Alternative titles; symbols
HGNC Approved Gene Symbol: CLCNKA
Cytogenetic location: 1p36.13 Genomic coordinates (GRCh38) : 1:16,022,036-16,034,050 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.13 | Bartter syndrome, type 4b, digenic | 613090 | Digenic recessive | 3 |
The CLCNKA gene, a member of the chloride channel (ClC) family, encodes a kidney-specific chloride channel that mediates transepithelial chloride transport in the thin ascending limb of the Henle loop (tAL) in the inner medulla (Matsumura et al., 1999). Transport of NaCl in the tAL is thought to be a component of urinary concentration in a passive model of the countercurrent multiplication system. Each member of the ClC family is thought to have 12 transmembrane domains and intracellular N and C termini (Jentsch and Gunther, 1997).
Kieferle et al. (1994) cloned 2 closely related putative chloride channels from both rat kidney and human kidney. The human genes, designated ClCK1 and ClCK2 (CLCNKB; 602023) by them, each comprise 687 amino acids and share approximately 90% identity.
Simon et al. (1997) demonstrated that the intron-exon organization of the CLCNKA and CLCNKB genes is 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 by in situ hybridization. Simon et al. (1997) confirmed that the CLCNKA and CLCNKB genes map to chromosome 1.
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.
In a child with renal salt wasting and deafness (Bartter syndrome type 4B; 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 infantile Bartter syndrome with sensorineural deafness caused by mutation in the BSND gene (Bartter syndrome type 4A; 602522), Schlingmann et al. (2004) concluded that this case supported the notion that the CLCK-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.
Matsumura et al. (1999) provided direct evidence that CLCK1 is involved in urine concentration. To analyze the physiologic function of CLCK1 in vivo, they generated mice lacking CLC-K1 by targeted gene disruption. Clcnk1 -/- mice were normal in physical appearance but produced approximately 5 times more urine than did heterozygous or homozygous normal mice. After 24 hours of water deprivation, the homozygous deficient mice were severely dehydrated and lethargic, with a decrease of approximately 27% in body weight. Intraperitoneal injection of dDAVP (1-desamino-8D-arginine vasopressin) induced a 3-fold increase in urine osmolarity in heterozygous and homozygous normal mice, whereas only a minimal increase was seen in the homozygous deficient mice, indicating nephrogenic diabetes insipidus. After in vitro perfusion of the tAL, the lumen-to-bath chloride gradient did not produce a diffusion potential in the homozygous deficient mice in contrast to the homozygous normal and heterozygous mice. These results established that CLCK1 has a role in urine concentration, and that the countercurrent system in the inner medulla is involved in the generation and maintenance of hypertonic medullary interstitium. Matsumura et al. (1999) suggested that mutations of CLCNKA may be associated with nephrogenic diabetes insipidus in those cases where mutations in the vasopressin V2 receptor (AVPR2; 300538) and the AQP2 water channel (107777) are lacking.
In a child with renal salt wasting and deafness (Bartter syndrome type 4B; 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 G-to-C transversion in exon 3 of the CLCNKA gene, resulting in a cys80-to-trp (C80W) mutation. 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 a 2-year-old Japanese girl with a severe form of Bartter syndrome with sensorineural deafness (613090), Nozu et al. (2008) identified a heterozygous 778C-T transition in exon 7 of the CLCNKA gene, resulting in a gln260-to-ter (Q260X) substitution, and a heterozygous splice site mutation in the CLCNKB gene (602023.0011), 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]
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]
Matsumura, Y., Uchida, S., Kondo, Y., Miyazaki, H., Ko, S. B. H., Hayama, A., Morimoto, T., Liu, W., Arisawa, M., Sasaki, S., Marumo, F. Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel. Nature Genet. 21: 95-98, 1999. [PubMed: 9916798] [Full Text: https://doi.org/10.1038/5036]
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., Marumo, 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]
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]