SLC4A1
protein-codingsolute carrier family 4 member 1 (Diego blood group), the group of Blood group antigens|CD molecules|Solute carrier family 4
Gene summary
The protein encoded by this gene is part of the anion exchanger (AE) family and is expressed in the erythrocyte plasma membrane, where it functions as a chloride/bicarbonate exchanger involved in carbon dioxide transport from tissues to lungs. The protein comprises two domains that are structurally and functionally distinct. The N-terminal 40kDa domain is located in the cytoplasm and acts as an attachment site for the red cell skeleton by binding ankyrin. The glycosylated C-terminal membrane-associated domain contains 12-14 membrane spanning segments and carries out the stilbene disulphonate-sensitive exchange transport of anions. The cytoplasmic tail at the extreme C-terminus of the membrane domain binds carbonic anhydrase II. The encoded protein associates with the red cell membrane protein glycophorin A and this association promotes the correct folding and translocation of the exchanger. This protein is predominantly dimeric but forms tetramers in the presence of ankyrin. Many mutations in this gene are known in man, and these mutations can lead to two types of disease: destabilization of red cell membrane leading to hereditary spherocytosis, and defective kidney acid secretion leading to distal renal tubular acidosis. Other mutations that do not give rise to disease result in novel blood group antigens, which form the Diego blood group system. Southeast Asian ovalocytosis (SAO, Melanesian ovalocytosis) results from the heterozygous presence of a deletion in the encoded protein and is common in areas where Plasmodium falciparum malaria is endemic. One null mutation in this gene is known, resulting in very severe anemia and nephrocalcinosis. [provided by RefSeq, Jul 2008]
- EPB3
- AE1
- DI
- WD
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~19.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012700
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0012700
Submitter: ClinGen
The *SLC4A1* gene is located on chromosome 17 at cytoband q21.31. The gene encodes both the erythroid (eAE1, band 3) and the kidney (kAE1) isoforms of the AE1 protein. There are two versions of this protein that differ in size: the 93kDa version in erythrocytes, and the 43kDa version in the alpha-intercalated cells in the kidney. The longer (93kDa) version of AE1, found in erythrocytes, has two regions: a 43kDa transmembrane chloride/bicarbonate exchanger protein and a 50kDa domain. In erythrocytes, the 43kDa transmembrane chloride/bicarbonate exchanger protein acts in facilitating carbon dioxide exchange between the erythrocytes and the tissues. In the kidney, the 43kDa transmembrane chloride/bicarbonate exchanger protein is found in the alpha-intercalated cells and is involved in release of acid into the urine (via Cl/HCO3- exchange). Importantly, this 43kDa transmembrane domain is fully functional on its own, including in the kidney. In addition to exchanging ions via the 43kDa transmembrane region, the longer AE1 protein (found in erythrocytes) has a 50kDa domain that anchors the membrane cytoskeleton to the membrane through an ankyrin-binding site (band 2.1) and also contains binding sites for hemoglobin and several glycolytic enzymes. Thus, SLC4A1 is a pleiotropic gene, with variation associated with both hematologic conditions (e.g., hereditary spherocytosis and ovalocytosis) and the renal disease entity of distal renal tubular acidosis (dRTA). Distal renal tubular acidosis (dRTA), also often referred to as type 1 RTA, is caused by a decreased capacity of the α-intercalated cells in the collecting duct to excrete protons. This process is mediated by two proteins: the H+-ATPase (expressed at apical/luminal membrane) and Cl−/HCO3− exchanger AE1 (basolateral membrane). Biochemically, this disorder is characterized by a hyperchloremic metabolic acidosis with normal plasma anion gap, hypokalaemia and hypercalciuria with hypocitraturia causing nephrocalcinosis. Due to disruption of urine acidification, urinary pH is >5.5. Common features of dRTA include: vomiting, diarrhea or constipation, failure to thrive and/or rickets. Patients may also present with muscle weakness or paralysis, which occurs secondary to severe hypokalemia, and/or polyuria, which may result from electrolyte imbalances. To date, multiple genes have been associated with dRTA: these include ATP6V1B1 and ATP6V0A4, genes encoding subunits of the vacuolar H+-ATPase, which are associated with an autosomal recessive form of dRTA, and SLC4A1, which has been associated with both autosomal dominant distal renal tubular acidosis (AD-dRTA; MONDO:0008368; OMIM MIM #179800) and autosomal recessive renal tubular acidosis, distal, 4, with hemolytic anemia (AR-dRTA; MONDO:0012700; OMIM MIM #611590). *SLC4A1* has also been associated with autosomal dominant distal renal tubular acidosis (AD-dRTA; MONDO:0008368; OMIM MIM #179800). As autosomal dominant SLC4A1-dRTA and autosomal recessive SLC4A1-dRTA have different modes of inheritance and molecular mechanisms of disease (as reviewed in PMID: 19565014), they were split and curated separately per the guidelines outlined by the ClinGen Lumping and Splitting Working Group and as approved by the ClinGen Tubulopathy Gene Curation Expert Panel. At least ten variants in *SLC4A1* have been associated with AR-dRTA with hemolytic anemia, including missense variants altering conserved amino acid residues in the transmembrane regions of the AE1 protein (e.g., p.G701D (PMID: 9854053) and p.S773P (PMID: 15211439) in transmembrane segments 9 and 10), as well as in-frame deletions (e.g., p.Val850del, PMID: 10926824) and protein-truncating variants (e.g., p.Q203*, PMID: 31933135). These variants have been identified in multiple cases, including homozygotes and compound heterozygotes, with familial segregation and supporting functional data (e.g., PMID: 9854053, PMID:22126643, PMID: 33068675, PMID: 20151848, PMID: 15211439, PMID: 15252044, PMID: 10942416, PMID: 17215882, PMID: 31933135, PMID: 10926824, PMID: 18266205, PMID: 20028337, PMID: 27718309) supporting the pathogenicity of these SLC4A1 variants for AR-dRTA with hemolytic anemia. The gene-disease association is further supported by multiple lines of experimental evidence, including biochemical function (PMID: 16239253), expression (PMID: 3618786), and rescue data (PMID: 21455273). There is also non-human model organism evidence: SLC4A1 knockout mouse models showed dRTA and nephrocalcinosis accompanied by hypercalciuria, hyperphosphaturia, and hypocitraturia (PMID: 17409310). In summary, the *SLC4A1* gene is Definitively associated with AR-dRTA with hemolytic anemia. The gene-disease association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 4/6/2022 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0008368
Submitter: Natera
Inheritance Pattern: Unknown
Disease ID:MONDO:0008494
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008368
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012700
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008494
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0008368
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012981
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012700
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008494
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012700
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008368
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008165
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017910
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019350
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008368
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008165
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008368
Submitter: ClinGen
The *SLC4A1* gene is located on chromosome 17 at cytoband q21.31. The gene encodes both the erythroid (eAE1, band 3) and the kidney (kAE1) isoforms of the AE1 protein. There are two versions of this protein that differ in size: the 93kDa version in erythrocytes, and the 43kDa version in the alpha-intercalated cells in the kidney. The longer (93kDa) version of AE1, found in erythrocytes, has two regions: a 43kDa transmembrane chloride/bicarbonate exchanger protein and a 50kDa domain. In erythrocytes, the 43kDa transmembrane chloride/bicarbonate exchanger protein acts in facilitating carbon dioxide exchange between the erythrocytes and the tissues. In the kidney, the 43kDa transmembrane chloride/bicarbonate exchanger protein is found in the alpha-intercalated cells and is involved in release of acid into the urine (via Cl/HCO3- exchange). Importantly, this 43kDa transmembrane domain is fully functional on its own, including in the kidney. In addition to exchanging ions via the 43kDa transmembrane region, the longer AE1 protein (found in erythrocytes) has a 50kDa domain that anchors the membrane cytoskeleton to the membrane through an ankyrin-binding site (band 2.1) and also contains binding sites for hemoglobin and several glycolytic enzymes. Thus, *SLC4A1* is a pleiotropic gene, with variation associated with both hematologic conditions (e.g., hereditary spherocytosis and ovalocytosis) and the renal disease entity of distal renal tubular acidosis (dRTA). Distal renal tubular acidosis (dRTA), also often referred to as type 1 RTA, is caused by a decreased capacity of the α-intercalated cells in the collecting duct to excrete protons. This process is mediated by two proteins: the H+-ATPase (expressed at apical/luminal membrane) and Cl−/HCO3− exchanger AE1 (basolateral membrane). Biochemically, this disorder is characterized by a hyperchloremic metabolic acidosis with normal plasma anion gap, hypokalaemia and hypercalciuria with hypocitraturia causing nephrocalcinosis. Due to disruption of urine acidification, urinary pH is >5.5. Common features of dRTA include: vomiting, diarrhea or constipation, failure to thrive and/or rickets. Patients may also present with muscle weakness or paralysis, which occurs secondary to severe hypokalemia, and/or polyuria, which may result from electrolyte imbalances. To date, multiple genes have been associated with dRTA: these include ATP6V1B1 and ATP6V0A4, genes encoding subunits of the vacuolar H+-ATPase, which are associated with an autosomal recessive form of dRTA, and *SLC4A1*, which has been associated with both autosomal dominant distal renal tubular acidosis (AD-dRTA; MONDO:0008368; OMIM MIM #179800) and autosomal recessive renal tubular acidosis, distal, 4, with hemolytic anemia (AR-dRTA; MONDO:0012700; OMIM MIM #611590). *SLC4A1* has also been associated with autosomal recessive distal renal tubular acidosis with hemolytic anemia (MONDO:0012700; OMIM MIM #611590). As autosomal dominant SLC4A1-dRTA and autosomal recessive SLC4A1-dRTA have different modes of inheritance and molecular mechanisms of disease (as reviewed in PMID: 19565014), they were split and curated separately per the guidelines outlined by the ClinGen Lumping and Splitting Working Group and as approved by the ClinGen Tubulopathy Gene Curation Expert Panel. At least eight variants in *SLC4A1* have been associated with AD-dRTA: these include missense variants altering conserved amino acid residues in the transmembrane regions of the AE1 protein (e.g., p.G609R and p.S613F in transmembrane segment 7) and deletions in the COOH-terminal region (e.g., p.R901X). Of note, the R589 residue, which is located in the intracellular loop between transmembrane segments 6 and 7, may be a mutational hotspot, with missense variants including p.R589H, p.R589S, and p.R589C, reported recurrently among individuals with AD-dRTA. Both case-level evidence, including de novo occurrences (e.g., PMID: 30230413, PMID: 9600966, PMID: 3025667) and familial segregation (e.g., PMID: 9312167, PMID: 9600966, PMID: 9497368), as well functional data (e.g., PMID: 11934690, PMID:16420521) support the pathogenicity of these *SLC4A1* variants for AD-dRTA, such that the maximum genetic evidence score of 12 is reached. The gene-disease association is further supported by multiple lines of experimental evidence, including biochemical function (PMID: 3529979), protein interaction (PMID: 10820026), expression (PMID: 3618786), and rescue data (PMID: 12933803, PMID: 20628050). The gene-disease association is further supported by multiple lines of experimental evidence, including biochemical function (as reviewed in PMID: 16239253; PMID: 3529979), protein interaction (PMID: 10820026), expression (PMID: 3618786), and rescue data (PMID: 12933803, PMID: 20628050). There is also non-human model organism evidence: heterozygous R607H (corresponding to the human p.R589H variant) knockin mouse models showed incomplete dRTA as evidenced by presenting with hyperchloremic metabolic acidosis (decreased blood pH and plasma [HCO3−] and increased blood [Cl−]) upon NH4Cl administration, recapitulating the human disease phenotype (PMID: 27932475). In summary, the *SLC4A1* gene is definitively associated with AD-dRTA. The gene-disease association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 6/2/2021 (SOP Version 8).
Clinical Genomic Database (CGD)
Manifestation: Hematologic; Renal
Intervention: Hematologic; Renal
Rationale: In Renal tubular acidosis, if detected early, therapeutic correction of the acidosis by alkali administration leads in most cases to improvement of biochemical abnormalities and resumption of normal growth, as well as beneficial regarding skeletal manifestations; As pertains to hematologic manifestations, splenectomy has been reported as being beneficial; Variants associated with a blood group may be important in specific situations (eg, related to transfusion)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC4A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000342.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 15 | 118 | 6 | 140 | |
| missense | 11 | 44 | 396 | 42 | 2 | 495 |
| nonsense | 20 | 23 | 2 | 45 | ||
| start loss | 0 | |||||
| frameshift | 38 | 71 | 5 | 114 | ||
| splice donor/acceptor (+/-2bp) | 12 | 32 | 2 | 46 | ||
| Total | 81 | 171 | 420 | 160 | 8 | 840 |
Highest pathogenic variant AF is 0.000026638616
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000333.1 | 19 | MANE Select | |
| Ensembl | ENSP00000262418.6 | 19 | MANE Select | |
| Ensembl | ENSP00000382190.3 | 14 | Standard | |
| Ensembl | ENSP00000382190.3 | 14 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| slc4a1b | Danio rerio | Structure: neuromast hair cell Quality: decreased efficacy abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Collecting duct acid secretion - Homo sapiens (human)
- O2/CO2 exchange in erythrocytes
- Transport of inorganic cations/anions and amino acids/oligopeptides
- SLC-mediated transmembrane transport
- Transport of small molecules
Biological Process
- anion transport
- chloride transport
- cellular ion homeostasis
- bicarbonate transport
- regulation of intracellular pH
Molecular Function
- inorganic anion exchanger activity
- protein binding
- anion transmembrane transporter activity
- bicarbonate transmembrane transporter activity
- chloride transmembrane transporter activity
Cellular Component
- plasma membrane
- integral component of plasma membrane
- integral component of membrane
- basolateral plasma membrane
- Z disc
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262418
- Coding exons
- 19
- Length
- 19757
- Individuals with no LoFs
- 125737
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125748
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.66 | 426 | 534 | 0.798 | 0.0000353 | 5848 |
| Missense (PolyPhen) | 162 | 231.02 | 0.70124 | 2545 | ||
| Synonymous | -0.575 | 241 | 230 | 1.05 | 0.0000155 | 1935 |
| Loss of Function | 4.81 | 8 | 41.4 | 0.193 | 0.00000214 | 456 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein. Major integral membrane glycoprotein of the erythrocyte membrane; required for normal flexibility and stability of the erythrocyte membrane and for normal erythrocyte shape via the interactions of its cytoplasmic domain with cytoskeletal proteins, glycolytic enzymes, and hemoglobin. Functions as a transporter that mediates the 1:1 exchange of inorganic anions across the erythrocyte membrane. Mediates chloride-bicarbonate exchange in the kidney, and is required for normal acidification of the urine. {ECO:0000269|PubMed:10926824, ECO:0000269|PubMed:14734552, ECO:0000269|PubMed:1538405, ECO:0000269|PubMed:20151848, ECO:0000269|PubMed:24121512}.;
- Disease
- DISEASE: Ovalocytosis, Southeast Asian (SAO) [MIM:166900]: A hereditary hematologic disorder characterized by ovalocytic erythrocytes that are rigid and exhibit reduced expression of many erythrocyte antigens. Clinical manifestations include mild hemolysis, intermittent jaundice and gallstones. However, the disorder is most often asymptomatic. {ECO:0000269|PubMed:1538405, ECO:0000269|PubMed:1722314}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spherocytosis 4 (SPH4) [MIM:612653]: Spherocytosis is a hematologic disorder leading to chronic hemolytic anemia and characterized by numerous abnormally shaped erythrocytes which are generally spheroidal. {ECO:0000269|PubMed:10580570, ECO:0000269|PubMed:10745622, ECO:0000269|PubMed:10942416, ECO:0000269|PubMed:11380459, ECO:0000269|PubMed:1378323, ECO:0000269|PubMed:15813913, ECO:0000269|PubMed:16227998, ECO:0000269|PubMed:7530501, ECO:0000269|PubMed:8547122, ECO:0000269|PubMed:8640229, ECO:0000269|PubMed:8943874, ECO:0000269|PubMed:9012689, ECO:0000269|PubMed:9207478, ECO:0000269|PubMed:9233560, ECO:0000269|PubMed:9973643}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Renal tubular acidosis, distal, autosomal dominant (AD- dRTA) [MIM:179800]: An autosomal dominant disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha- intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Renal tubular acidosis, distal, with hemolytic anemia (dRTA-HA) [MIM:611590]: A disease characterized by the association of hemolytic anemia with distal renal tubular acidosis, the reduced ability to acidify urine resulting in variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. {ECO:0000269|PubMed:10926824, ECO:0000269|PubMed:15211439, ECO:0000269|PubMed:9854053}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Renal tubular acidosis, distal, with normal red cell morphology (dRTA-NRC) [MIM:611590]: A disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha- intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. {ECO:0000269|PubMed:15211439}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cryohydrocytosis (CHC) [MIM:185020]: An autosomal dominant disorder of red cell membrane permeability characterized by cold-induced changes in cell volume, resulting in cold- sensitive stomatocytosis, and increased erythrocyte osmotic fragility and autohemolysis at 4 degrees Celsius. Patients present with mild to moderate hemolytic anemia, splenomegaly, fatigue, and pseudohyperkalemia due to a potassium leak from the erythrocytes. {ECO:0000269|PubMed:16227998}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry.;
Recessive Scores
- pRec
- 0.577
Intolerance Scores
- LoFtool
- 0.160
- RVIS EVS
- -0.79
- RVIS percentile EVS
- 12.62
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.917
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |