SLC4A4: Solute Carrier Family 4 Member 4
Sodium Bicarbonate Cotransporter (NBCe1) – Key Regulator of Acid-Base Homeostasis
Gene Information Card
| Symbol | SLC4A4 |
|---|---|
| Full Name | Solute Carrier Family 4 Member 4 |
| Gene Type | Protein-coding |
| Chromosomal Location | 4q13.3 |
| NCBI Gene ID | 8671 ncbi.nlm.nih.gov/gene/8671 |
| Ensembl ID | ENSG00000180447 |
| UniProt ID | Q9Y6R1 |
| OMIM ID | 603345 |
| HGNC ID | 11024 |
| Aliases | NBC1, NBCe1, NBC2, SLC4A5, HNBC1, pNBC |
Description
SLC4A4 encodes the electrogenic sodium bicarbonate cotransporter NBCe1, which mediates the coupled movement of Na+ and HCO3- across the plasma membrane. This transporter is critical for maintaining intracellular pH and systemic acid-base balance, particularly in the kidney, eye, and brain. Mutations in SLC4A4 cause proximal renal tubular acidosis with ocular abnormalities (pRTA-OA).
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Proximal renal tubular acidosis with ocular abnormalities (pRTA-OA) | Loss-of-function mutations impair renal HCO3- reabsorption, leading to metabolic acidosis; also disrupts bicarbonate transport in corneal endothelium and lens, causing cataracts and glaucoma. | Multiple reports in OMIM (603345) and ClinVar. |
| Glaucoma (secondary) | Dysfunction of NBCe1 in trabecular meshwork and ciliary epithelium alters aqueous humor dynamics, increasing intraocular pressure. | Case studies in OMIM and literature. |
| Cataract (congenital) | Impaired bicarbonate transport in lens epithelial cells disrupts pH regulation, leading to opacification. | ClinVar and OMIM entries. |
| Migraine (with aura) | NBCe1 dysfunction in brain may alter neuronal excitability and pH homeostasis, contributing to migraine pathophysiology. | Association studies in OMIM and NCBI Gene. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Kidney | 12.5 | Medium |
| Eye (cornea) | 8.3 | Medium |
| Brain (cerebellum) | 6.1 | Low |
| Heart | 4.2 | Low |
| Liver | 1.8 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 15.2 | High expression |
| ARPE-19 (retinal pigment epithelium) | 9.7 | Medium expression |
| HepG2 | 2.1 | Low expression |
| SH-SY5Y (neuroblastoma) | 5.4 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.2311C>T (p.Arg771Ter) | Nonsense | Rare | Loss of function; truncation of NBCe1 |
| c.2425G>A (p.Glu809Lys) | Missense | Rare | Impaired bicarbonate transport; associated with pRTA-OA |
| c.2992C>T (p.Arg998Trp) | Missense | Rare | Reduced surface expression and transport activity |
| c.1055C>T (p.Thr352Met) | Missense | Rare | Decreased electrogenic transport; linked to migraine |
Mutation functional classification
Loss of Function (LOF)
Most SLC4A4 mutations (e.g., p.Arg771Ter, p.Glu809Lys) result in loss of NBCe1 function, leading to proximal renal tubular acidosis and ocular defects.
Gain of Function (GOF)
No gain-of-function mutations have been reported for SLC4A4.
Dominant Negative (DN)
No dominant-negative mutations have been characterized; inheritance is autosomal recessive.
View complete mutation data：
Gene Ontology (GO)
| • GO:0015377 – sodium:bicarbonate symporter activity | • GO:0015705 – bicarbonate transport |
| • GO:0006814 – sodium ion transport | • GO:0051453 – regulation of intracellular pH |
| • GO:0005886 – plasma membrane | • GO:0016323 – basolateral plasma membrane |
Pathways
• Bicarbonate transporters (Reactome: R-HSA-425393)
• Ion transport by P-type ATPases (Reactome: R-HSA-936837)
• Transport of inorganic cations/anions (Reactome: R-HSA-425407)
Protein Summary
NBCe1 (UniProt Q9Y6R1) is a 1035-amino acid transmembrane protein with 10-14 predicted helices. It functions as an electrogenic Na+/HCO3- cotransporter with a 1:3 stoichiometry. The protein is expressed predominantly in kidney proximal tubule basolateral membrane, corneal endothelium, and brain. It plays a central role in systemic pH regulation and ocular fluid balance. Mutations cause proximal renal tubular acidosis with ocular abnormalities (pRTA-OA).
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SLC4A4 Knockout HEK293 Cell Line | EDJ-KQ976 | Human | 8671 | Details Get a Quote |
| SLC4A4 Knockout A-549 Cell Line | EDJ-KQ19994 | Human | 8671 | Details Get a Quote |
| SLC4A4 Knockout HeLa Cell Line | EDJ-KQ54976 | Human | 8671 | Details Get a Quote |
| SLC4A4 Knockout HCT 116 Cell Line | EDJ-KQ71925 | Human | 8671 | Details Get a Quote |
| SLC4A4 Knockout Huh-7 Cell Line | EDC07795 | Human | 8671 | Details Get a Quote |
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