Alternative titles; symbols
HGNC Approved Gene Symbol: SLC12A2
Cytogenetic location: 5q23.3 Genomic coordinates (GRCh38): 5:128,083,766-128,189,677 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q23.3 | Deafness, autosomal dominant 78 | 619081 | Autosomal dominant | 3 |
| Delpire-McNeill syndrome | 619083 | Autosomal dominant | 3 | |
| Kilquist syndrome | 619080 | Autosomal recessive | 3 |
By moving chloride into epithelial cells, the Na-K-Cl cotransporter SLC12A2 aids transcellular movement of chloride across both secretory and absorptive epithelia (Payne et al., 1995).
See also SLC12A1 (600839) and SLC12A3 (600968).
Using cDNA probes from the elasmobranch secretory Na-K-Cl cotransporter reported by Xu et al. (1994) to screen a human colonic carcinoma cDNA library, Payne et al. (1995) identified the SLC12A2 gene, which they referred to as NKCC1. The deduced 1,212-amino acid protein contains 12 transmembrane segments and shows 91% identity to mouse Nkcc1. Two sites for N-glycosylation were predicted on an extracellular loop between putative transmembrane segments 7 and 8, and a single potential phosphorylation site was present in the predicted cytoplasmic C-terminal domain. Northern blot analysis detected a 7.2-kb NKCC1 mRNA transcript in mammalian colon, kidney, lung, and stomach. The molecular mass of the expressed protein is approximately 132 kD.
Using RNA-sequencing analysis, Haering et al. (2015) showed that Nkcc1 was highly expressed in mouse olfactory epithelium (OE).
Mutai et al. (2020) found expression of SLC12A2 gene in the basolateral membrane of strial marginal cells and lateral wall fibrocytes in non-human primate cochlea, similar to that observed in rodent cochleae. The findings suggested a conserved role for SLC12A2 in homeostasis of the endolymph by recycling K+ from the perilymph to the stria vascularis in mammalian cochlea, including humans. The authors noted that there is normally alternative splicing of exon 21, which contains 17 residues that comprise a long cytoplasmic domain after the 12 transmembrane domains. The longer isoform contains exon 21, whereas the shorter isoform excludes exon 21 and yields an in-frame 16-residue truncated isoform. Although several residues within exon 21 are conserved in vertebrates, several are unique to SLC12A2, suggesting that this region confers a special function. In vitro studies in HEK293T cells transfected with wildtype SLC12A2 resulted in the presence of both isoforms: a longer one with both exons 21 and 22 and a shorter one lacking exon 21. The exon 21-included transcript was expressed at higher levels in cochlear tissues that the shorter isoform. These isoforms showed differential expression patterns in various regions of the brain in humans and non-human primates, suggesting tissue-specific function.
In the human brain, McNeill et al. (2020) found that SLC12A2 was highly expressed in neuroanatomical regions with high neurogenesis, including the ventricular and subventricular zones, compared with regions of less active neurogenesis, such as the cortical plate. In fetal brain tissue, SLC12A2 localized to neurons in the radial glia, suggesting an active role in neurogenesis. The authors stated that the gene undergoes alternative splicing with 8 isoforms that have been identified. SLC12A2 isoforms specifically lacking exon 21 were found in some regions of the developing brain, whereas only SLC12A2 isoforms containing exon 21 were expressed in the developing mouse cochlea.
Cryoelectron Microscopy
Chew et al. (2019) determined the cryoelectron microscopy structure of the Na-K-Cl cotransporter Nkcc1 from Danio rerio. The structure defined the architecture of this protein family and revealed how cytosolic and transmembrane domains are strategically positioned for communication.
By fluorescence in situ hybridization, Payne et al. (1995) mapped the human cotransporter gene to chromosome 5q23.3.
In contrast to the renal-specific sodium/potassium/chloride cotransporter SLC12A1, SLC12A2 is expressed in many tissues, including the basolateral membrane of secretory epithelia (Quaggin et al., 1995).
The diuretic bumetanide is a potent NKCC1 antagonist (Xu et al., 1994).
Using immunofluorescent studies and Western blot analysis, Dzhala et al. (2005) found high expression of NKCC1 in human developing cortical neurons. NKCC1 expression peaked at approximately 3-fold at 35 postconception weeks and rapidly decreased during the first year of life to adult levels. Expression of the chloride-extruding transporter KCC2 (SLC12A5; 606726) was significantly lower during the fetal and neonatal period than in the adult period and increased during the first year of life. Similar findings were observed in rat cortex. The data suggested that expression of the NKCC1 chloride transporter in perinatal human cortex would result in high intracellular chloride concentrations. Activation of GABA receptors would cause chloride extrusion and depolarization of the membrane potential, potentially resulting in epileptic activity. This sequence of events could contribute to GABA-mediated excitation in the immature nervous system and a poor response of neonatal seizures to GABAergic anticonvulsants. Dzhala et al. (2005) also showed in rat that inhibition of NKCC1 by bumetanide suppressed interictal and ictal-like activity in perinatal hippocampal slices in vitro and attenuated seizure activity in vivo.
Nakajima et al. (2007) found that Ngf (NGFB; 162030) treatment increased expression of rat Nkcc1 in pheochromocytoma cells and that knockdown of Nkcc1 by RNA interference diminished Ngf-induced neurite outgrowth. Confocal microscopy showed that fluorescent Nkcc1 localized mainly to the plasma membrane at the growth cone during neurite outgrowth. Nakajima et al. (2007) concluded that NKCC1 is fundamental in NGF-induced neurite outgrowth.
SLC12A2 is the entry site for Na+, K+, and 2Cl- from the intrastrial space to the strial marginal cells in the cochlear lateral wall of the ear, and thus plays a role in endolymph homeostasis (summary by Mutai et al., 2020).
Kilquist Syndrome
In a 5.5-year-old boy, born of unrelated parents of mixed European ancestry, with Kilquist syndrome (KILQS; 619080), Macnamara et al. (2019) identified a homozygous 22-kb intragenic deletion in the SLC12A2 gene (600840.0001). The deletion, which was found by a combination of whole-genome microarray analysis and next-generation sequencing and confirmed by Sanger sequencing, was inherited from the unaffected father who had isodisomy of chromosome 5. Analysis of patient fibroblasts showed that the deletion introduced a splicing defect with premature termination and absence of the SLC12A2 (NKCC1) protein, consistent with a loss of function. Macnamara et al. (2019) noted that mice with disruption of Slc12a2 show phenotypic overlap with their patient (see ANIMAL MODEL).
In 2 sisters, born of unrelated Swedish parents, with Kilquist syndrome, Stodberg et al. (2020) identified compound heterozygous loss-of-function mutations in the SLC12A2 gene (600840.0002 and 600840.0003). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was present in the gnomAD database. The findings were consistent with complete loss of SLC12A2 function. Stodberg et al. (2020) noted that SLC12A2 is the main chloride exporter in neurons and thus regulates GABA neurotransmission and neuronal excitability.
Autosomal Dominant Deafness 78
In 5 members spanning 4 generations of a Japanese family (family 1) with autosomal dominant deafness-78 (DFNA78; 619081), Mutai et al. (2020) identified a heterozygous missense mutation in exon 21 of the SLC12A2 gene (D981Y; 600840.0004). De novo heterozygous mutations, including 2 missense and 1 splice site, in the SLC12A2 gene (600840.0005-600840.0007) were subsequently identified in 3 additional Japanese individuals with nonsyndromic deafness. The mutations, which were found by exome sequencing or candidate gene sequencing and confirmed by Sanger sequencing, were not present in public databases, including gnomAD. All variants, including the splice site mutation, affected exon 21 and did not result in degradation of the mutant transcript. The authors stated that exon 21 encodes a long cytoplasmic domain after the 12 transmembrane domains. There are 2 isoforms, with and without exon 21, that show differential expression in the cochlea and brain tissues. In vitro functional expression studies in transfected HEK293T cells showed that all the mutations resulted in decreased chloride influx compared to controls, which may impair endolymph secretion in the cochlea. Mutai et al. (2020) suggested that haploinsufficiency is unlikely to be the pathogenic mechanism for hearing loss in these patients, and postulated a dominant-negative or gain-of-function effect, possibly by disrupting an unknown function of SLC12A2. Although 2 patients had mild motor delay that resolved with age and may have been due to vestibular impairment, none of the patients had systemic or cognitive involvement. Mutai et al. (2020) noted that homozygous disruption of the Slc12a2 gene in mice causes deafness and vestibular defects due to endolymph disturbances in the inner ear (see ANIMAL MODEL).
In 3 patients from 2 unrelated families with DFNA78, McNeill et al. (2020) identified heterozygous missense mutations affecting exon 21 of the SLC21A2 gene (E979K, 600840.0007 and E980K, 600840.0008). The mutation was inherited in an autosomal dominant pattern in 1 family and occurred de novo in an unrelated patient. The patients were ascertained through the GeneMatcher program after having undergone exome sequencing. In vitro functional expression studies in Xenopus oocytes transfected with the mutations showed that they resulted in decreased K+ influx compared to controls.
Delpire-McNeill Syndrome
In 6 unrelated patients (patients 1-6) with Delpire-McNeill syndrome (DELMNES; 619083), McNeill et al. (2020) identified 6 different de novo heterozygous mutations in the SLC12A2 gene (see, e.g., 600840.0009-600840.0012). The mutations were found by exome sequencing. Four of the mutations were missense that occurred in the transmembrane domain; 3 were not present in the gnomAD database, but 1 (R410Q) was present twice in gnomAD (frequency of 7.0 x 10(-6)). The remaining 2 mutations were a nonsense and a frameshift. In vitro functional expression studies in Xenopus oocytes transfected with the mutations showed that all resulted in decreased K+ influx compared to controls.
Associations Pending Confirmation
Delpire et al. (2016) reported a 13-year-old girl with a multisystemic disorder associated with a de novo heterozygous 11-bp deletion (c.3076_3086del, NM_001046.2) in exon 22 of the SLC12A2 gene. The deletion resulted in a frameshift and premature termination (Val1026PhefsTer2) and truncation of the protein at the C-terminal tail. The deletion, which was found by exome sequencing, was not present in the ExAC database. In vitro functional expression studies in Xenopus oocytes transfected with the deletion showed that it resulted in decreased K+ influx compared to controls, consistent with a loss of function. There was no evidence of a dominant-negative effect. The mutant protein was detected at the cell surface alongside the wildtype protein, with some evidence of enhanced dimerization or misfolded aggregation. The patient carried several variants in other genes that, although potentially pathogenic, were thought not to contribute to the phenotype. However, the authors noted that they could not definitively establish causality between the deletion and the patient's phenotype. The patient presented at 6 months of age with a complex phenotype including orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, metabolic decompensation, pancreatic insufficiency, dilated cardiomyopathy, seizure-like episodes, and multiorgan failure involving the gut and bladder. Notably, she did not have sensorineural deafness, developmental delay, or cognitive impairment. Delpire et al. (2016) postulated that disruption of the SLC12A2 gene may cause abnormal neurotransmission or cell contraction with adverse effects on sensory, autonomic, and smooth muscle function.
The endolymph in the inner ear is an extracellular fluid with an atypical composition that resembles the intracellular milieu, high in potassium ions and low in sodium ions. An important role of potassium ion channels in endolymph secretion and mechanical transduction is clear from studies of deafness as well as physiologic studies. Coupled electroneutral transport of sodium, potassium, and chloride ions is mediated by 2 isoforms of the Na-K-2Cl cotransporter: the absorptive isoform BSC1 (also called NKCC2, encoded by Slc12a1 in mouse) that is exclusively expressed in kidney; and BSC2/NKCC1 (encoded by Slc12a2 in mouse), the secretory isoform that has a wider pattern of expression including epithelia, muscle cells, neurons, and red blood cells. These 2 cotransporters share 57% homology at the amino acid level and are pharmacologically inhibited by loop diuretics. There is functional and biochemical evidence for the presence of the secretory isoform of the cotransporter in the inner ear of gerbil, rat, and rabbit. Delpire et al. (1999) disrupted mouse Slc12a2 and found that the -/- mice are deaf and exhibit classic shaker/waltzer behavior, indicative of inner-ear defects. They localized the cotransporter to key secreting epithelia of the mouse inner ear and showed that absence of functional cotransporter leads to structural changes in the inner ear consistent with a decrease in endolymph secretion.
Dixon et al. (1999) identified deletion of the Slc12a2 gene in the Shaker-with-syndactylism (sy) mouse and an insertion mutation in the Shaker-without-syndactylism (syns) mouse. The authors concluded that the basolateral sodium-potassium-chloride cotransporter is essential for the production of endolymph in the inner ear and that their data provided the molecular basis of another link in the chain of potassium recycling in the cochlea.
Evans et al. (2000) tested directly the possibility that the salivary fluid secretory mechanism requires Na+/K+/2Cl- cotransporter-mediated Cl- uptake. They studied the in vivo and in vitro functioning of acinar cells from the parotid glands of mice with targeted disruption of the Nkcc1 gene, which encodes the salivary cotransporter. In wildtype mice Nkcc1 was localized to the basolateral membranes of parotid acinar cells, whereas expression was not detected in duct cells. The lack of functional Nkcc1 resulted in a dramatic reduction (greater than 60%) in the volume of saliva secreted in response to a muscarinic agonist, the primary in situ salivation signal. Expression of the chloride/bicarbonate exchanger AE2 (SLC4A2; 109280) was enhanced, suggesting that this transporter compensates for the loss of functional Nkcc1. The ability of the parotid gland to conserve NaCl was abolished in Nkcc1-deficient mice. Evans et al. (2000) suggested that some cases of 'idiopathic' dry mouth disease may have a basis in a defect of Nkcc1.
Nguyen et al. (2007) generated congenic mice lacking Nkcc1 and investigated the inflammatory response after lung infection with Klebsiella pneumoniae. These mice showed lower lung bacterial burden and reduced bacteremia and hypothermic sepsis compared with wildtype littermates. The protection was accompanied by increased cell numbers in the airways, without an increase in vascular permeability. In contrast, more severe disease was observed when bacteria were introduced into the peritoneal cavity. Nguyen et al. (2007) concluded that NKCC1 plays an important role in inflammatory responses in the lung and that inhibition of NKCC1 may be beneficial in treatment of sepsis.
Prasad et al. (2008) found that Ae3 (SLC4A3; 106195) -/- Nkcc1 -/- double-knockout mice showed impaired cardiac contractility, although heart weight/body weight ratio was similar to wildtype. Cardiac myocytes from Ae3 -/- Nkcc1 -/- mice showed reduced basal contraction and impaired Ca(2+) handling. Further analysis of Ae3 -/- Nkcc1 -/- cardiac myocytes revealed altered expression and phosphorylation of sarcoplasmic reticulum-associated Ca(2+)-handling proteins, increased Na+/Ca(2+) exchanger-mediated Ca(2+) efflux, increased expression of the PP1 catalytic subunit (see 176875), and altered carboxymethylation and localization of the PP2A catalytic subunit (see 176915).
Using molecular and behavioral assessments of mice that carry null or tissue-specific mutations of Slc12a2, Antoine et al. (2013) found that inner ear dysfunction causes motor hyperactivity by increasing in the nucleus accumbens the levels of phosphorylated CREB (pCREB; 123810) and phosphorylated ERK (pERK; see 601795), key mediators of neurotransmitter signaling and plasticity. Hyperactivity was remedied by local administration of the pERK inhibitor SL327. Antoine et al. (2013) concluded that their findings revealed that a sensory impairment, such as inner ear dysfunction, can induce specific molecular changes in the brain that cause maladaptive behaviors, such as hyperactivity, that have been traditionally considered exclusively of cerebral origin.
Haering et al. (2015) found that loss of Nkcc1 in mice affected expression of genes involved in OE signal transduction. Nkcc1 -/- mice had reduced neuronal layer thickness due to decreased mature neurons in the OE, leading to impaired odorant detection.
In a 5.5-year-old boy, born of unrelated parents of mixed European ancestry, with Kilquist syndrome (KILQS; 619080), Macnamara et al. (2019) identified a homozygous 22-kb intragenic deletion in the SLC12A2 gene. The deletion was found by a combination of whole-genome microarray analysis and next-generation sequencing and confirmed by Sanger sequencing. The deletion was inherited from the unaffected father who had isodisomy of chromosome 5. The deletion extended from intron 1 of the SLC12A2 gene to the beginning of exon 7 (chr5:127441491_127471419), including an inversion of 34 bp, which the authors referred to as chr5:127441491_127471419delins34. Large homozygous deletions in this gene were not observed in the gnomAD database. Analysis of mRNA from patient fibroblasts showed that the deletion introduced a splicing defect with premature termination in exon 9. RT-PCR analysis showed decreased mutant mRNA expression (80% of control values), and absence of the SLC12A2 (NKCC1) protein, consistent with a loss of function.
In 2 sisters, born of unrelated Swedish parents, with Kilquist syndrome (KILQS; 619080), Stodberg et al. (2020) identified compound heterozygous loss-of-function mutations in the SLC12A2 gene: a 1-bp deletion (c.1431delT, NM_001046) in exon 8, resulting in a frameshift and premature termination, and a G-to-A transition in intron 12 (c.2006-1G-A; 600840.0003), resulting in a splice site alteration. The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, The splicing defect was confirmed by PCR analysis and Sanger sequencing; the frameshift mutation resulted in nonsense-mediated mRNA decay. Neither mutation was present in the gnomAD database. The findings were consistent with complete loss of SLC12A2 function.
For discussion of the G-to-A transition in intron 12 of the SLC12A gene (c.2006-1G-A, NM_0010463), resulting in a splice site alteration, that was found in compound heterozygous state in 2 sisters with Kilquist syndrome (KILQS; 619080) by Stodberg et al. (2020), see 600840.0002.
In 5 affected members of a 4-generation Japanese family (family 1) with autosomal dominant deafness-78 (DFNA78; 619081), Mutai et al. (2020) identified a heterozygous c.2941G-T transversion (c.2941G-T, NM_001046.2) in exon 21 of the SLC12A2 gene, resulting in an asp981-to-tyr (D981Y) substitution at a highly conserved residue among vertebrates. The substitution occurred in the long cytoplasmic stretch of the protein after the transmembrane region and affected the long SLC12A2 isoform. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases, including gnomAD and an in-house database of Japanese individuals. In vitro functional expression studies in transfected HEK293T cells showed that the mutation resulted in decreased chloride influx compared to controls, which may impair endolymph secretion in the cochlea.
In a 1.5-year-old Japanese girl (family 2) with autosomal dominant deafness-78 (DFNA78; 619081), Mutai et al. (2020) identified a de novo heterozygous intronic A-to-G transition in the SLC12A2 gene (c.2930-2A-G, NM_001046.2) that was predicted to result in a splicing defect with the skipping of exon 21. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including gnomAD and an in-house database of Japanese individuals. Analysis of HEK293T cells transfected with the mutation showed production of only a transcript skipping exon 21. In normal mice cochlea, the exon 21-included transcript was expressed at higher levels than the exon 21-skipped transcript: these 2 isoforms showed differential expression in various brain regions. In vitro functional expression studies in transfected HEK293T cells showed that the mutation resulted in decreased chloride influx compared to controls, which may impair endolymph secretion in the cochlea. The patient had mild motor delay that resolved with age; this may have been due to vestibular impairment.
In a 22-month-old Japanese boy (family 3) with autosomal dominant deafness-78 (DFNA78; 619081), Mutai et al. (2020) identified a de novo heterozygous c.2962C-A transversion (c.2962C-A, NM_001046.2) in exon 21 of the SLC12A2 gene, resulting in a pro988-to-thr (P988T) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including gnomAD. In vitro functional expression studies in transfected HEK293T cells showed that the mutation caused decreased chloride efflux compared to controls, which may impair endolymph secretion in the cochlea. The patient had mild motor delay that resolved with age; this may have been due to vestibular impairment.
In a 7-month-old Japanese girl (patient 4) with autosomal dominant deafness-78 (DFNA78; 619081), Mutai et al. (2020) identified a de novo heterozygous c.2935G-A transition (c.2935G-A, NM_001046.2) in exon 21 of the SLC12A2 gene, resulting in a glu979-to-lys (E979K) substitution at a residue that is conserved among vertebrates. This residue is located in a long cytoplasmic stretch of the protein after the 12 transmembrane domains. The mutation, which was found by candidate gene sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a father and son (family S1585) with DFNA78, McNeill et al. (2020) identified a heterozygous E979K substitution in the SLC12A2 gene. The patients were ascertained through the GeneMatcher program after exome sequencing identified the mutation. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed that it caused a decrease in K+ influx compared to controls.
In a 2-year-old boy (patient 7) with autosomal dominant deafness-78 (DFNA78; 619081), McNeill et al. (2020) identified a de novo heterozygous c.2938G-A transition (c.2938G-A, NM_001046.3) in exon 21 of the SLC12A2 gene, resulting in a glu980-to-lys (E980K) substitution at a conserved residue. The patient were ascertained through the GeneMatcher program after exome sequencing identified the mutation. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed that it caused a decrease in K+ influx compared to controls. The patient was also XXY.
In a 12-month-old boy (patient 1, 270188) with Delpire-McNeill syndrome (DELMNES; 619083), McNeill et al. (2020) identified a de novo heterozygous c.980C-T transition (c.980C-T, NM_001046.3) in exon 4 of the SLC12A2 gene, resulting in an ala327-to-val (A327V) substitution at a conserved residue in the transmembrane domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed that it resulted in decreased K+ influx compared to controls.
In a 15-year-old girl (patient 3, 278327) with Delpire-McNeill syndrome (DELMNES; 619083), McNeill et al. (2020) identified a de novo heterozygous c.2675G-A transition (c.2675G-A, NM_001046.3) in exon 18 of the SLC12A2 gene, resulting in a trp892-to-ter substitution at the C terminus. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed that it resulted in decreased K+ influx compared to controls.
In a 3-year-old girl (patient 4, 293333) with Delpire-McNeill syndrome (DELMNES; 619083), McNeill et al. (2020) identified a de novo heterozygous c.1127A-T transversion (c.1127A-T, NM_001046.3) in exon 5 of the SLC12A2 gene, resulting in an asn376-to-ile (N376I) substitution at a conserved residue in the transmembrane domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed that it resulted in decreased K+ influx compared to controls.
In a 6-year-old girl (patient 5, 296317) with Delpire-McNeill syndrome (DELMNES; 619083), McNeill et al. (2020) identified a de novo heterozygous 1-bp duplication (c.555dupG, NM_001046.3) in exon 1 of the SLC12A2 gene, resulting in a frameshift and premature termination (His186AlafsTer17) in the N terminus. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed that it resulted in decreased K+ influx compared to controls.
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