Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: SLC12A6
SNOMEDCT: 702439002;
Cytogenetic location: 15q14 Genomic coordinates (GRCh38) : 15:34,229,784-34,338,057 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q14 | Agenesis of the corpus callosum with peripheral neuropathy | 218000 | Autosomal recessive | 3 |
| Charcot-Marie-Tooth disease, axonal, type 2II | 620068 | Autosomal dominant | 3 |
Cation chloride cotransporters, including the potassium-chloride cotransporters (KCCs), are involved in the electroneutral movement of ions across the plasma membrane. Under most physiologic conditions, KCCs function as efflux pathways (Hiki et al., 1999; Mount et al., 1999).
Using differential display PCR on vascular endothelial cells treated with vascular endothelial growth factor (VEGF; 192240), Hiki et al. (1999) identified a cDNA encoding SLC12A6, which they called KCC3. The predicted 1,099-amino acid SLC12A6 protein contains 12 membrane-spanning segments and 5 N-glycosylation sites. SLC12A6 shares 77% amino acid identity with the ubiquitously expressed KCC1 (SLC12A4; 604119) and 73% identity with the brain-restricted KCC2 (SLC12A5; 606726). Northern blot analysis detected strong expression of 9-, 7.5-, and 4.5-kb SLC12A6 transcripts in brain, heart, skeletal muscle, and kidney. Western blot analysis showed expression of a 150-kD SLC12A6 protein that was reduced to 120 kD by glycosidase treatment. Functional analyses confirmed that SLC12A6 is a KCC.
By searching EST databases, Mount et al. (1999) identified a full-length cDNA encoding SLC12A6, which they initially termed KCC4 but later renamed KCC3. This cDNA encodes a deduced 1,150-amino acid protein. Northern blot analysis detected 2 SLC12A6 transcripts of 6- to 7-kb, consistent with alternative splicing, in muscle, brain, lung, heart, and kidney. Mount (2000) designated the longer SLC12A6 isoform KCC3A (Mount et al., 1999) and the shorter SLC12A6 isoform KCC3B (Hiki et al., 1999). KCC3A is transcribed from a promoter approximately 23 kb 5-prime of KCC3B, and the additional N-terminal sequence contains a cluster of potential protein kinase C phosphorylation sites.
Hiki et al. (1999) mapped the SLC12A6 gene to chromosome 15q13 using FISH. By radiation hybrid and somatic cell hybrid analyses, Mount et al. (1999) mapped the SLC12A6 gene to 15q14.
Jiao et al. (2008) mapped the mouse Slc12a6 gene to chromosome 2.
Using a yeast 2-hybrid approach, Salin-Cantegrel et al. (2008) found that the last 18 amino acids of the C-terminal domain of KCC3 directly interacted with brain-specific creatine kinase (CKB; 123280), an ATP-generating enzyme that is also a partner of KCC2. The interaction of KCC3 with CKB was confirmed by GST pull-down assay, followed by sequencing of the pulled-down complexes. Studies in transfected cultured cells indicated that CKB colocalized with wildtype KCC3 in vitro. However, mutant KCC3 lacking the C terminus was unable to interact with CKB. Functional studies in Xenopus oocytes showed that an inhibitor of CKB reduced KCC3 transport activity, indicating the proper KCC3 function is dependent on interaction with functional CKB. Salin-Cantegrel et al. (2008) hypothesized that disruption of ATP trafficking in patients with KCC3 mutations may influence the osmotic integrity of neurons, resulting in neurologic disease.
Agenesis of the Corpus Callosum with Peripheral Neuropathy
The SLC12A6 gene maps to the same region of 15q as agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), also known as Andermann syndrome. ACCPN is transmitted in autosomal recessive fashion and is found at a high frequency in the province of Quebec in Canada. In patients with ACCPN, Howard et al. (2002) identified 4 distinct protein-truncating mutations in the SLC12A6 gene: 2 in the French Canadian population (604878.0001-604878.0002) and 2 in non-French Canadian families (604878.0003-604878.0004).
In 3 unrelated patients with Andermann syndrome, Uyanik et al. (2006) identified 4 different mutations in the SLC12A6 gene (604878.0005-604878.0008). Two were of Turkish descent and 1 was German.
Salin-Cantegrel et al. (2011) showed in in vitro studies that mutant SLC12A6 mutations (see, e.g., 604878.0001; 604878.0008; 604878.0010) caused a loss of function by 2 mechanisms, either defective interaction with brain-type creatine kinase or defective trafficking to the plasma membrane. One missense mutation (R207C; 604878.0008) was retained in the endoplasmic reticulum, and cell treatment with curcumin partially corrected the mislocalization.
Axonal Charcot-Marie-Tooth Disease Type 2II
In a 10-year-old boy with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Kahle et al. (2016) identified a de novo heterozygous missense mutation in the SLC12A6 gene (T991A; 604878.0011). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including dbSNP, Exome Variant Server, and ExAC. In vitro functional expression studies in patient fibroblasts and HEK293 cells transfected with the T991A mutation showed about 50% reduced phosphorylation of thr991, which in the phosphorylated state inhibits SLC12A6 transporter activity. Cells with the mutation demonstrated increased transporter activity compared to controls, and showed a compromised swelling response to acute hypotonic stress. These findings were consistent with a gain-of-function effect. Kahle et al. (2016) suggested that these alterations could lead to impaired cell volume homeostasis in peripheral nerves that may result in secondary axonal degeneration or loss, as well as altered neuronal excitability.
In 3 unrelated patients with CMT2II, Park et al. (2020) identified de novo heterozygous missense mutations at highly conserved residues in the SLC12A6 gene (R207H; 604878.0012 and Y679C 604878.0013). The mutations, which were found by trio-based exome sequencing, were not present in public databases, including gnomAD. In vitro functional expression studies in transfected Xenopus oocytes showed that both mutations impaired K+ influx under hypotonic shock compared to controls, consistent with a loss-of-function effect. R207H resulted in a complete loss of function, whereas Y679C caused a partial loss of function.
In 11 patients from 7 unrelated Japanese families with CMT2II, Ando et al. (2022) identified heterozygous mutations in the SLC12A6 gene (see, e.g., 604878.0012; 604878.0014-604878.0015). There were 3 missense variants and 1 in-frame deletion. The mutations were confirmed by Sanger sequencing and segregated with the disorder in 2 families in which genetic material was available from affected individuals. The mutations occurred de novo in 2 of the families. The mutations occurred throughout the gene, affected highly conserved residues, and were absent from the gnomAD database. Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a cohort of 2,598 individuals with clinically suspected CMT who underwent genetic studies.
Howard et al. (2002) found that mice with a targeted deletion of the Slc12a6 gene had a locomotor deficit, peripheral neuropathy, and a sensorimotor gating deficit, similar to the human disease. The findings suggested a critical role for SLC12A6 in the development and maintenance of the nervous system.
Giant axonopathy (gaxp) is an autosomal recessive mutation in mice. Homozygous mutants exhibit ataxia, characteristically lifting their hind legs too high and wobbling side-to-side as they walk. The swollen axons observed in gaxp/gaxp mice have lightly packed organelles, suggesting that swelling is due in part to increased water uptake. Jiao et al. (2008) identified the gaxp mutation as a 17-base deletion within exon 4 of the Slc12a6 gene. Western blot analysis showed no mutant protein in brain or kidney of gaxp/gaxp mice.
Kahle et al. (2016) found that CRISPR/Cas9-mediated gene editing used to express the T991A mutation in mice resulted in increased cellular K+ influx due to constitutive activation of the SLC12A6 transporter. Heterozygous mutant mice did not show impaired motor performance, but homozygous mutant mice had significant motor deficits. Electrophysiologic studies showed motor and sensory conduction defects, and peripheral nerve biopsy showed myelination defects, particularly in homozygous mutant animals.
In 20 French Canadians with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000) from the Charlevoix and Saguenay-Lac-Saint-Jean regions of the province of Quebec in Canada, Howard et al. (2002) found homozygosity for a guanine deletion in exon 18 at nucleotide 2436 (c.2436delG) of the KCC3A open reading frame. The deletion converted GT at the splice donor site of exon 18 to TA, suggesting an effect on RNA splicing. Furthermore, this splice site mutation was predicted to cause a premature stop codon at amino acid 813, removing the last 338 amino acids from the KCC3 protein (2436delG, Thr813fsTer813). Functional expression studies in Xenopus oocytes showed that the truncated mutant protein was appropriately glycosylated and expressed at the cellular membrane, but was nonfunctional.
For discussion of the 2436del mutation in the SLC12A6 gene that was found in compound heterozygous state in a patient with ACCPN by Howard et al. (2002), see 604878.0002.
Variant Function
Salin-Cantegrel et al. (2011) found that the mutant T813X protein had abnormal intracellular localization around the nucleus in brain tissue from a patient with the mutation. The mutant protein was not found in swollen axons. The findings suggested a transit defect of the mutant protein.
In a French Canadian patient with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Howard et al. (2002) found that 1 chromosome 15 allele carried the predominant French Canadian mutation c.2436delG (604878.0001) in exon 18, and the other a deletion of adjacent cytosine and thymine nucleotides, along with the insertion of 1 guanine, at positions c.1584 and c.1585 in exon 11 of the SLC12A6 gene. This mutation caused a frameshift and a premature stop codon, predicted to truncate 619 amino acids from the KCC3 protein (Phe529fsTer532). Sequencing both parents indicated that 1 carried the c.2436delG mutation and the other carried the deletion/insertion mutation.
In 2 sibs of Turkish origin with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Howard et al. (2002) found a c.3031C-T transition in exon 22 of the SLC12A6 gene, resulting in an arg1011-to-ter (R1011X) substitution.
Salin-Cantegrel et al. (2007) identified homozygosity for the R1011X mutation in affected members of 5 unrelated non-French Canadian families with ACCPN. Two families were Afrikaner from South Africa, 2 were from Turkey, and 1 from the Netherlands. Haplotype analysis showed 2 different haplotypes, 1 of which was shared by the Afrikaner and Dutch patients. In vitro functional expression studies showed that the R1011X mutation completely abolished transporter activity, although the mutant protein was weakly expressed at the cell membrane.
In 2 sibs of Italian origin with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Howard et al. (2002) found a homozygous c.2023C-T transition in exon 15 of the SLC12A6 gene, predicted to result in an arg675-to-ter (R675X) substitution.
In a 3.5-year-old German girl with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Uyanik et al. (2006) identified compound heterozygosity for 2 mutations in the SLC12A6 gene: a 1-bp insertion (c.2031insT) and an 8-bp deletion (604878.0006). Both mutations were predicted to result in a frameshift and premature termination of the protein. Each unaffected parent was heterozygous for 1 of the mutations.
In a 3.5-year-old German girl with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Uyanik et al. (2006) identified compound heterozygosity for 2 mutations in the SLC12A6 gene: an 8-bp deletion (c.1478delTTCCCTCT) and a 1-bp insertion (604878.0005). Both mutations were predicted to result in a frameshift and premature termination of the protein. Each unaffected parent was heterozygous for 1 of the mutations.
In a Turkish girl with agenesis of the corpus callosum with peripheral neuropathy (ACCPN, 218000), born of consanguineous parents, Uyanik et al. (2006) identified a homozygous 1-bp deletion (c.901delA) in the SLC12A6 gene, resulting in premature termination of the protein at codon 315.
In a 10.5-year-old Turkish boy with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), born of consanguineous parents, Uyanik et al. (2006) identified a homozygous c.619C-T transition in the SLC12A6 gene, resulting in an arg207-to-cys (R207C) substitution. This patient had slightly less severe neuropathy and also had white matter abnormalities not previously reported in this disorder. The authors noted that this was the first SLC12A6 missense mutation associated with ACCPN and postulated that a dysfunctional SLC12A6 protein may lead to a different phenotype.
Variant Function
By in vitro studies in mammalian cells, Salin-Cantegrel et al. (2011) demonstrated that the R207C mutant protein interacted with brain-type creatine kinase (CKB; 123280), but had decreased transport activity when expressed in Xenopus oocytes. The mutant protein showed strong localization to the perinuclear region and endoplasmic reticulum, as well as poor membrane localization when expressed in HeLa cells, suggesting a trafficking defect. Western blot analysis showed that the mutant R207C protein also formed stable homodimers, which may have affected transit to the plasma membrane. Treatment with curcumin partially corrected the mislocalization.
In 2 brothers, born of consanguineous Sudanese parents, with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Salin-Cantegrel et al. (2007) identified a homozygous 10-bp deletion (nucleotides 2995 to 3003) in exon 22 of the SLC12A6 gene, resulting in a frameshift and premature termination.
In affected members of a consanguineous Algerian family with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), Salin-Cantegrel et al. (2011) identified a homozygous c.3402C-T transition in exon 25 of the SLC12A6 gene, resulting in an arg1134-to-ter (R1134X) substitution and a truncated protein missing only the last 17 residues. In vitro immunofluorescence studies in HeLa cells showed that the mutant truncated protein did not interact properly with brain-type creatine kinase (CKB; 123280) and did not have transport activity when expressed in Xenopus oocytes, consistent with a loss of function. The mutant protein also showed abnormal localization within the cytoplasm, not at the cell membrane, suggesting a defect in trafficking.
In a 10-year-old boy with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Kahle et al. (2016) identified a de novo heterozygous c.2971A-G transition (c.2971A-G, NM_133647.1) in exon 22 of the SLC12A6 gene, resulting in a thr991-to-ala (T991A) substitution at a highly conserved residue in the cytoplasmic C-terminal regulatory site of SLC12A6 activity. The mutation, which was found by trio-based whole-exome sequencing, was not present in major public databases, including dbSNP, Exome Variant Server, and ExAC. In vitro functional expression studies in patient fibroblasts and HEK293 cells transfected with the T991A mutation showed about 50% reduced phosphorylation of thr991, which in the phosphorylated state inhibits SLC12A6 transporter activity. Cells with the mutation demonstrated increased transporter activity compared to controls, and showed a compromised swelling response to acute hypotonic stress. These findings were consistent with a gain-of-function effect. Kahle et al. (2016) suggested that these alterations could lead to impaired cell volume homeostasis in peripheral nerves that may result in secondary axonal degeneration or loss, as well as altered neuronal excitability.
In 2 unrelated boys (P1 and P2) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Park et al. (2020) identified a de novo heterozygous c.620G-A transition (c.620G-A, NM_133647.1) in the SLC12A6 gene, resulting in an arg207-to-his (R207H) substitution at a highly conserved residue. The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed impaired K+ influx under hypotonic shock compared to controls, consistent with a complete loss-of-function effect.
In a 31-year-old Chinese man with CMT2II, Shi et al. (2021) identified a heterozygous R207H mutation in exon 5 of the SLC12A6 gene. The mutation was found by whole-exome sequencing and was not present in public databases, including dbSNP and gnomAD. Functional studies of the variant were not performed, but molecular modeling suggested that it may interfere with homo- or heterodimer formation and cause a dominant-negative effect.
Ando et al. (2022) identified a de novo heterozygous R207H mutation in an 8-year-old Japanese girl (patient 1) with CMT2II. Functional studies of the variant and studies of patient cells were not performed. The patient also had progressive visual loss.
In a 15-year-old girl (patient 3) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Park et al. (2020) identified a de novo heterozygous c.2036A-G transition (c.2036A-G, NM_133647.1) in the SLC12A6 gene, resulting in a tyr679-to-cys (Y679C) substitution. The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. In vitro functional expression studies in Xenopus oocytes transfected with the mutation showed impaired K+ influx under hypotonic shock compared to controls, consistent with a partial loss-of-function effect.
In 4 affected members of a Japanese family (family 2) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068) Ando et al. (2022) identified a heterozygous c.865G-A transition (c.865G-A, NM_133647) in the SLC12A6 gene, resulting in a glu289-to-lys (E289K) substitution at a highly conserved residue. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family. The same heterozygous E289K mutation was found in a 40-year-old Japanese woman (family 3) who had onset of the disorder at 10 years of age. Her mother, sister, and son were similarly affected, but DNA was not available for familial segregation studies. The mutation was not present in the gnomAD database; functional studies of the variant and studies of patient cells were not performed.
In 3 unrelated Japanese patients (families 4, 5, and 6) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Ando et al. (2022) identified a heterozygous 3-bp in-frame deletion (c.1731delCTT, NM_133647) in the SLC12A6 gene, resulting in the deletion of conserved residue phe578 (Phe578del). The mutation, which was confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was demonstrated to be inherited from the affected father in family 4, consistent with autosomal dominant inheritance. There were additional affected family members in families 5 and 6, but genetic analysis was performed only for the probands. Functional studies of the variant and studies of patient cells were not performed. The authors noted that patients with this mutation had a slightly later age at onset, between 19 and 40 years, compared to patients with other mutations who had onset in the first decade.
In a 26-year-old Japanese woman (patient 7) with axonal Charcot-Marie-Tooth disease type 2II (CMT2II; 620068), Ando et al. (2022) identified a de novo heterozygous c.2036A-C transversion (c.2036A-C, NM_133647) in the SLC12A6 gene, resulting in a tyr679-to-ser (Y679S) substitution at a highly conserved residue. The mutation, which was confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. In addition to peripheral neuropathy, the patient had impaired intellectual development (IQ of 46), seizures, frontal and temporal lobe atrophy on brain imaging, and hemolytic anemia.
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