SLC12A3: Solute Carrier Family 12 Member 3
Thiazide-Sensitive Sodium-Chloride Cotransporter (NCC) – Key Regulator of Renal Ion Transport and Blood Pressure
Gene Information Card
| Symbol | SLC12A3 |
|---|---|
| Full Name | Solute carrier family 12 member 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 16q13 |
| NCBI Gene ID | 6559 ncbi.nlm.nih.gov/gene/6559 |
| Ensembl ID | ENSG00000170989 |
| UniProt ID | P55017 |
| OMIM ID | 600968 |
| HGNC ID | 10912 |
| Aliases | NCC, TSC, FLJ96321 |
Description
SLC12A3 (solute carrier family 12 member 3) encodes the thiazide-sensitive sodium-chloride cotransporter (NCC), a membrane protein primarily expressed in the distal convoluted tubule of the kidney. NCC mediates electroneutral reabsorption of sodium and chloride ions, playing a critical role in electrolyte homeostasis, blood pressure regulation, and renal salt handling. Loss-of-function mutations cause Gitelman syndrome, an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Gitelman syndrome | Loss-of-function mutations in SLC12A3 impair NCC-mediated NaCl reabsorption in the distal convoluted tubule, leading to renal salt wasting, hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. | Multiple reports in OMIM (600968) and ClinVar; confirmed by functional studies. |
| Primary hypertension | Common variants in SLC12A3 (e.g., intronic SNPs) have been associated with altered blood pressure regulation and response to thiazide diuretics. | GWAS and candidate gene studies (NCBI Gene, ClinVar). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Kidney | 27.8 | High |
| Adrenal gland | 0.9 | Low |
| Testis | 0.5 | Low |
| Liver | 0.2 | Not detected |
| Heart | 0.1 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 0.0 | Not expressed (transient transfection used for functional studies) |
| HK-2 (kidney proximal tubule) | 0.0 | Not expressed (NCC is distal tubule-specific) |
| MDCK (distal tubule model) | 12.5 | Moderate (endogenous expression) |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1196_1197delCT (p.Pro399Argfs*?) | Frameshift | Rare | Loss of function – truncated protein, no transport activity |
| c.2221G>A (p.Gly741Arg) | Missense | Rare | Loss of function – impaired membrane trafficking |
| c.2888G>A (p.Arg963Gln) | Missense | Rare | Loss of function – reduced ion transport |
| c.506C>T (p.Thr169Met) | Missense | Rare | Loss of function – decreased surface expression |
Mutation functional classification
Loss of Function (LOF)
Majority of SLC12A3 mutations cause loss of NCC function, leading to Gitelman syndrome. Mechanisms include impaired protein folding, trafficking defects, reduced ion transport activity, or complete loss of protein expression.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported in SLC12A3.
Dominant Negative (DN)
No dominant-negative effects described; Gitelman syndrome is autosomal recessive, requiring biallelic loss-of-function.
View complete mutation data：
Gene Ontology (GO)
| • sodium:chloride symporter activity (GO:0008510) | • symporter activity (GO:0015293) |
| • integral component of plasma membrane (GO:0005887) | • transmembrane transport (GO:0055085) |
| • sodium ion transport (GO:0006814) | • chloride transport (GO:0006821) |
| • diet-induced thermogenesis (GO:0002024) | • renal sodium ion absorption (GO:0003091) |
Pathways
• Aldosterone-regulated sodium reabsorption (KEGG hsa04960)
• Transport of inorganic cations/anions (Reactome R-HSA-425393)
• SLC-mediated transmembrane transport (Reactome R-HSA-425407)
Protein Summary
The SLC12A3 protein (NCC) is a 1021-amino acid integral membrane protein with 12 transmembrane domains, belonging to the SLC12 family of cation-chloride cotransporters. It mediates the electroneutral symport of Na+ and Cl- across the apical membrane of distal convoluted tubule cells. NCC is the pharmacological target of thiazide diuretics, which inhibit its activity to reduce blood pressure. Post-translational regulation includes phosphorylation by WNK kinases and dephosphorylation by phosphatases, modulating its surface expression and activity.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SLC12A3 Knockout HEK293 Cell Line | EDJ-KQ5784 | Human | 6559 | Details Get a Quote |
| SLC12A3 Knockout HeLa Cell Line | EDJ-KQ54507 | Human | 6559 | Details Get a Quote |
| SLC12A3 Knockout A-549 Cell Line | EDJ-KQ62992 | Human | 6559 | Details Get a Quote |
| SLC12A3 Knockout HCT 116 Cell Line | EDJ-KQ71463 | Human | 6559 | Details Get a Quote |
Displaying Records 1 To 4 Of 4 Records
