Affinage

SLC12A3

Solute carrier family 12 member 3 · UniProt P55017

Length
1021 aa
Mass
113.1 kDa
Annotated
2026-04-28
100 papers in source corpus 22 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC12A3 encodes NCC, the thiazide-sensitive Na⁺-Cl⁻ cotransporter that mediates electroneutral NaCl reabsorption at the apical membrane of the distal convoluted tubule (PMID:8812482). NCC activity is principally governed by a WNK-SPAK/OSR1 kinase cascade in which WNK4 autophosphorylation triggers SPAK-mediated phosphorylation of NCC N-terminal sites; this signaling is compartmentalized at the apical membrane and within cytoplasmic WNK bodies that require Kir4.1 for plasma K⁺ sensing and Cab39 for proper SPAK targeting (PMID:31736353, PMID:38258567, PMID:29846116). NCC abundance is additionally controlled by NEDD4-2– and Cullin-dependent ubiquitin-mediated degradation in response to dietary potassium and magnesium, by angiotensin II and norepinephrine (via α1-adrenoceptors) as activating signals, and by aldosterone/SGK1-promoted physical interaction with ENaC in the DCT2 segment (PMID:31364380, PMID:35011657, PMID:31608673, PMID:27422782, PMID:28646163). Loss-of-function mutations in SLC12A3 cause Gitelman syndrome through diverse mechanisms including nonsense-mediated mRNA decay, pseudoexon insertion from deep intronic variants, exon skipping due to disrupted splicing enhancers, defective plasma membrane trafficking, and intrinsically reduced ion transport activity (PMID:17329572, PMID:21051746, PMID:25060058, PMID:22009145).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    Molecular cloning of SLC12A3 established the identity and predicted topology of the thiazide-sensitive Na⁺-Cl⁻ cotransporter, resolving the gene responsible for NCC function in the distal nephron.

    Evidence cDNA cloning, predicted 12-transmembrane topology, chromosomal mapping to 16q13, kidney-specific expression

    PMID:8812482

    Open questions at the time
    • No functional transport data in this study
    • No post-translational regulatory information
  2. 2007 High

    Systematic analysis of SLC12A3 mutations revealed that Gitelman syndrome arises through at least three distinct molecular mechanisms — nonsense-mediated mRNA decay, defective protein trafficking, and intrinsically impaired transport — and that mutation type and sex modify clinical severity.

    Evidence Genomic sequencing, MLPA, allele-specific transcript quantification, and functional reconstitution in Xenopus oocytes

    PMID:17329572

    Open questions at the time
    • Genotype–phenotype correlations not established for all mutation classes
    • Trafficking defects not mapped to specific folding intermediates
  3. 2009 High

    Deep intronic mutations and tissue-specific WNK3 isoforms expanded the regulatory landscape of NCC, showing that cryptic exon inclusion abolishes NCC function and that WNK3 isoforms exert opposing kinase-dependent and -independent effects on NCC activity.

    Evidence RT-PCR from patient leukocytes identifying pseudoexon (intron 13); Xenopus oocyte reconstitution with renal vs. brain WNK3 isoforms and NCC phosphosite mutants

    PMID:19470486 PMID:19668106

    Open questions at the time
    • In vivo relevance of WNK3 isoform-specific regulation not confirmed in animal models
    • Pseudoexon mechanism not yet shown for intron 21 mutation at this point
  4. 2010 High

    A knockin mouse model and human renal biopsy studies confirmed that nonsense-mediated mRNA decay is the primary mechanism of NCC loss for truncating mutations, and revealed compensatory upregulation of TRPV5/6 and potassium channels that explain the electrolyte phenotype of Gitelman syndrome.

    Evidence Ser707X knockin mouse, qRT-PCR, Western blot, immunohistochemistry; haplotype and immunohistochemistry analysis of deep intronic mutations in patient renal tissue

    PMID:20848653 PMID:21051746

    Open questions at the time
    • Compensatory channel upregulation mechanism not defined
    • Whether all truncating mutations trigger equivalent NMD is unclear
  5. 2011 High

    Functional classification of multiple NCC missense mutants distinguished surface-expressed but transport-impaired variants from trafficking-defective variants, suggesting that some mutations affect ion translocation or regulation rather than protein folding.

    Evidence 22Na⁺ uptake and surface expression assays in Xenopus oocytes for seven missense mutants

    PMID:22009145

    Open questions at the time
    • Structural basis for ion affinity changes not resolved
    • No distinction between regulatory phosphorylation defects and intrinsic pore defects
  6. 2014 High

    Exonic splicing enhancer disruption was established as a pathogenic mechanism for SLC12A3 missense variants, bridging the gap between seemingly benign coding changes and loss of NCC function.

    Evidence Minigene splicing assays and patient cDNA analysis showing exon 16 skipping from p.M672I; functional transport assay confirming loss of activity

    PMID:25060058

    Open questions at the time
    • Frequency of ESE-disrupting variants among all SLC12A3 missense mutations unknown at this point
    • Trans-acting splicing factor involvement not identified
  7. 2015 High

    SPAK was identified as the kinase that phosphorylates NCC N-terminal sites in vivo, with low-K⁺ diet dramatically increasing both SPAK activation and NCC phosphorylation, though residual regulation in SPAK-knockout mice indicated additional kinases contribute.

    Evidence Phospho-specific antibody analysis in wild-type and SPAK-knockout mice under dietary K⁺ manipulation

    PMID:25651563

    Open questions at the time
    • Identity of additional kinase(s) for NCC phosphorylation not resolved
    • Direct SPAK–NCC interaction site not mapped
  8. 2016 High

    NCC was shown to physically associate with α- and γ-ENaC subunits in the DCT2 segment, establishing a direct molecular link between the two principal sodium reabsorption pathways of the distal nephron.

    Evidence Blue native PAGE, coimmunoprecipitation, mammalian two-hybrid, FRET, and immunogold EM

    PMID:27422782

    Open questions at the time
    • Stoichiometry and structural basis of the NCC–ENaC complex unknown
    • Functional consequence of this interaction on ENaC gating not fully defined
  9. 2017 Medium

    Aldosterone and SGK1 were shown to promote the NCC–ENaC physical interaction, placing hormonal control over the coordinated sodium transport in the DCT2.

    Evidence Electron microscopy colocalization and coimmunoprecipitation after aldosterone treatment and SGK1 co-expression

    PMID:28646163

    Open questions at the time
    • Whether SGK1 phosphorylates NCC directly to promote ENaC interaction is unresolved
    • Functional transport consequence of increased NCC–ENaC interaction not quantified
  10. 2018 High

    The kidney-specific WNK1 isoform was shown to activate NCC by promoting WNK4 autophosphorylation independently of intracellular chloride, establishing a hierarchical WNK signaling cascade upstream of SPAK.

    Evidence Xenopus oocyte reconstitution with KS-WNK1 and WNK4, coimmunoprecipitation, phospho-specific antibodies, WNK463 kinase inhibitor

    PMID:29846116

    Open questions at the time
    • Whether KS-WNK1 interacts with WNK4 directly or through a scaffold is unresolved
    • Relevance of chloride-independent activation under physiological conditions not tested in vivo
  11. 2019 High

    Converging studies established plasma K⁺ as the master regulator of NCC activity, acting through WNK4-containing WNK bodies that depend on Kir4.1 for K⁺ sensing, SPAK/OSR1 for phosphorylation relay, and NEDD4-2 and α1-adrenoceptor signaling as parallel modulatory inputs.

    Evidence WNK4-deficient and Kir4.1 kidney-specific deletion mice with phospho-specific imaging; NEDD4-2 nephron-specific knockout mice under Mg²⁺ restriction; norepinephrine infusion with selective adrenoceptor antagonists in rats; γENaC-deficient mice with dietary manipulation

    PMID:29371419 PMID:31364380 PMID:31608673 PMID:31736353

    Open questions at the time
    • How WNK body phase separation is initiated and resolved is unknown
    • Relative quantitative contributions of NEDD4-2 vs. cullin-mediated degradation not established
    • Whether norepinephrine regulation occurs in human DCT is unconfirmed
  12. 2021 Medium

    Cullin E3-ubiquitin ligases were identified as mediators of K⁺-dependent NCC degradation, with Cul3 mutant mice showing attenuated high-K⁺ suppression of NCC phosphorylation, complementing the known NEDD4-2 pathway.

    Evidence Dietary K⁺ manipulation in Cul3 mutant mice, ex vivo tubule assays, pan-cullin inhibitor MLN4924, phospho-NCC Western blots

    PMID:35011657

    Open questions at the time
    • Specific cullin-adaptor complex and ubiquitination sites on NCC not identified
    • Interplay between cullin and NEDD4-2 pathways not delineated
  13. 2023 High

    PHAII knockin mouse models confirmed that constitutive NCC phosphorylation via WNK-OSR1/SPAK is the primary pathogenic mechanism of pseudohypoaldosteronism type II (Gordon syndrome), mirroring the loss-of-function mechanism of Gitelman syndrome in reverse.

    Evidence PHAII knockin mice with anti-phospho-NCC antibodies and Western blot

    PMID:36685207

    Open questions at the time
    • Quantitative threshold of NCC phosphorylation that produces hypertension not defined
    • Whether therapeutic NCC dephosphorylation reverses PHAII phenotype not shown
  14. 2023 Medium

    Systematic minigene analysis of SLC12A3 missense variants revealed that pre-mRNA splicing disruption is a more prevalent pathogenic mechanism than previously appreciated, affecting exonic splicing regulatory elements across the gene.

    Evidence Bioinformatic screening of 342 missense variants followed by minigene splicing assay for selected candidates

    PMID:36597580

    Open questions at the time
    • Functional transport consequences of individual exon-skipped transcripts not tested for all variants
    • Endogenous splicing patterns may differ from minigene context
  15. 2024 High

    Cab39 was shown to be essential for SPAK localization to the apical membrane and NCC phosphorylation, establishing Cab39 as a scaffold that compartmentalizes WNK-SPAK signaling; its loss phenocopies Gitelman syndrome.

    Evidence Cab39/Cab39l double-knockout mice with immunofluorescence localization, phospho-NCC Western blot, and electrolyte measurements

    PMID:38258567

    Open questions at the time
    • Whether Cab39 directly binds SPAK or acts through MO25/LKB1 in the DCT is not resolved
    • Role of Cab39 in WNK body formation versus apical targeting not distinguished

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structure of full-length NCC exists, and the mechanistic basis for how phosphorylation at N-terminal sites converts NCC from inactive to active conformation, and how distinct mutation classes differentially affect ion translocation versus trafficking, remains structurally unresolved.
  • No cryo-EM or crystal structure of NCC
  • Phosphorylation-induced conformational change not characterized
  • Structural basis for thiazide binding and inhibition unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4
Localization
GO:0005886 plasma membrane 6
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-382551 Transport of small molecules 4
Partners
CAB39NEDD4LOXSR1SCNN1ASCNN1GSTK39WNK1WNK4
Complex memberships
NCC-ENaC complex (DCT2)

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Human SLC12A3 encodes a 1021 amino acid (112 kDa) thiazide-sensitive Na-Cl cotransporter (NCC) with a central region harboring 12 transmembrane domains and two intracellular hydrophilic amino and carboxyl termini, expressed specifically in the kidney and mapped to chromosome 16q13. cDNA cloning, predicted protein structure analysis, fluorescence in situ hybridization, expression pattern analysis Genomics High 8812482
2007 Splicing mutations in SLC12A3 lead to frameshifted mRNA subject to degradation by nonsense-mediated decay; a novel class of NCC mutants with defective intrinsic transport activity but absent cell surface expression was identified, and the nature/position of SLC12A3 mutations combined with male gender determines severity of Gitelman syndrome. Genomic DNA sequencing, MLPA, cDNA analysis, allele-specific transcript quantification, functional analysis in Xenopus laevis oocytes Journal of the American Society of Nephrology : JASN High 17329572
2009 A deep intronic mutation (c.1670-191C>T) in SLC12A3 creates a new donor splice site within intron 13, resulting in inclusion of a novel cryptic exon in mRNA, causing Gitelman syndrome by producing a truncated, nonfunctional NCC protein. RT-PCR from leukocyte and urine sediment mRNA, genomic DNA sequencing of intron 13 Pediatric research Medium 19668106
2010 The nonsense mutation Ser707X in NCC/SLC12A3 causes markedly reduced NCC mRNA and virtually absent NCC protein expression in kidneys primarily due to nonsense-mediated mRNA decay; compensatory upregulation of TRPV5/V6, ROMK1 and Maxi-K channels occurs in the distal tubule, contributing to hypocalciuria and hypokalemia in Gitelman syndrome. Knockin mouse model generation, qRT-PCR, Western blot, immunohistochemistry, electron microscopy of DCT Human mutation High 20848653
2010 Two recurrent deep intronic mutations (c.1670-191C>T in intron 13 and c.2548+253C→T in intron 21) in SLC12A3 create pseudoexons containing premature termination codons, leading to defective NCC expression and Gitelman syndrome; apical NCC expression in DCT is markedly diminished in affected patients. cDNA analysis from leukocytes, sequencing of introns, haplotype analysis, immunohistochemistry of renal biopsy Clinical journal of the American Society of Nephrology : CJASN High 21051746
2011 Novel NCC missense mutations (Thr392Ile, Asn442Ser, Gln1030Arg) cause loss of transport activity or impaired trafficking to the plasma membrane in Xenopus oocytes; other missense mutants (Glu121Asp, Pro751Leu, Ser475Cys, Tyr489His) reach the plasma membrane but have reduced NaCl uptake, suggesting effects on NCC regulation or ion affinity. Xenopus laevis oocyte expression system with direct sequencing of all 26 SLC12A3 exons European journal of human genetics : EJHG High 22009145
2013 NCC (SLC12A3) is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule and is regulated by a complex network including WNK kinases, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3; NCC is activated by angiotensin II and inhibited by dietary potassium. Review integrating multiple functional studies including phospho-specific antibodies, mouse models, and kinase assays Pflugers Archiv : European journal of physiology High 24310820
2014 Exonic mutations in SLC12A3 (p.A356V and p.M672I) cause exon skipping by disrupting exonic splicing enhancer sequences; the p.M672I mutation causes exclusion of exon 16 in SLC12A3 mRNA, and the resulting aberrant protein has no sodium transport activity. Bioinformatics (ESE score analysis), minigene splicing assay, patient cDNA sequencing, functional transport analysis Journal of the American Society of Nephrology : JASN High 25060058
2015 SPAK kinase phosphorylates NCC at specific N-terminal sites in the distal convoluted tubule; low-K+ diet strongly increases total NCC expression and NCC phosphorylation via increased SPAK expression and phosphorylation at the S383 activation site, though other kinases also contribute. Phospho-specific antibody Western blot, immunolocalization in wild-type and SPAK knockout mice fed low-K+ or control diets American journal of physiology. Renal physiology High 25651563
2016 NCC (SLC12A3) physically associates with α- and γ-ENaC subunits in the second part of the distal convoluted tubule (DCT2); this interaction is demonstrable by blue native PAGE, coimmunoprecipitation, mammalian two-hybrid assay, FRET, and immunogold EM, and inhibition of NCC affects ENaC function. Blue native PAGE, coimmunoprecipitation, mammalian two-hybrid assay, FRET, immunogold EM, functional transport assay The Biochemical journal High 27422782
2017 Aldosterone promotes increased NCC-αENaC interaction in the DCT2, as demonstrated by electron microscopy colocalization and coimmunoprecipitation; co-expression of aldosterone-induced SGK1 further increases NCC-αENaC interaction. Electron microscopy colocalization, coimmunoprecipitation, aldosterone treatment, SGK1 co-expression Scientific reports Medium 28646163
2018 Kidney-specific WNK1 isoform (KS-WNK1) activates NCC by interacting with WNK4 and promoting WNK4 autophosphorylation at serine 335 (T-loop) independent of changes in intracellular chloride concentration; this leads to downstream SPAK phosphorylation and NCC activation. Xenopus oocyte microinjection, coimmunoprecipitation, phospho-specific antibodies, kinase inhibitor (WNK463) treatment, chloride measurement American journal of physiology. Renal physiology High 29846116
2019 In K+ deficiency, WNK4 is the primary active WNK isoform in WNK bodies (spherical cytoplasmic domains in the DCT) and catalyzes SPAK/OSR1 phosphorylation therein; phosphorylated SPAK/OSR1 is present both at the apical membrane and in WNK bodies, and WNK body formation requires Kir4.1 for plasma K+ sensing. Genetically engineered mouse lines (WNK4-deficient, Kir4.1 kidney-specific deletion), dietary K+ manipulation, immunofluorescence with phospho-specific antibodies American journal of physiology. Renal physiology High 31736353
2019 Mg2+ restriction decreases total NCC abundance and phosphorylated NCC via NEDD4-2 ubiquitin ligase; NCC downregulation by Mg2+ restriction is absent in inducible nephron-specific NEDD4-2 knockout mice, and this occurs independently of SPAK/OSR1 kinase activity. Dietary manipulation in mice, inducible NEDD4-2 knockout mice, SPAK/OSR1 double knockout mice, Western blot with phospho-specific antibodies American journal of physiology. Renal physiology High 31364380
2019 Norepinephrine activates NCC through an α1-adrenoceptor-gated WNK/SPAK/OxSR1 signaling pathway; α1-adrenoceptor antagonism restores dietary Na+-evoked suppression of NCC expression, phosphorylation, and activity, while β-adrenoceptor antagonism does not. Selective adrenoceptor antagonism in norepinephrine-infused Sprague-Dawley rats, Western blot with phospho-specific antibodies, NCC mRNA expression, in vivo NCC activity measurement American journal of physiology. Renal physiology Medium 31608673
2019 Multiple SLC12A3 missense mutations (T60M, D486N, R928C, L215F, N534K, Q617R) significantly reduce thiazide-sensitive 22Na+ uptake in Xenopus laevis oocytes and alter predicted 3D protein structure, confirming their pathogenic loss-of-function mechanism. Site-directed mutagenesis, 22Na+ uptake in Xenopus oocytes, 3D structure prediction by I-TASSER, thiazide test in patients Endocrine connections High 34860177
2019 Plasma potassium concentration is the determining factor regulating NCC activity, regardless of Na+ balance, in γENaC-deficient mice; NCC is suppressed at baseline by elevated plasma potassium and is activated when potassium is eliminated from the diet. Nephron-specific γENaC knockout mice, dietary manipulation (HNa+/LK+ rescue diet), Western blot for NCC and phospho-NCC Journal of the American Society of Nephrology : JASN Medium 29371419
2021 Cullin E3-ubiquitin ligases (Cul1, 3, 4, 5) mediate potassium effects on NCC phosphorylation and abundance; high dietary K+ effects on phospho-NCC are attenuated in Cul3 mutant mice; short-term low extracellular K+-mediated NCC phosphorylation response requires cullins. Dietary K+ manipulation in mice, Cul3 mutant mice, ex vivo renal tubule K+ manipulation, MLN4924 pan-cullin inhibitor, Western blot with phospho-specific antibodies Cells Medium 35011657
2023 The WNK-OSR1/SPAK-NCC signaling cascade mediates phosphorylation and activation of NCC; constitutive NCC activation and increased NCC phosphorylation are the primary pathogenesis of pseudohypoaldosteronism type II (Gordon syndrome) in vivo, established using PHAII knockin mouse models and anti-phosphorylated NCC antibodies. PHAII knockin mouse model, anti-phosphorylated NCC antibodies (against putative NCC phosphorylation sites), Western blot Frontiers in physiology High 36685207
2024 Cab39 (calcium-binding protein 39) proteins are required for SPAK localization to the apical membrane with NCC; in Cab39 double knockout mice, SPAK and OSR1 are confined to intracellular puncta rather than the apical membrane, resulting in absent NCC phosphorylation and a Gitelman syndrome-like phenotype with loss of NCC function. Global Cab39l knockout and tamoxifen-inducible NCC-driven Cab39 knockout, double knockout mice, low-K+ diet challenge, Western blot, immunofluorescence localization of SPAK/OSR1, blood and urine electrolyte measurements Hypertension (Dallas, Tex. : 1979) High 38258567
2023 Six SLC12A3 exonic variants (c.602G>A, c.602G>T, c.1667C>T, c.1925G>A, c.2548G>C, c.2549G>C) cause complete or incomplete exon skipping by affecting exonic splicing regulatory elements and/or disrupting canonical splice sites, establishing pre-mRNA splicing disruption as a pathogenic mechanism for SLC12A3 missense variants. Bioinformatics analysis of 342 SLC12A3 missense variants, minigene splicing assay in vitro Molecular genetics & genomic medicine Medium 36597580
2019 NCC activity is modulated by plasma K+ concentration via WNK4-SPAK/OSR1 interactions within WNK bodies, which depend on Kir4.1 for DCT K+ sensing; NCC phosphorylation is regulated by SPAK both at the apical membrane and within WNK body compartments. WNK4-deficient mice, Kir4.1 kidney-specific deletion mice, dietary K+ manipulation, phospho-specific immunofluorescence American journal of physiology. Renal physiology High 31736353
2009 Renal and brain isoforms of WNK3 have opposing effects on NCC expression: the renal isoform increases NCC expression and activity in a kinase-dependent manner, while the brain isoform decreases NCC expression, with brain WNK3 acting in tandem with SPAK, while renal WNK3 upregulates NCC through a SPAK-independent pathway. Xenopus oocyte expression system, kinase-inactivating mutations in WNK3 isoforms, NCC T58A/T58D mutant analysis Journal of the American Society of Nephrology : JASN High 19470486

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Dysregulation of the TSC-mTOR pathway in human disease. Nature genetics 818 15624019
2013 The TSC-mTOR pathway regulates macrophage polarization. Nature communications 511 24280772
2003 Rheb fills a GAP between TSC and TOR. Trends in biochemical sciences 392 14607085
2010 Biallelic TSC gene inactivation in tuberous sclerosis complex. Neurology 128 20498439
2007 Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. Journal of the American Society of Nephrology : JASN 118 17329572
2021 G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling. Cell 116 33497611
2005 Growth control under stress: mTOR regulation through the REDD1-TSC pathway. Cell cycle (Georgetown, Tex.) 106 16258273
2011 The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling. Oncogene 105 21258412
1996 Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3). Genomics 101 8812482
2009 Critical roles for the TSC-mTOR pathway in β-cell function. American journal of physiology. Endocrinology and metabolism 93 19690069
2021 Structural insights into TSC complex assembly and GAP activity on Rheb. Nature communications 89 33436626
2003 Cell size regulation by the human TSC tumor suppressor proteins depends on PI3K and FKBP38. Oncogene 87 12894220
2017 Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway. Dermatologic clinics 85 27890237
2018 Genetics, genomics, and genotype-phenotype correlations of TSC: Insights for clinical practice. American journal of medical genetics. Part C, Seminars in medical genetics 77 30255984
2012 Genotype, phenotype, and follow-up in Taiwanese patients with salt-losing tubulopathy associated with SLC12A3 mutation. The Journal of clinical endocrinology and metabolism 69 22679066
2011 Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome. European journal of human genetics : EJHG 64 22009145
2002 Growth signaling: TSC takes its place. Current biology : CB 64 12445406
2015 The clinical profile of tuberous sclerosis complex (TSC) in the United Kingdom: A retrospective cohort study in the Clinical Practice Research Datalink (CPRD). European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 62 26706603
2009 Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis. Human molecular genetics 60 19321600
2013 The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation. Pflugers Archiv : European journal of physiology 58 24310820
2008 Role of TSC-mTOR pathway in diabetic nephropathy. Diabetes research and clinical practice 58 18926585
2019 Platelet-rich clots as identified by Martius Scarlet Blue staining are isodense on NCCT. Journal of neurointerventional surgery 56 30952688
2015 SPAK-mediated NCC regulation in response to low-K+ diet. American journal of physiology. Renal physiology 56 25651563
2018 DDIT4 and Associated lncDDIT4 Modulate Th17 Differentiation through the DDIT4/TSC/mTOR Pathway. Journal of immunology (Baltimore, Md. : 1950) 55 29378913
2010 Generation and analysis of the thiazide-sensitive Na+ -Cl- cotransporter (Ncc/Slc12a3) Ser707X knockin mouse as a model of Gitelman syndrome. Human mutation 55 20848653
2019 WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia. American journal of physiology. Renal physiology 53 31736353
2018 Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC. American journal of physiology. Renal physiology 52 29846116
2020 The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC). Frontiers in neuroanatomy 50 32765227
2010 Recurrent deep intronic mutations in the SLC12A3 gene responsible for Gitelman's syndrome. Clinical journal of the American Society of Nephrology : CJASN 50 21051746
2012 Multifaceted roles of PTEN and TSC orchestrate growth and differentiation of Drosophila blood progenitors. Development (Cambridge, England) 48 22951642
2010 Hypertension, dietary salt intake, and the role of the thiazide-sensitive sodium chloride transporter NCCT. Cardiovascular therapeutics 47 21167012
2021 Uterine PEComas: correlation between melanocytic marker expression and TSC alterations/TFE3 fusions. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 45 34131293
2014 Modulation of TSC-mTOR signaling on immune cells in immunity and autoimmunity. Journal of cellular physiology 45 23804073
2009 Renal and brain isoforms of WNK3 have opposite effects on NCCT expression. Journal of the American Society of Nephrology : JASN 44 19470686
2004 A new mutation (intron 9 +1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies. Kidney international 44 14675033
2001 Regulation of the sodium transporters NHE3, NKCC2 and NCC in the kidney. Current opinion in nephrology and hypertension 44 11496061
2020 Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension. Acta pharmaceutica Sinica. B 42 34094823
2010 Animal models of lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC). Lymphatic research and biology 41 20235887
2014 Exonic mutations in the SLC12A3 gene cause exon skipping and premature termination in Gitelman syndrome. Journal of the American Society of Nephrology : JASN 39 25060058
2019 Effects of antiepileptic drugs in a new TSC/mTOR-dependent epilepsy mouse model. Annals of clinical and translational neurology 38 31353861
2016 The sodium chloride cotransporter (NCC) and epithelial sodium channel (ENaC) associate. The Biochemical journal 38 27422782
2021 The TSC Complex-mTORC1 Axis: From Lysosomes to Stress Granules and Back. Frontiers in cell and developmental biology 37 34778262
2002 Novel NCCT gene mutations as a cause of Gitelman's syndrome and a systematic review of mutant and polymorphic NCCT alleles. Kidney & blood pressure research 34 12590198
2003 The tuberous sclerosis complex (TSC) pathway and mechanism of size control. Biochemical Society transactions 33 12773160
2009 A deep intronic mutation in the SLC12A3 gene leads to Gitelman syndrome. Pediatric research 29 19668106
2015 Circadian exosomal expression of renal thiazide-sensitive NaCl cotransporter (NCC) and prostasin in healthy individuals. Proteomics. Clinical applications 28 25931204
2003 Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours. Biochemical Society transactions 28 12773163
2020 The Rag GTPase Regulates the Dynamic Behavior of TSC Downstream of Both Amino Acid and Growth Factor Restriction. Developmental cell 26 32898476
2019 Genetic Analysis of SLC12A3 Gene in Chinese Patients with Gitelman Syndrome. Medical science monitor : international medical journal of experimental and clinical research 26 31398183
2018 Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific γENaC Knockout. Journal of the American Society of Nephrology : JASN 26 29371419
2017 Acquired Gitelman syndrome in a primary Sjögren syndrome patient with a SLC12A3 heterozygous mutation: A case report and literature review. Nephrology (Carlton, Vic.) 26 28685938
2020 Sympathetic Regulation of the NCC (Sodium Chloride Cotransporter) in Dahl Salt-Sensitive Hypertension. Hypertension (Dallas, Tex. : 1979) 24 32981364
2019 Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats. American journal of physiology. Renal physiology 24 31608673
2016 Is mTOR Inhibitor Good Enough for Treatment All Tumors in TSC Patients? Journal of Cancer 24 27698899
2020 GSK-3-TSC axis governs lysosomal acidification through autophagy and endocytic pathways. Cellular signalling 23 32173369
2003 Regulation of tuberous sclerosis complex (TSC) function by 14-3-3 proteins. Biochemical Society transactions 23 12773161
2017 Aldosterone Modulates the Association between NCC and ENaC. Scientific reports 22 28646163
2004 Role of TSC-22 during early embryogenesis in Xenopus laevis. Development, growth & differentiation 21 15610143
2022 Synthesis, Antileishmanial Activity and in silico Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Leishmania chagasi Amastigotes. Medicinal chemistry (Shariqah (United Arab Emirates)) 20 33593264
2019 Digenetic inheritance of SLC12A3 and CLCNKB genes in a Chinese girl with Gitelman syndrome. BMC pediatrics 20 30999883
2019 Mg2+ restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia. American journal of physiology. Renal physiology 20 31364380
2019 Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion. The Journal of experimental medicine 20 31506280
2014 Genetic and biological effects of sodium-chloride cotransporter (SLC12A3) in diabetic nephropathy. American journal of nephrology 20 25401745
2011 Exploring the intricate regulatory network controlling the thiazide-sensitive NaCl cotransporter (NCC). Pflugers Archiv : European journal of physiology 20 21927811
2016 Association of rs11643718 SLC12A3 and rs741301 ELMO1 Variants with Diabetic Nephropathy in South Indian Population. Annals of human genetics 18 27699784
2015 Identification of two novel mutations in SLC12A3 gene in two Chinese pedigrees with Gitelman syndrome and review of literature. Clinical endocrinology 18 25990047
2013 Molecular insights from dysregulation of the thiazide-sensitive WNK/SPAK/NCC pathway in the kidney: Gordon syndrome and thiazide-induced hyponatraemia. Clinical and experimental pharmacology & physiology 17 23683032
2022 The non-essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain and neuron growth. Cell reports 16 35584673
2021 Potassium Effects on NCC Are Attenuated during Inhibition of Cullin E3-Ubiquitin Ligases. Cells 16 35011657
2018 Less common manifestations in TSC. American journal of medical genetics. Part C, Seminars in medical genetics 16 30156054
2021 Identifying the temporal electrophysiological and molecular changes that contribute to TSC-associated epileptogenesis. JCI insight 15 34877936
2022 Genetic and Biological Effects of SLC12A3, a Sodium-Chloride Cotransporter, in Gitelman Syndrome and Diabetic Kidney Disease. Frontiers in genetics 14 35591852
2009 TSC-22D1 isoforms have opposing roles in mammary epithelial cell survival. Cell death and differentiation 14 19745830
2023 NCC regulation by WNK signal cascade. Frontiers in physiology 13 36685207
2008 Evaluating PVALB as a candidate gene for SLC12A3-negative cases of Gitelman's syndrome. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 13 18469313
2006 A novel splicing mutation in SLC12A3 associated with Gitelman syndrome and idiopathic intracranial hypertension. American journal of kidney diseases : the official journal of the National Kidney Foundation 13 17059986
2024 Renal upregulation of NCC counteracts empagliflozin-mediated NHE3 inhibition in normotensive but not in hypertensive male rat. American journal of physiology. Cell physiology 12 38557357
2019 Establishment and characterization of a novel cell line, NCC-MFS1-C1, derived from a patient with myxofibrosarcoma. Human cell 12 30737712
2017 dTBC1D7 regulates systemic growth independently of TSC through insulin signaling. The Journal of cell biology 12 29187524
2024 Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC. Hypertension (Dallas, Tex. : 1979) 11 38258567
2021 Tuberous Sclerosis Complex (TSC): Renal and Extrarenal Imaging. Academic radiology 11 33487538
2021 Benign tumors in TSC are amenable to treatment by GD3 CAR T cells in mice. JCI insight 11 34806651
2019 Structure-function relationships in the renal NaCl cotransporter (NCC). Current topics in membranes 11 31196605
2019 Arg913Gln variation of SLC12A3 gene is associated with diabetic nephropathy in type 2 diabetes and Gitelman syndrome: a systematic review. BMC nephrology 11 31660880
2018 Establishment and characterization of the NCC-SS1-C1 synovial sarcoma cell line. Human cell 11 29450702
2017 TSC-22 inhibits CSF-1R function and induces apoptosis in cervical cancer. Oncotarget 11 29228668
2005 Patterns of expression of TSC-22 protein in astrocytic gliomas. Experimental oncology 10 16404353
2023 Minigene splicing assays reveal new insights into exonic variants of the SLC12A3 gene in Gitelman syndrome. Molecular genetics & genomic medicine 9 36597580
2023 Updated Genotype-Phenotype Correlations in TSC. Seminars in pediatric neurology 9 37919037
2021 Establishment and characterization of NCC-DDLPS3-C1: a novel patient-derived cell line of dedifferentiated liposarcoma. Human cell 9 33677797
2021 Simultaneous Homozygous Mutations in SLC12A3 and CLCNKB in an Inbred Chinese Pedigree. Genes 9 33807568
2021 Tsc Gene Locus Disruption and Differences in Renal Epithelial Extracellular Vesicles. Frontiers in physiology 9 34262466
2021 Differential Modulation of Matrix Metalloproteinases-2 and -7 in LAM/TSC Cells. Biomedicines 9 34944575
2019 microRNA-1 Regulates NCC Migration and Differentiation by Targeting sec63. International journal of biological sciences 9 31754327
2007 Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes. DNA sequence : the journal of DNA sequencing and mapping 9 17654016
2003 Exclusion of mutations in FXYD2, CLDN16 and SLC12A3 in two families with primary renal Mg2+ loss. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 9 12584272
2022 Frequent SLC12A3 mutations in Chinese Gitelman syndrome patients: structure and function disorder. Endocrine connections 8 34860177
2020 Establishment and characterization of NCC-DFSP3-C1: a novel patient-derived dermatofibrosarcoma protuberans cell line. Human cell 8 32356243
2019 Establishment and characterization of a novel dedifferentiated chondrosarcoma cell line, NCC-dCS1-C1. Human cell 8 30737713
2018 Establishment and proteomic characterization of a novel synovial sarcoma cell line, NCC-SS2-C1. In vitro cellular & developmental biology. Animal 8 29626278