at least 9 mammalian chloride channels. Each is believed to have 12 transmembrane domains and intracellular N and C termini. The prototype of the family in Torpedo is gated by both voltage and chloride (Jentsch and Gunther, 1997).
Kieferle et al. (1994) cloned rat and human homologs of 2 closely related chloride channels found specifically in mammalian kidney, which they called ClCK1 and ClCK2. In the rat, ClCK1 and ClCK2 appear to be expressed along the nephron from the thin ascending limb of the Henle loop onwards. The human homologs of these 2 genes, CLCNKA (602024) and CLCNKB, encode proteins of 687 amino acids (Saito-Ohara et al., 1996).
Simon et al. (1997) demonstrated that the intron-exon organization of the CLCNKA and CLCNKB genes was identical, with each channel encoded by 19 exons. Overall, the genes show 94% DNA sequence identity in exons. The 2 genes are transcribed from the same DNA strand, with CLCNKA 5-prime of CLCNKB. The 2 genes are separated by 11 kb of genomic DNA.
Saito-Ohara et al. (1996) mapped the CLCNKA and CLCNKB genes to chromosome 1p36.
Considering CLCNKA and CLCNKB as candidate genes in families with classic Bartter syndrome (BARTS3; 607364), Simon et al. (1997) isolated PAC and cosmid genomic clones encoding these genes. They found that both genes were present in all 6 PAC clones, indicating that they are closely linked to one another, as previously suggested by in situ hybridization using CLCK cDNA (Saito-Ohara et al., 1996). Using a marker polymorphism in exon 13 of the CLCNKA gene, Simon et al. (1997) showed that in CEPH kindreds the gene is linked to chromosome 1; a multipoint lod score of 15.8 at a recombination fraction of 0.0 was obtained with D1S436.
Estevez et al. (2001) demonstrated that barttin (BSND; 606412) acts as an essential beta subunit for CLCNKA and CLCNKB chloride channels, with which it colocalizes in basolateral membranes of renal tubules and of potassium-secreting epithelia of the inner ear. Disease-causing mutations in either CLCNKB or barttin compromise currents through heteromeric channels. Currents can be stimulated further by mutating a proline-tyrosine (PY) motif on barttin. Estevez et al. (2001) concluded that their work described the first known beta subunit for CLC chloride channels and revealed that heteromers formed by chloride channels and barttin are crucial for renal salt reabsorption and potassium recycling in the inner ear.
Bartter Syndrome Type 3
In affected members of 10 kindreds with classic Bartter syndrome type 3 (BARTS3; 607364), Simon et al. (1997) found homozygous deletion of the CLCNKB gene. Two kindreds showed homozygous loss of part of CLCNKB. The tight linkage and topology of CLCNKA and CLCNKB raised the question of unequal crossing over between these genes or blocks of homologous flanking sequences as a mechanism for deletion of CLCNKB sequences. Simon et al. (1997) found reciprocal loss of CLCNKA and CLCNKB sequences consistent with this mechanism. They also demonstrated 7 mutations altering the CLCNKB gene and cosegregating with the disease (e.g., 602023.0001). In 4 kindreds, affected persons were homozygous for identified mutations, 2 index cases were compound heterozygotes, and a single mutation was identified in 1 kindred.
Jeck et al. (2000) described 3 unrelated patients presenting with the typical laboratory findings of Gitelman syndrome (263800). Mutation analysis in these 3 patients revealed no abnormality in the SLC12A3 (600968) gene. Instead, all patients were found to carry previously described mutations in the CLCNKB gene: 2 were homozygous for complete deletion of the gene (602023.0006) and 1 was homozygous for an A-G substitution at the splice acceptor site of intron 7 (602023.0007) (Konrad et al., 2000). Further clinical investigation revealed features more typical of Bartter syndrome than of Gitelman syndrome. Jeck et al. (2000) suggested that the phenotypic overlap may indicate a physiologic cooperation of the apical thiazide-sensitive NaCl cotransporter (SLC12A3) and the basolateral chloride channel (CLCNKB) for salt reabsorption in the distal convoluted tubule.
Schurman et al. (2001) studied 5 African American children with Bartter syndrome. Like the African American children reported by Simon et al. (1997), these children demonstrated homozygous deletion of the CLCNKB gene (602023.0006). They had partial correction of hypokalemia, normal calciotropic activity, suboptimal growth despite therapy, and abnormal renal ultrasounds but no nephrocalcinosis.
Fukuyama et al. (2004) reported 2 Japanese patients who suffered from clinically diagnosed classic Bartter syndrome but who had hypocalciuria. Hypocalciuria is believed to be a pathognomic finding of Na-Cl cotransporter malfunction. They identified mutations in the CLCNKB gene, including a premature termination mutation (602023.0009) and a splice site mutation (602023.0010). The authors concluded that some CLCNKB mutations may affect calcium handling in renal tubular cells.
Bartter Syndrome Type 4B
In a child with renal salt wasting and sensorineural deafness (BARTS4B; 613090) who had no mutation in the BSND gene (606412), Schlingmann et al. (2004) identified both a homozygous deletion of the CLCNKB gene (602023.0008) and a homozygous trp80-to-cys mutation in the CLCNKA gene (W80C; 602024.0001). Because this combined impairment of the CLCNKA and CLCNKB genes resulted in a phenotype mimicking the form of neonatal Bartter syndrome with sensorineural deafness caused by mutation in the BSND gene (BARTS4A; 602522), Schlingmann et al. (2004) concluded that this case with digenic inheritance supported the notion that the CLCNK-type channels are regulated by barttin and offered strong evidence of genetic heterogeneity in patients who have both severe renal salt wasting and deafness.
Nozu et al. (2008) reported a 2-year-old Japanese girl with a severe form of Bartter syndrome with sensorineural deafness who was born of nonconsanguineous parents. Genetic analysis showed 2 heterozygous mutations in the CLCNKA (602024.0002) and CLCNKB (602023.0011) genes on the paternal allele, and a 12-kb deletion involving portions of the CLCNKA and CLCNKB genes on the maternal allele. Neither parent was clinically affected. The findings indicated clear digenic inheritance in this patient and confirmed that loss of function of all 4 alleles of the CLCNKA and CLCNKB genes can result in Bartter syndrome type 4B.
In 2 apparently unrelated Turkish kindreds, Simon et al. (1997) found that children with classic Bartter syndrome (BARTS3; 607364) were homozygous for the identical mutation, a substitution of leucine for proline at codon 124 of the CLCNKB gene. This proline residue is conserved among all mammalian members of the CLC family.
In 2 Spanish kindreds, Simon et al. (1997) found that individuals with classic Bartter syndrome (BARTS3; 607364) were homozygous for substitution of threonine for alanine at codon 204 in the fifth transmembrane domain of the CLCNKB gene. All CLC channel members, including the CLC-related channel of yeast, have alanine or glycine at this position, within a highly conserved hydrophobic segment (amino acids AAAA or AGAA).
One of the missense mutations in the CLCNKB gene identified by Simon et al. (1997) in classic Bartter syndrome (BARTS3; 607364) patients was arg438 to cys (R438C), where R438 is conserved among all members of the CLC family.
One of the missense mutations identified by Simon et al. (1997) in the CLCNKB gene in patients with classic Bartter syndrome (BARTS3; 607364) was ala349 to asp (A349D), which introduces a charged residue in the predicted eighth transmembrane domain of the channel.
One of the mutations identified by Simon et al. (1997) in the CLCNKB gene in classic Bartter syndrome (BARTS3; 607364) patients was a tyr432-to-his (Y432H) substitution.
In 3 patients, the offspring of consanguineous parents, presenting with biochemical findings consistent with the diagnosis of Gitelman syndrome (263800), Jeck et al. (2000) detected 2 mutations previously described by Konrad et al. (2000): homozygous deletion of the CLCNKB gene was present in 2 patients, and homozygous exchange of guanine for adenine at the consensus acceptor site of intron 7 (602023.0007) was present in the third. Review of medical history revealed early onset of the disease, within the first year of life. Clinical presentation included episodes of dehydration, weakness, and failure to thrive, much more suggestive of classic Bartter syndrome (BARTS3; 607364) than of Gitelman syndrome. The coexistence of hypomagnesemia and hypocalciuria was not present from the beginning. In the follow-up, a drop of both parameters below normal range was a consistent finding reflecting a transition from classic Bartter syndrome to Gitelman syndrome phenotype. Jeck et al. (2000) suggested that the phenotypic overlap may indicate a physiologic cooperation of the apical thiazide-sensitive NaCl cotransporter and the basolateral chloride channel for salt reabsorption in the distal convoluted tubule.
For discussion of the splice site mutation (IVS7-2A-G) in the CLCNKB gene that was found in compound heterozygous state in patients with classic Bartter syndrome by Jeck et al. (2000), see 602023.0006.
In a child with renal salt wasting and deafness (BARTS4B; 613090) who had no mutation in the BSND gene (606412), Schlingmann et al. (2004) identified both a homozygous deletion of the CLCNKB gene and a homozygous cys80-to-trp (C80W) mutation in the CLCNKA gene (C80W; 602024.0001). The patient was born prematurely to consanguineous parents, and the pregnancy was complicated by severe maternal polyhydramnios during the last 6 weeks of gestation.
In 2 Japanese patients who had been diagnosed with classic Bartter syndrome (BARTS3; 607364) but who presented with hypocalciuria, Fukuyama et al. (2004) found a G-to-A transition at nucleotide 1830 in exon 16 of the CLCNKB gene that resulted in premature termination (trp610 to ter; W610X).
In a Japanese patient who had been diagnosed with classic Bartter syndrome (BARTS3; 607364) but who presented with hypocalciuria, Fukuyama et al. (2004) identified compound heterozygosity for 2 mutations in the CLCNKB gene. One was a G-to-C transversion at the 3-prime splice site of intron 2; the other was a premature termination mutation (W610X; 602023.0009).
In a 2-year-old Japanese girl with a severe form of Bartter syndrome with sensorineural deafness (BARTS4B; 613090), Nozu et al. (2008) identified a heterozygous G-to-A transition in intron 7 of the CLCNKB gene, resulting in a splice site mutation, and a heterozygous mutation in the CLCNKA gene (Q260X; 602024.0002), both inherited from the father. The maternal allele had a 12-kb deletion including portions of both CLCNKA and CLCNKB. Neither parent was clinically affected. The findings indicated clear digenic inheritance in this patient and confirmed that loss of function of all 4 alleles of the CLCNKA and CLCNKB genes can result in Bartter syndrome type 4B.
Estevez, R., Boettger, T., Stein, V., Birkenhager, R., Otto, E., Hildebrandt, F., Jentsch, T. J. Barttin is a Cl- channel beta-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion. Nature 414: 558-561, 2001. [PubMed: 11734858] [Full Text: https://doi.org/10.1038/35107099]
Fukuyama, S., Hiramatsu, M., Akagi, M., Higa, M., Ohta, T. Novel mutations of the chloride channel Kb gene in two Japanese patients clinically diagnosed as Bartter syndrome with hypocalciuria. J. Clin. Endocr. Metab. 89: 5847-5850, 2004. [PubMed: 15531551] [Full Text: https://doi.org/10.1210/jc.2004-0775]
Jeck, N., Konrad, M., Peters, M., Weber, S., Bonzel, K. E., Seyberth, H. W. Mutations in the chloride channel gene, CLCNKB, leading to a mixed Bartter-Gitelman phenotype. Pediat. Res. 48: 754-758, 2000. [PubMed: 11102542] [Full Text: https://doi.org/10.1203/00006450-200012000-00009]
Jentsch, T. J., Gunther, W. Chloride channels: an emerging molecular picture. Bioessays 19: 117-126, 1997. [PubMed: 9046241] [Full Text: https://doi.org/10.1002/bies.950190206]
Kieferle, S., Fong, P., Bens, M., Vandewalle, A., Jentsch, T. J. Two highly homologous members of the ClC chloride channel family in both rat and human kidney. Proc. Nat. Acad. Sci. 91: 6943-6947, 1994. [PubMed: 8041726] [Full Text: https://doi.org/10.1073/pnas.91.15.6943]
Konrad, M., Vollmer, M., Lemmink, H. H., van den Heuvel, L. P. W. J., Jeck, N., Vargas-Poussou, R., Lakings, A., Ruf, R., Deschenes, G., Antignac, C., Guay-Woodford, L., Knoers, N. V. A. M., Seyberth, H. W., Feldmann, D., Hildebrandt, F. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J. Am. Soc. Nephrol. 11: 1449-1459, 2000. [PubMed: 10906158] [Full Text: https://doi.org/10.1681/ASN.V1181449]
Nozu, K., Inagaki, T., Fu, X. J., Nozu, Y., Kaito, H., Kanda, K., Sekine, T., Igarashi, T., Nakanishi, K., Yoshikawa, N., Iijima, K., Matsuo, M. Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness. J. Med. Genet. 45: 182-186, 2008. [PubMed: 18310267] [Full Text: https://doi.org/10.1136/jmg.2007.052944]
Saito-Ohara, F., Uchida, S., Takeuchi, Y., Sasaki. S., Hayashi, A., Maraumo, F., Ikeuchi, T. Assignment of the genes encoding the human chloride channels, CLCNKA and CLCNKB, to 1p36 and of CLCN3 to 4q32-q33 by in situ hybridization. Genomics 36: 372-374, 1996. [PubMed: 8812470] [Full Text: https://doi.org/10.1006/geno.1996.0479]
Schlingmann, K. P., Konrad, M., Jeck, N., Waldegger, P., Reinalter, S. C., Holder, M., Seyberth, H. W., Waldegger, S. Salt wasting and deafness resulting from mutations in two chloride channels. New Eng. J. Med. 350: 1314-1319, 2004. [PubMed: 15044642] [Full Text: https://doi.org/10.1056/NEJMoa032843]
Schurman, S. J., Perlman, S. A., Sutphen, R., Campos, A., Garin, E. H., Cruz, D. N., Shoemaker, L. R. Genotype/phenotype observations in African Americans with Bartter syndrome. J. Pediat. 139: 105-110, 2001. [PubMed: 11445802] [Full Text: https://doi.org/10.1067/mpd.2001.115020]
Simon, D. B., Bindra, R. S., Mansfield, T. A., Nelson-Williams, C., Mendonca, E., Stone, R., Schurman, S., Nayir, A., Alpay, H., Bakkaloglu, A., Rodriguez-Soriano, J., Morales, J. M., Sanjad, S. A., Taylor, C. M., Pilz, D., Brem, A., Trachtman, H., Griswold, W., Richard, G. A., John, E., Lifton, R. P. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nature Genet. 17: 171-178, 1997. [PubMed: 9326936] [Full Text: https://doi.org/10.1038/ng1097-171]