Alternative titles; symbols
HGNC Approved Gene Symbol: KCNJ1
SNOMEDCT: 700109009;
Cytogenetic location: 11q24.3 Genomic coordinates (GRCh38): 11:128,838,020-128,867,296 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q24.3 | Bartter syndrome, type 2 | 241200 | Autosomal recessive | 3 |
The inward rectifier class of potassium channels controls the resting potential and membrane excitability. KCNJ1 is an inward-rectifying apical potassium channel expressed in the thick ascending limb of Henle and throughout the distal nephron of the kidney (summary by Lorenz et al., 2002).
Ho et al. (1993) cloned the rat Romk1 cDNA from kidney and showed that the predicted protein had only 2 transmembrane domains, in contrast to the 6 seen in other potassium channels.
Yano et al. (1994) used PCR with primers based on the rat Romk1 sequence to create a probe from a human kidney cDNA library. The library was then screened and 2 classes of cDNA were isolated. Two isoforms of KCNJ1, which they termed ROMK1A (with 389 codons) and ROMK1B (with 372 codons), differ at their 5-prime ends as a consequence of alternative splicing. Both isoforms of KCNJ1 were detected in the kidney, but other tissues only showed the A form. ROMK1A shows 93% similarity to the rat homolog.
Shuck et al. (1994) used the rat kidney Romk1 potassium channel cDNA to clone the homolog from human kidney. In addition to the human species homolog of the rat gene, 4 additional transcripts formed by alternative splicing of a single human gene were also characterized. All 5 transcripts share a common 3-prime exon that encodes the majority of the channel protein, and in 3 of the isoforms translation is initiated at a start codon contained within this exon.
Krishnan et al. (1995) identified a novel 308-bp PCR product from human cerebral cortex mRNA, the expression of which was found to be restricted to a 3.0-kb band in the kidney by probing a human multiple tissue Northern blot.
Inwardly rectifying potassium (Kir) channels are important regulators of resting membrane potential and cell excitability. The activity of Kir channels is critically dependent on the integrity of channel interactions with phosphatidylinositol 4,5-bisphosphate (PIP2). Using targeted mutations in KCNJ2 (600681) and KCNJ1, which the authors called Kir2.1 and Kir1.1, Lopes et al. (2002) identified residues important for PIP2 interaction. Mutations in residues associated with Andersen syndrome (170390) and Bartter syndrome (241200) decreased the strength of channel-PIP2 interactions. Lopes et al. (2002) concluded that a decrease in channel-PIP2 interactions underlies the molecular mechanism of Andersen and Bartter syndromes when these mutations are present in patients.
Lin et al. (2005) found that Romk1 immunoprecipitated from rat kidney cortex and outer medulla was monoubiquitinated. Mutation analysis indicated that lys22 was the modified residue. Lin et al. (2005) presented evidence that monoubiquitination of ROMK1 regulates channel activity by reducing expression of ROMK1 at the cell surface.
He et al. (2007) showed that mammalian Wnk1 (605232) and Wnk4 (601844) interacted with the endocytic scaffold protein intersectin-1 (ITSN1; 602442) and that these interactions were crucial for stimulation of Romk1 endocytosis. Stimulation of Romk1 endocytosis by Wnk1 and Wnk4 required their proline-rich motifs, but it did not require their kinase activities. Pseudohypoaldosteronism II (PHA2B; 614491)-causing mutations in Wnk4 enhanced the interactions of Wnk4 with Itsn1 and Romk1, leading to increased endocytosis of Romk1.
Yano et al. (1994) used fluorescence in situ hybridization to map the ROMK1 gene to chromosome 11q24. Using fluorescence in situ hybridization to human metaphase chromosomes, Krishnan et al. (1995) confirmed the mapping of the KCNJ1 gene to 11q.
Mutations in the sodium/potassium/chloride transporter-2 gene, (SLC12A1; 600839), a mediator of renal salt reabsorption, cause antenatal Bartter syndrome type 1 (BARTS1; 601678), featuring salt wasting, hypokalemic alkalosis, hypercalciuria, and low blood pressure. SLC12A1 mutations had been excluded in some Bartter kindreds, prompting examination of regulators of cotransporter activity. ROMK is believed to be one such regulator; it is an ATP-sensitive potassium channel that 'recycles' reabsorbed potassium back to the tubule lumen. In 4 kindreds, Simon et al. (1996) found mutations in the ROMK gene that cosegregated with antenatal Bartter syndrome and disrupted ROMK function (600359.0001-600359.0006). The disorder has since been designated antenatal Bartter syndrome type 2 (BARTS2; 241200).
The International Collaborative Study Group for Bartter-like Syndromes (1997) reported mutations in the KCNJ1 gene (600359.0007-600359.0009) in 3 kindreds and 5 sporadic cases with antenatal Bartter syndrome type 2. Functional coupling of ROMK and the luminal Na-K-2Cl cotransporter is crucial for NaCl reabsorption. Therefore, loss of function in ROMK, as well as in NKCC2, would be predicted to disrupt electrogenic chloride reabsorption in the medullary thick ascending limb of the loop of Henle.
Schwalbe et al. (1998) introduced 4 mutations associated with antenatal Bartter syndrome into rat Kcnj1 and characterized the channels expressed in Sf9 insect cells. Three of the mutations produced channels with significantly reduced K(+) fluxes; however, the mechanisms in each case were different and included abnormalities in phosphorylation, proteolytic processing, and protein trafficking.
Jeck et al. (2001) assessed the functional consequences of 9 different mutations in the ROMK gene categorized by location: within the core region, truncation at the cytosolic C terminus, and within putative promoter elements. Although the majority of the core mutations exhibited a dominant-negative effect, there was a variable effect on channel conductance, suggesting a spectrum of mechanisms involved in loss of channel function.
O'Donnell et al. (2017) expressed 4 ROMK mutations, all resulting in type II Bartter syndrome and all known to affect protein trafficking, in yeast and HEK293 cells. The mutations were predicted to fall within beta-strands in the C-terminal cytoplasmic immunoglobulin-like domain. All 4 mutant proteins were retained in the endoplasmic reticulum (ER) and were subject to ER-associated degradation (ERAD). Degradation was proteasome-dependent, relied on the AAA+ ATPase Cdc48 (VCP; 601023), and was mediated by the molecular chaperone Hsp70 (see 140550). O'Donnell et al. (2017) concluded that mutations in the immunoglobulin-like domain target ROMK for ERAD.
Lorenz et al. (2002) developed Kcnj1-null mice. Young null mutants had hydronephrosis, were severely dehydrated, and about 95% died before 3 weeks of age. Those that survived beyond weaning grew to adulthood; however, they had metabolic acidosis, elevated blood concentrations of Na(+) and Cl(-), reduced blood pressure, polydipsia, polyuria, and poor urinary concentrating ability. Whole kidney glomerular filtration rate was reduced, apparently as a result of hydronephrosis, and fractional excretion of electrolytes was elevated. Micropuncture analysis revealed that the single nephron glomerular filtration rate was relatively normal, absorption of NaCl in thick ascending limb of Henle was reduced, and tubuloglomerular feedback was impaired.
Lu et al. (2002) bred surviving null males from the work reported by Lorenz et al. (2002) with heterozygous females to enhance survival. These Kcnj1-null mice showed 25% survival to adulthood. Those that died showed significant hydronephrosis, whereas surviving null mice did not. Mutant mice were polyuric and natriuretic with an elevated hematocrit consistent with mild extracellular volume depletion. Patch-clamp analysis of cortical collecting ducts and thick ascending limb of wildtype mice revealed the presence of small-conductance K(+) channel activity that was missing in mutant mice. Despite the loss of Kcnj1 expression, the normokalemic null mice exhibited significantly increased kaliuresis, indicating alternative mechanisms for K(+) absorption/secretion in the nephron.
In a family with antenatal Bartter syndrome type 2 (BARTS2; 241200) in which linkage to the NKCC2 gene was excluded, Simon et al. (1996) found a tyr60-to-ter nonsense mutation in the KCNJ1 gene. The mutation truncated the protein prior to the first transmembrane domain. In this family with first-cousin parents, there were 2 affected children who were homozygous for the mutation.
In a consanguineous family with antenatal Bartter syndrome (BARTS2; 241200) in which linkage to the NKCC2 gene was excluded, Simon et al. (1996) found homozygosity for insertion of a single T into a sequence of 6 consecutive T residues spanning codons 13 and 14 of the KCNJ1 gene, resulting in a frameshift mutation changing the encoded protein from amino acid 15 onward and resulting in premature termination at codon 54.
In affected members of the BAR208 family with antenatal Bartter syndrome type 2 (BARTS2; 241200), Simon et al. (1996) identified compound heterozygous mutations in the NKCC2 gene. One mutation substituted arginine for serine at codon 200. The other mutation was a premature termination at codon 58 (W58X; 600359.0004), truncating the encoded protein prior to the first transmembrane domain.
Schwalbe et al. (1998) characterized this mutation in rat Kcnj1 expressed in Sf9 insect cells. Patch clamp recordings indicated a lack of whole-cell currents, and Western blot analysis revealed 2 proteins with significantly reduced apparent molecular masses. Schwalbe et al. (1998) proposed that the introduction of arginine at this site creates a potential cleavage site for trypsin-like proteases.
For discussion of the trp58-to-ter (W58X) mutation in the KCNJ1 gene that was found in compound heterozygous state in individuals with antenatal Bartter syndrome (BARTS2; 241200) by Simon et al. (1996), see 600359.0003.
In nonconsanguineous family BAR206, Simon et al. (1996) found compound heterozygosity for mutations in the KCNJ1 gene in members affected by antenatal Bartter syndrome (BARTS2; 241200). One variant represented a 4-bp deletion, spanning the last base of codon 313 and all of codon 314, resulting in a frameshift mutation and altering the encoded protein from amino acid 315 onward and ending at a new stop codon at position 350. The second variant in this kindred arose from substitution of valine for alanine at amino acid 195 in the cytoplasmic C-terminal region of ROMK.
Schwalbe et al. (1998) studied this mutation in rat Kcnj1 and determined that it hindered phosphorylation of a nearby serine and lead to fast channel rundown.
In outbred Bartter syndrome (BARTS2; 241200) kindred BAR139 in which no NKCC2 variant had been identified, Simon et al. (1996) identified a single ROMK variant, substituting threonine for methionine at amino acid 338; this variant was not seen on 80 chromosomes from unaffected subjects. No mutation was identified on the other ROMK allele in the affected patient.
In a North African family with antenatal Bartter syndrome (BARTS2; 241200) studied in Paris, the International Collaborative Study Group for Bartter-like Syndromes (1997) identified a G-to-A transition at nucleotide 1153 of the KCNJ1 gene, resulting in an ala198-to-thr amino acid substitution.
In a family of Indian origin studied in Marburg, Germany, the International Collaborative Study Group for Bartter-like Syndromes (1997) found the cause of antenatal Bartter syndrome (BARTS2; 241200) to be a G-to-A transition at nucleotide 1062 of the KCNJ1 gene, resulting in a gly167-to-glu amino acid substitution.
In a Turkish family with antenatal Bartter syndrome (BARTS2; 241200) studied in Marburg, Germany, the International Collaborative Study Group for Bartter-like Syndromes (1997) identified a G-to-C transversion at nucleotide 883 of the KCNJ1 gene, resulting in an asp108-to-his (D108H) amino acid substitution, as the cause of antenatal Bartter syndrome.
Derst et al. (1997) analyzed the electrophysiologic function of this D108H ROMK channel mutation and 4 others: val72glu (V72E), pro110leu (P110L), ala198-to-thr (A198T; 600359.0007), and val315gly (V315G). In whole-cell patch-clamp recordings, mutated ROMK1 cDNAs transfected into COS-7 kidney cells showed either no or only infrequently small currents. Loss of tubular potassium channel function probably prevents apical membrane potassium recycling with secondary inhibition of Na-K-2Cl-cotransport in the thick ascending limb of the Henle loop (TALH). Derst et al. (1997) concluded that mutations in the potassium channel ROMK are the primary events causing renal salt wasting in the subset of patients with the antenatal variant of Bartter syndrome.
In a sporadic case of hyperprostaglandin E syndrome (BARTS2; 241200), Derst et al. (1998) described a lys124-to-asn (K124N) missense mutation located in the extracellular M1-H5 linker region of the KCNJ1 gene. When heterologously expressed in Xenopus oocytes and mammalian cells, current amplitudes from mutant Kir1.1a channels were reduced by a factor of approximately 12 as compared with wildtype. A lysine at the equivalent position is present in only 1 of the known Kir subunits, the newly identified Kir1.3, which is also fully expressed in the recombinant system. When the lysine residue in guinea pig Kir1.3 isolated from a genomic library was changed to an asparagine, mutant channels yielded macroscopic currents with amplitudes increased 6 fold. From single channel analysis, it became apparent that the decrease in mutant Kir1.1 channels and the increase in guinea pig Kir1.3 macroscopic currents were mainly due to the number of expressed functional channels. Coexpression experiments revealed a dominant-negative effect of the mutant Kir1.1a on macroscopic current amplitudes when fully expressed with wildtype Kir1.1a. Thus, Derst et al. (1998) postulated that in Kir1.3 channels the extracellular positively charged lysine is of crucial functional importance. The hyperprostaglandin E syndrome phenotype in man can be explained by the lower expression of functional channels by the Kir1.1a unit.
Derst, C., Konrad, M., Kockerling, A., Karolyi, L., Deschenes, G., Daut, J., Karschin, A., Seyberth, H. W. Mutations in the ROMK gene in antenatal Bartter syndrome are associated with impaired K(+) channel function. Biochem. Biophys. Res. Commun. 230: 641-645, 1997. [PubMed: 9015377] [Full Text: https://doi.org/10.1006/bbrc.1996.6024]
Derst, C., Wischmeyer, E., Preisig-Muller, R., Spauschus, A., Konrad, M., Hensen, P., Jeck, N., Seyberth, H. W., Daut, J., Karschin, A. A hyperprostaglandin E syndrome mutation in Kir1.1 (renal outer medullary potassium) channels reveals a crucial residue for channel function in Kir1.3 channels. J. Biol. Chem. 273: 23884-23891, 1998. [PubMed: 9727001] [Full Text: https://doi.org/10.1074/jbc.273.37.23884]
He, G., Wang, H.-R., Huang, S.-K., Huang, C.-L. Intersectin links WNK kinases to endocytosis of ROMK1. J. Clin. Invest. 117: 1078-1087, 2007. [PubMed: 17380208] [Full Text: https://doi.org/10.1172/JCI30087]
Ho, K., Nichols, C. G., Lederer, W. J., Lytton, J., Vassilev, P. M., Kanazirska, M. V., Hebert, S. C. Cloning and expression of an inwardly rectifying ATP-regulated potassium channel. Nature 362: 31-38, 1993. [PubMed: 7680431] [Full Text: https://doi.org/10.1038/362031a0]
International Collaborative Study Group for Bartter-like Syndromes. Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. Hum. Molec. Genet. 6: 17-26, 1997. Note: Erratum: Hum. Molec. Genet. 6: 650 only, 1997. [PubMed: 9002665] [Full Text: https://doi.org/10.1093/hmg/6.1.17]
Jeck, N., Derst, C., Wischmeyer, E., Ott, H., Weber, S., Rudin, C., Seyberth, H. W., Daut, J., Karschin, A., Konrad, M. Functional heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome. Kidney Int. 59: 1803-1811, 2001. [PubMed: 11318951] [Full Text: https://doi.org/10.1046/j.1523-1755.2001.0590051803.x]
Krishnan, S. N., Desai, T., Ward, D. C., Haddad, G. G. Isolation and chromosomal localization of a human ATP-regulated potassium channel. Hum. Genet. 96: 155-160, 1995. [PubMed: 7635463] [Full Text: https://doi.org/10.1007/BF00207372]
Lin, D.-H., Sterling, H., Wang, Z., Babilonia, E., Yang, B., Dong, K., Hebert, S. C., Giebisch, G., Wang, W.-H. ROMK1 channel activity is regulated by monoubiquitination. Proc. Nat. Acad. Sci. 102: 4306-4311, 2005. [PubMed: 15767585] [Full Text: https://doi.org/10.1073/pnas.0409767102]
Lopes, C. M. B., Zhang, H., Rohacs, T., Jin, T., Yang, J., Logothetis, D. E. Alterations in conserved Kir channel-PIP(2) interactions underlie channelopathies. Neuron 34: 933-944, 2002. [PubMed: 12086641] [Full Text: https://doi.org/10.1016/s0896-6273(02)00725-0]
Lorenz, J. N., Baird, N. R., Judd, L. M., Noonan, W. T., Andringa, A., Doetschman, T., Manning, P. A., Liu, L. H., Miller, M. L., Shull, G. E. Impaired renal NaCl absorption in mice lacking the ROMK potassium channel, a model for type II Bartter's syndrome. J. Biol. Chem. 277: 37871-37880, 2002. [PubMed: 12122007] [Full Text: https://doi.org/10.1074/jbc.M205627200]
Lu, M., Wang, T., Yan, Q., Yang, X., Dong, K., Knepper, M. A., Wang, W., Giebisch, G., Shull, G. E., Hebert, S. C. Absence of small conductance K(+) channel (SK) activity in apical membranes of thick ascending limb and cortical collecting duct in ROMK (Bartter's) knockout mice. J. Biol. Chem. 277: 37881-37887, 2002. [PubMed: 12130653] [Full Text: https://doi.org/10.1074/jbc.M206644200]
O'Donnell, B. M., Mackie, T. D., Subramanya, A. R., Brodsky, J. L. Endoplasmic reticulum-associated degradation of the renal potassium channel, ROMK, leads to type II Bartter syndrome. J. Biol. Chem. 292: 12813-12827, 2017. [PubMed: 28630040] [Full Text: https://doi.org/10.1074/jbc.M117.786376]
Schwalbe, R. A., Bianchi, L., Accili, E. A., Brown, A. M. Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment. Hum. Molec. Genet. 7: 975-980, 1998. [PubMed: 9580661] [Full Text: https://doi.org/10.1093/hmg/7.6.975]
Shuck, M. E., Bock, J. H., Benjamin, C. W., Tsai, T.-D., Lee, K. S., Slightom, J. L., Bienkowski, M. J. Cloning and characterization of multiple forms of the human kidney ROM-K potassium channel. J. Biol. Chem. 269: 24261-24270, 1994. [PubMed: 7929082]
Simon, D. B., Karet, F. E., Rodriguez-Soriano, J., Hamdan, J. H., DiPietro, A., Trachtman, H., Sanjad, S. A. Lifton, R. P.: Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K(+) channel, ROMK. Nature Genet. 14: 152-156, 1996. [PubMed: 8841184] [Full Text: https://doi.org/10.1038/ng1096-152]
Yano, H., Philipson, L. H., Kugler, J. L., Tokuyama, Y., Davis, E. M., Le Beau, M. M., Nelson, D. J., Bell, G. I., Takeda, J. Alternative splicing of human inwardly rectifying K+ channel ROMK1 mRNA. Molec. Pharm. 45: 854-860, 1994. [PubMed: 8190102]