Alternative titles; symbols
HGNC Approved Gene Symbol: SLC12A1
SNOMEDCT: 700107006;
Cytogenetic location: 15q21.1 Genomic coordinates (GRCh38): 15:48,206,302-48,304,078 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.1 | Bartter syndrome, type 1 | 601678 | Autosomal recessive | 3 |
The Na-K-Cl cotransporters are a family of integral membrane proteins that mediate the coupled transport of Na+, K+, and Cl- across the plasma membrane; see also SLC12A2 (600840) and SLC12A3 (600968).
Simon et al. (1996) isolated the predominant form of human NKCC2 from a human kidney cDNA library and found that it encodes a protein of 1,099 amino acids that shows strong sequence similarity to NKCC2 from rabbit and rat (95% and 93%, respectively).
Simon et al. (1996) determined that the NKCC2 protein is encoded in 26 exons, and the coding region spans 80 kb of genomic DNA with introns that range in length from 120 bp to 15 kb. The location of intron/exon boundaries are very similar to those seen in SLC10A3 through exon 19. Three alternative forms of exon 4 are encoded in genomic DNA, as reported in other species.
In the mouse, Slc12a1 was shown by Quaggin et al. (1995) to be linked to Thbs1 (188060) proximally and interleukin-1 beta (147720) distally, both being genes known to reside on mouse chromosome 2. In the mouse, Slc12a1 appeared to map within a region of chromosome 2 that has homology of synteny with human chromosome 15. The gene for fibrillin-1 in the mouse (134797), which is the most distal known gene in a linkage group that is syntenic with human 15q11-q22, is 1.3 cM proximal to the interleukin-1 complex and is therefore probably distal to Slc12a1. Accordingly, Quaggin et al. (1995) predicted that the SLC12A1 gene maps to human chromosome 15.
Simon et al. (1996) used a (GT)n dinucleotide repeat sequence to map the human NKCC2 gene to 15q15-q21, consistent with the location of the mouse homolog of NKCC2 on mouse chromosome 2.
Quaggin et al. (1995) noted that in the mammalian kidney, an Na-K-Cl cotransporter, previously called NKCC2, mediates active reabsorption of sodium chloride in the thick ascending limb of the loop of Henle and represents the site of action of the clinically important diuretics furosemide and bumetanide. The gene, symbolized SLC12A1 in human and mouse, is structurally related (64% amino acid identity in the mouse) to another Na-K-Cl cotransporter (SLC12A2; previously called NKCC1) which, unlike the kidney-specific SLC12A1, is expressed in many tissues, including the basolateral membrane of secretory epithelia, where it mediates active chloride secretion.
Quaggin et al. (1995) stated that antenatal Bartter syndrome (BARTS1; 601678) is a candidate disorder for mutation in SLC12A1. In 6 families with antenatal Bartter syndrome, Simon et al. (1996) identified 6 novel mutations in the SLC12A1 gene that segregated with the disease and resulted in frameshifts or amino acid substitutions in highly conserved residues (see 600839.0001 and 600839.0002).
Using SSCP analysis of the coding sequence and the exon-intron boundaries of the NKCC2 gene, Vargas-Poussou et al. (1998) performed molecular analysis in 15 probands with antenatal Bartter syndrome belonging to 13 families. They found 14 novel mutations in affected patients, as well as 3 isoforms of human NKCC2 that arise from alternative splicing.
In 3 of 9 Costa Rican patients with a variant form of antenatal Bartter syndrome type 1, Kurtz et al. (1997) identified homozygosity for a nonsense mutation in the SLC12A1 gene (600839.0003); in 3 of the patients, only 1 mutated allele was identified. The mutant allele was contained on a single common haplotype, suggesting that most patients with antenatal Bartter syndrome in Costa Rica share a single common ancestor.
Nozu et al. (2009) reported a 7-year-old Japanese girl with Bartter syndrome type 1 who was compound heterozygous for mutations in the SLC12A1 gene (600839.0004 and 600839.0005).
In 2 brothers, born of African American parents, with BARTS1, Li et al. (2016) identified compound heterozygous mutations in the SLC12A1 gene (600839.0006 and 600839.0007). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The presentation in these boys was unusual in that they had significant hyperparathyroidism, hypercalcemia, hypercalciuria, and nephrocalcinosis. Li et al. (2016) noted that SLC12A1 is not expressed in the parathyroid gland, suggesting that loss of SLC12A1 function is unlikely to affect parathyroid function directly. The authors hypothesized that increased prostaglandin E2 may be responsible for increased serum parathyroid hormone (PTH; 168450).
In 4 patients from 3 unrelated families of Hispanic descent with BARTS, Wongsaengsak et al. (2017) identified biallelic mutations in the SLC12A1 gene (see, e.g., 600839.0008-600839.0010). The mutations were found by whole-exome sequencing; functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function. In addition to classic features of the disorder, including polyhydramnios, hyponatremia, hypokalemic metabolic alkalosis, and increased renin activity, the patients had hyperparathyroidism, hypercalcemia, nephrocalcinosis, and nephrogenic diabetes insipidus. Wongsaengsak et al. (2017) postulated that the calcium and parathyroid abnormalities in these patients may be due to modulation of CaSR (601199) function.
Takahashi et al. (2000) used homologous recombination to disrupt the mouse Nkcc2 gene. Homozygous Nkcc2 -/- pups were born in expected numbers and appeared normal. However, by day 1 they showed signs of extracellular volume depletion with elevated hematocrits. They subsequently failed to thrive. By day 7, they were small and markedly dehydrated and exhibited renal insufficiency, high plasma potassium, metabolic acidosis, hydronephrosis of varying severity, and high plasma renin concentrations. None survived to weaning. Treatment of -/- pups with indomethacin from day 1 prevented growth retardation, and 10% of those treated for 3 weeks survived, although as adults they exhibited severe polyuria, extreme hydronephrosis, low plasma potassium, high blood pH, hypercalciuria, and proteinuria. Wildtype mice treated with furosemide, an inhibitor of NaK2Cl cotransporters, had a phenotype similar to the indomethacin-rescued -/- adults except that hydronephrosis was mild. The polyuria, polycalciuria, and proteinuria of the -/- adults and furosemide-treated wildtype mice were unresponsive to inhibitors of the renin angiotensin system, vasopressin, and further indomethacin. Thus, absence of Nkcc2 in the mouse causes polyuria that is not compensated elsewhere in the nephron.
In a patient with antenatal Bartter syndrome type 1 (BARTS1; 601678), Simon et al. (1996) identified a G-to-A transition in the last base of exon 14, representing the first base of codon 648, changing aspartic acid-648 to asparagine (D648N) in the NKCC2 protein.
In a patient with antenatal Bartter syndrome type 1 (BARTS1; 601678), Simon et al. (1996) identified a G-to-T transversion in the first base of codon 272 in the SLC12A1 gene, altering valine-272 to phenylalanine (V272F).
Kurtz et al. (1997) analyzed the SLC12A1 gene in 9 patients from 7 Costa Rican families with a congenital syndrome that bore strong similarities to the antenatal Bartter syndrome type 1 (BARTS1; 601678) but also had several distinct features. Homozygosity for a 1894G-A transition, resulting in a trp625-to-ter (W625X) substitution in the SLC12A1 gene, was identified in 3 patients, and the mutation was detected on only 1 allele in 3 patients. The mutant allele was contained on a single common haplotype, suggesting that most patients with antenatal Bartter syndrome in Costa Rica share a single common ancestor.
In a 7-year-old Japanese girl with Bartter syndrome type 1 (BARTS1; 601678), Nozu et al. (2009) identified compound heterozygosity for mutations in the SLC12A1 gene: a 724+4A-G transition in intron 5, predicted to result in skipping of exon 5 with creation of a premature stop codon in exon 6, and a 1-bp deletion in exon 16 (2095delG; 600839.0005), predicted to cause an immediate stop codon and premature termination of the protein. The unaffected parents were each heterozygous for 1 of the mutations; the intronic mutation was not detected in 100 controls. RT-PCR analysis of mRNA extracted from the proband's urinary sediment confirmed complete absence of exon 5 sequences, and RT-PCR results using mRNA from patient leukocytes showed no bands, indicating that the leukocytes did not express SLC12A1 mRNA. Nozu et al. (2009) stated that this was the first study to use noninvasive methods for both an in vivo assay and an in vitro functional splicing assay of inherited kidney disease.
For discussion of the 1-bp deletion in the SLC12A1 gene (2095delG) that was found in compound heterozygous state in a patient with Bartter syndrome type 1 (BARTS1; 601678) by Nozu et al. (2009), see 600839.0004.
In 2 brothers, born of African American parents, with Bartter syndrome type 1 (BARTS1; 601678), Li et al. (2016) identified compound heterozygous mutations in the SLC12A1 gene: a c.1883C-A transversion, resulting in an ala628-to-asp (A628D) substitution, and a 1-bp insertion (c.2786_2787insC; 600839.0007), resulting in a frameshift and premature termination (Thr931fsTer10). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in more than 2,000 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed. The presentation in these boys was unusual in that they had significant hyperparathyroidism, hypercalcemia, hypercalciuria, and nephrocalcinosis.
For discussion of the 1-bp insertion (c.2786_2787insC) in the SLC12A1 gene, resulting in a frameshift and premature termination (Thr931fsTer10), that was found in compound heterozygous state in 2 brothers with Bartter syndrome type 1 (BARTS1; 601678) by Li et al. (2016), see 600839.0006.
In a Hispanic girl with Bartter syndrome type 1 (BARTS1; 601678), Wongsaengsak et al. (2017) identified compound heterozygous mutations in the SLC12A1 gene: a 1-bp deletion (c.1137del), resulting in a frameshift (Phe380fs), and a 2-bp deletion (c.2498_2499del; 600839.0009), resulting in a frameshift (Arg833Ilefs). The mutations were found by whole-exome sequencing; functional studies of the variants and studies of patient cells were not performed, but the mutations were was predicted to result in a loss of function.
For discussion of the 2-bp deletion (c.2498_2499del) in the SLC12A1 gene, resulting in a frameshift (Arg833Ilefs), that was found in compound heterozygous state in a girl with Bartter syndrome type 1 (BARTS1; 601678) by Wongsaengsak et al. (2017), see 600839.0008.
In a Hispanic boy with Bartter syndrome type 1 (BARTS1; 601678), Wongsaengsak et al. (2017) identified a homozygous 1-bp deletion (c.1833delT) in the SLC12A1 gene, resulting in a frameshift (Phe611fs). The mutation was found by whole-exome sequencing; functional studies of the variants and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function.
Kurtz, C. L., Karolyi, L., Seyberth, H. W., Koch, M. C., Vargas, R., Feldmann, D., Vollmer, M., Knoers, N. V. A. M., Madrigal, G., Guay-Woodford, L. M. A common NKCC2 mutation in Costa Rican Bartter's syndrome patients: evidence for a founder effect. J. Am. Soc. Nephrol. 8: 1706-1711, 1997. [PubMed: 9355073] [Full Text: https://doi.org/10.1681/ASN.V8111706]
Li, D., Tian, L., Hou, C., Kim, C. E., Hakonarson, H., Levine, M. A. Association of mutations in SLC12A1 encoding the NKCC2 cotransporter with neonatal primary hyperparathyroidism. J. Clin. Endocr. Metab. 101: 2196-2200, 2016. [PubMed: 26963954] [Full Text: https://doi.org/10.1210/jc.2016-1211]
Nozu, K., Iijima, K., Kawai, K., Nozu, Y., Nishida, A., Takeshima, Y., Fu, X. J., Hashimura, Y., Kaito, H., Nakanishi, K., Yoshikawa, N., Matsuo, M. In vivo and in vitro splicing assay of SLC12A1 in an antenatal salt-losing tubulopathy patient with an intronic mutation. Hum. Genet. 126: 533-538, 2009. [PubMed: 19513753] [Full Text: https://doi.org/10.1007/s00439-009-0697-7]
Quaggin, S. E., Payne, J. A., Forbush, B., III, Igarashi, P. Localization of the renal Na-K-C1 cotransporter gene (Slc12a1) on mouse chromosome 2. Mammalian Genome 6: 557-561, 1995. [PubMed: 8589530] [Full Text: https://doi.org/10.1007/BF00356178]
Simon, D. B., Karet, F. E., Hamdan, J. M., Di Pietro, A., Sanjad, S. A., Lifton, R. P. Bartter's syndrome, hypokalemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nature Genet. 13: 183-188, 1996. [PubMed: 8640224] [Full Text: https://doi.org/10.1038/ng0696-183]
Takahashi, N., Chernavvsky, D. R., Gomez, R. A., Igarashi, P., Gitelman, H. J., Smithies, O. Uncompensated polyuria in a mouse model of Bartter's syndrome. Proc. Nat. Acad. Sci. 97: 5434-5439, 2000. [PubMed: 10779555] [Full Text: https://doi.org/10.1073/pnas.090091297]
Vargas-Poussou, R., Feldmann, D., Vollmer, M., Konrad, M., Kelly, L., van den Heuvel, L. P. W. J., Tebourbi, L., Brandis, M., Karolyi, L., Hebert, S. C., Lemmink, H. H., Deschenes, G., Hildebrandt, F., Seyberth, H. W., Guay-Woodford, L. M., Knoers, N. V. A. M., Antignac, C. Novel molecular variants of the Na-K-2Cl cotransporter gene are responsible for antenatal Bartter syndrome. Am. J. Hum. Genet. 62: 1332-1340, 1998. [PubMed: 9585600] [Full Text: https://doi.org/10.1086/301872]
Wongsaengsak, S., Vidmar, A. P., Addala, A., Kamil, E. S., Sequeira, P., Fass, B., Pitukcheewanont, P. A novel SLC12A1 gene mutation associated with hyperparathyroidism, hypercalcemia, nephrogenic diabetes insipidus, and nephrocalcinosis in four patients. Bone 97: 121-125, 2017. [PubMed: 28095294] [Full Text: https://doi.org/10.1016/j.bone.2017.01.011]