SLC22A4

Summary

SLC22A4 (solute carrier family 22 member 4, HGNC:10968) is a protein-coding gene on chromosome 5q31.1, encoding Solute carrier family 22 member 4 (Q9H015). Transporter that mediates the transport of endogenous and microbial zwitterions and organic cations.

Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is an organic cation transporter and plasma integral membrane protein containing eleven putative transmembrane domains as well as a nucleotide-binding site motif. Transport by this protein is at least partially ATP-dependent.

Source: NCBI Gene 6583 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hearing loss, autosomal recessive (Limited, ClinGen)
• GWAS associations: 46
• Clinical variants (ClinVar): 54 total — 1 pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes
• MANE Select transcript: NM_003059

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10968
Approved symbol	SLC22A4
Name	solute carrier family 22 member 4
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	OCTN1, MGC34546
Ensembl gene	ENSG00000197208
Ensembl biotype	protein_coding
OMIM	604190
Entrez	6583

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000200652, ENST00000425923, ENST00000491257, ENST00000897522, ENST00000897523, ENST00000897524, ENST00000897525, ENST00000947747, ENST00000947748, ENST00000947749, ENST00000947750

RefSeq mRNA: 1 — MANE Select: NM_003059 NM_003059

CCDS: CCDS4153

Canonical transcript exons

ENST00000200652 — 10 exons

Exon	Start	End
ENSE00000762455	132327277	132327403
ENSE00000762456	132331756	132331850
ENSE00000762457	132334718	132334932
ENSE00000762458	132335818	132336000
ENSE00000762459	132340565	132340700
ENSE00001124255	132343760	132344190
ENSE00001124260	132294394	132295009
ENSE00003511548	132312161	132312264
ENSE00003570081	132322184	132322355
ENSE00003651527	132313614	132313768

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 99.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.5158 / max 461.7969, expressed in 1236 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58434	4.6350	1048
58435	1.9359	616
58437	0.9711	160
58433	0.7164	190
58436	0.2574	76

Top tissues by expression

276 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	99.34	gold quality
epithelium of bronchus	UBERON:0002031	98.57	gold quality
bronchus	UBERON:0002185	97.70	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.38	gold quality
right uterine tube	UBERON:0001302	91.80	gold quality
trabecular bone tissue	UBERON:0002483	91.02	gold quality
nasal cavity epithelium	UBERON:0005384	90.15	gold quality
blood	UBERON:0000178	89.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.79	gold quality
bone marrow	UBERON:0002371	87.91	gold quality
epithelium of nasopharynx	UBERON:0001951	85.76	gold quality
monocyte	CL:0000576	84.89	gold quality
mononuclear cell	CL:0000842	84.49	gold quality
nasal cavity mucosa	UBERON:0001826	83.89	gold quality
leukocyte	CL:0000738	83.88	gold quality
jejunal mucosa	UBERON:0000399	83.45	gold quality
nephron tubule	UBERON:0001231	82.52	gold quality
pancreatic ductal cell	CL:0002079	82.14	silver quality
endothelial cell	CL:0000115	81.36	silver quality
gastrocnemius	UBERON:0001388	81.18	gold quality
ileal mucosa	UBERON:0000331	80.89	gold quality
bone marrow cell	CL:0002092	80.42	gold quality
muscle of leg	UBERON:0001383	79.29	gold quality
cartilage tissue	UBERON:0002418	79.00	gold quality
stromal cell of endometrium	CL:0002255	78.33	gold quality
kidney epithelium	UBERON:0004819	77.31	silver quality
renal glomerulus	UBERON:0000074	76.67	silver quality
metanephric glomerulus	UBERON:0004736	76.27	silver quality
granulocyte	CL:0000094	75.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.51	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6058	no	9.10
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB, RUNX1, SP1, TP63

miRNA regulators (miRDB)

35 targeting SLC22A4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-455-3P	98.94	67.68	878
HSA-MIR-412-3P	98.86	66.89	712
HSA-MIR-6754-3P	98.84	66.60	889
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-6755-3P	98.61	66.90	834
HSA-MIR-509-3P	98.12	67.25	612
HSA-MIR-5087	98.01	69.09	965
HSA-MIR-6831-3P	97.49	69.29	505
HSA-MIR-1910-5P	97.42	66.36	844
HSA-MIR-194-3P	97.36	65.96	1027
HSA-MIR-10397-5P	97.31	69.06	710
HSA-MIR-3126-3P	97.17	66.51	468

Literature-anchored findings (GeneRIF, showing 40)

• An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis (PMID:14608356)
• Missense substitution in SLC22A4 is associated with Crohn disease (PMID:15107849)
• Review. SLC22A4 is a susceptibility gene for rheumatoid arthritis. A functional SNP has an allele-specific effect on expression through variable binding of RUNX1. (PMID:15184985)
• We conclude that the single nucleotide polymorphism that causes the amino acid mutation G462E abrogates transport activity, presumably affecting the physiological function of OCTN1 and/or the pharmacological characteristics of its substrates. (PMID:15459889)
• 2 functionally relevant polymorphisms in the SLC22A4 / 22A5 genes at the IBD5 locus that alter gene/protein function and are associated with increased risk for Crohn’s disease. (PMID:15685536)
• key substrate of this transporter is ergothioneine (PMID:15795384)
• OCTN1 is involved in renal excretion of organic cations across the apical membrane. (PMID:15832501)
• antibody raised to an epitope during C. jejuni or M. paratuberculosis enterocolitis may crossreact with an intestinal epithelial cell functional variant of OCTN1, an already less efficient carnitine transporter, initiating inflammatory bowel disease (PMID:16246312)
• The 1672C>T SLC22A4 and -207G>C SLC22A5 polymorphisms are genetic markers of susceptibility/protection haplotypes for Crohn’s disease. (PMID:16333318)
• the 1672T variant of the OCTN1 gene and the -207C variant of the OCTN2 gene represent risk factors for Crohn disease in the Greek population (PMID:16437728)
• the SLC22A4 and RUNX1 polymorphisms did not show a significant role in rheumatoid arthritis susceptibility in a Spanish (PMID:16652416)
• Results showed endogenous expression of native OCTN1 in HepG2 cell mitochondria. (PMID:16729965)
• A recent report identified polymorphisms in SLC22A4 (OCTN1) and SLC22A5 (OCTN2) as being responsible for the IBD5 association inflammatory bowel disease). (PMID:16773684)
• One of the tested polymorphisms in the SLC22A4 gene at 1672 showed significant association with type 1 diabetes. (PMID:16796743)
• The frequency of the NOD2/CARD15 susceptibility variants in the Hungarian pediatric CD population is high. SLC22A4 and SLC22A5 mutation screening do not confirm the assumption that the carriage of these genotypes means an obligatory susceptibility to CD. (PMID:17006998)
• The IBD5 locus is associated with CD in the Swedish population. The strongest association is with the marker SNP IGR2096a_1, lying p-telomeric to SLC22A4 and SLC22A5. The effect of the TC haplotype was not an independent determinant in this population. (PMID:17340776)
• The SLC22A4 1672T allele frequency was 46.7% in the patients with UC and 46.4% in the controls (PMID:17387389)
• polymorphisms associated with pediatric onset of Crohn’s disease (PMID:17451203)
• OCTN1 contributes to active tubular secretion of gabapentin, an effect that may be diminished or absent in individuals carrying the OCTN1-Leu503Phe polymorphism. (PMID:17609685)
• two of the variants (D165G and R282X) resulted in complete loss of transport function, and one variant (M205I) caused a reduction in activity to approximately 50% of the reference sequence protein (PMID:17700366)
• There was no evidence for epistasis between the IL23R gene and the Crohn’s disease susceptibility genes CARD15 and SLC22A4/5. (PMID:17786191)
• SLC22A4 gene single nucleotide polymorphism was associated with rheumatoid arthritis (PMID:18087673)
• Data of the current study do not confirm the universal and population independent susceptibility role of the SLC22A4 C6607T and RUNX1 G24658C variants for rheumatoid arthritis. (PMID:18328148)
• OCTN1 and OCTN2 mRNA expression was detected in HCLE and HCjE cells of rabbits and humans. OCTN1 and OCTN2 were predominately localized in the apical membranes of the cells. (PMID:18641280)
• Additional independent studies are required to clarify the role of SLC22A4 polymorphisms in the etiology of rheumatoid arthritis. (PMID:18709696)
• Determine OCTN1/2 and CARD15 gene polymorphisms in Chinese patients with inflammatory bowel disease. (PMID:18756601)
• we analyzed the sequence of the proximal promoter regions of OCTN1 and OCTN2 in four ethnic groups and determined the effects of the identified genetic variants on transcriptional activities (PMID:19141711)
• expressed in resident skin cells and epidermal keratinocytes (PMID:19439218)
• The organic cation transporter, OCTN1, expressed in the human heart, potentiates antagonism of the HERG potassium channel. (PMID:19528813)
• SLC22A4 my play a role in the development of inflammatory bowel diseases. (PMID:19581171)
• functional variants in FCRL3, SLC22A4 and MHC2TA do not show a convincing effect on RA susceptibility in the United Kingdom. (PMID:19605748)
• Required for functional heme biosynthesis in erythroid cells. (PMID:19656490)
• SLC22A4 (solute carrier protein 22 A4) and SLC22A5 (solute carrier protein 22 A5) genes are unlikely to play a major role in susceptibility to Crohns disease in the Chinese Han population. (PMID:19659785)
• Carrying a variant OCTN1 gene does not adversely affect most individuals in a normal diet but this variant confers sensitivity to mushrooms in Crohn disease cases. (PMID:19660151)
• Substrate discrimination by ergothioneine transporter SLC22A4 and carnitine transporter SLC22A5: gain-of-function by interchange of selected amino acids. (PMID:19814996)
• Twenty four genetic variants of SLC22A4, including 14 were found to be novel, 16 in the coding exons (10 nonsynonymous and 6 synonymous variations) and 8 in the introns. (PMID:19881261)
• ipratropium and tiotropium are taken up primarily by OCTN2, and to a lesser extent by OCTN1, in bronchial epithelial cells (PMID:20020740)
• These results indicate that OCTN1 plays a pivotal role for maintenance of systemic and intestinal exposure of ergothioneine providing a possible diagnostic tool to distinguish the inflammatory bowel diseases (PMID:20224991)
• Variants carried by the haplotypes of SLC22A4, SLC22A5 and KIF3A region potentially contribute to tuberculosis susceptibility among the Thai population. (PMID:20485362)
• Results replicated the association of the OCTN1 rs1050152 (L503F) variant with Crohn’s disease and inflammatory bowel disease. A weak gender-specific effect of rs1050152 (L503F) on male Ulcerative Colitis and female Crohn’s Disease was observed. (PMID:21122496)

Cross-species orthologs

48 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc22a4	ENSDARG00000005335
danio_rerio	oatx	ENSDARG00000019713
danio_rerio	si:dkey-166k12.1	ENSDARG00000054690
danio_rerio	si:dkey-119m7.4	ENSDARG00000071049
danio_rerio	si:dkey-119m7.8	ENSDARG00000096654
mus_musculus	Slc22a4	ENSMUSG00000020334
rattus_norvegicus	Slc22a4	ENSRNOG00000046195
drosophila_melanogaster	Orct	FBGN0019952
drosophila_melanogaster	CG15221	FBGN0030331
drosophila_melanogaster	Balat	FBGN0033778
drosophila_melanogaster	CG5592	FBGN0035645
drosophila_melanogaster	CG10486	FBGN0035647
drosophila_melanogaster	CG14691	FBGN0037829
drosophila_melanogaster	CG14855	FBGN0038260
drosophila_melanogaster	CG14856	FBGN0038261
drosophila_melanogaster	CG14857	FBGN0038262
drosophila_melanogaster	CG12783	FBGN0038448
drosophila_melanogaster	CG7333	FBGN0038715
drosophila_melanogaster	CG7342	FBGN0038716
drosophila_melanogaster	CG17751	FBGN0038717
drosophila_melanogaster	CG17752	FBGN0038718
drosophila_melanogaster	CG16727	FBGN0038719
drosophila_melanogaster	CG6231	FBGN0038720
drosophila_melanogaster	CG4465	FBGN0038750
drosophila_melanogaster	CG4462	FBGN0038752
drosophila_melanogaster	CG4459	FBGN0038753
drosophila_melanogaster	CG6356	FBGN0039178
drosophila_melanogaster	CG3690	FBGN0040350
drosophila_melanogaster	CG31103	FBGN0051103
drosophila_melanogaster	CG31106	FBGN0051106
drosophila_melanogaster	CG31272	FBGN0051272
drosophila_melanogaster	CG33233	FBGN0053233
drosophila_melanogaster	CG33234	FBGN0053234
drosophila_melanogaster	Orct2	FBGN0086365
drosophila_melanogaster	CG42269	FBGN0259164
drosophila_melanogaster	CG44098	FBGN0264907
caenorhabditis_elegans		WBGENE00003837
caenorhabditis_elegans	oct-1	WBGENE00003842
caenorhabditis_elegans		WBGENE00003843
caenorhabditis_elegans		WBGENE00006220
caenorhabditis_elegans		WBGENE00008110
caenorhabditis_elegans		WBGENE00011456
caenorhabditis_elegans		WBGENE00014127
caenorhabditis_elegans		WBGENE00015088
caenorhabditis_elegans		WBGENE00017751
caenorhabditis_elegans		WBGENE00019408
caenorhabditis_elegans		WBGENE00020701
caenorhabditis_elegans		WBGENE00044455

Paralogs (22): SLC22A16 (ENSG00000004809), SLC22A17 (ENSG00000092096), SLC22A2 (ENSG00000112499), SLC22A7 (ENSG00000137204), SLC22A23 (ENSG00000137266), SLC22A14 (ENSG00000144671), SLC22A3 (ENSG00000146477), SLC22A8 (ENSG00000149452), SLC22A9 (ENSG00000149742), SVOPL (ENSG00000157703), SLC22A15 (ENSG00000163393), SVOP (ENSG00000166111), SLC22A11 (ENSG00000168065), SLC22A13 (ENSG00000172940), SLC22A1 (ENSG00000175003), SLC22A10 (ENSG00000184999), SLC22A25 (ENSG00000196600), SLC22A5 (ENSG00000197375), SLC22A24 (ENSG00000197658), SLC22A12 (ENSG00000197891), SLC22A6 (ENSG00000197901), SLC22A31 (ENSG00000259803)

Protein

Protein identifiers

Solute carrier family 22 member 4 — Q9H015 (reviewed: Q9H015)

Alternative names: Ergothioneine transporter, Organic cation/carnitine transporter 1

All UniProt accessions (1): Q9H015

UniProt curated annotations — full annotation on UniProt →

Function. Transporter that mediates the transport of endogenous and microbial zwitterions and organic cations. Functions as a Na(+)-dependent and pH-dependent high affinity microbial symporter of potent food-derived antioxidant ergothioeine. Transports one sodium ion with one ergothioeine molecule. Involved in the absorption of ergothioneine from the luminal/apical side of the small intestine and renal tubular cells, and into non-parenchymal liver cells, thereby contributing to maintain steady-state ergothioneine level in the body. Also mediates the bidirectional transport of acetycholine, although the exact transport mechanism has not been fully identified yet. Most likely exports anti-inflammatory acetylcholine in non-neuronal tissues, thereby contributing to the non-neuronal cholinergic system. Displays a general physiological role linked to better survival by controlling inflammation and oxidative stress, which may be related to ergothioneine and acetycholine transports. May also function as a low-affinity Na(+)-dependent transporter of L-carnitine through the mitochondrial membrane, thereby maintaining intracellular carnitine homeostasis. May contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier.

Subunit / interactions. Interacts with PDZK1.

Subcellular location. Apical cell membrane. Basal cell membrane. Mitochondrion membrane.

Tissue specificity. Widely expressed. Highly expressed in kidney, trachea, ileum, bone marrow and whole blood. Expressed in small intestines. Weakly expressed in skeletal muscle, prostate, lung, pancreas, placenta, heart, uterus, spleen and spinal cord. Expressed in testis, primarily to the basal membrane of Sertoli cells. Expressed in brain. Expressed in liver. Highly expressed in intestinal cell types affected by Crohn disease, including epithelial cells. Expressed in CD68 macrophage and CD43 T-cells but not in CD20 B-cells. Predominantly expressed in CD14 cells in peripheral blood mononuclear cells. Expressed in fetal liver, kidney and lung.

Disease relevance. Rheumatoid arthritis (RA) [MIM:180300] An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Allosterically activated by intracellular ATP.

Induction. Overexpressed upon TNF treatment.

Miscellaneous. Mediates the Na(+)-independent and pH-dependent bidirectional transport of exogenous prototype organic cation tetraethylammonium (TEA).

Similarity. Belongs to the major facilitator (TC 2.A.1) superfamily. Organic cation transporter (TC 2.A.1.19) family.

RefSeq proteins (1): NP_003050* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004749	Orgcat_transp/SVOP	Family
IPR005828	MFS_sugar_transport-like	Family
IPR005829	Sugar_transporter_CS	Conserved_site
IPR020846	MFS_dom	Domain
IPR036259	MFS_trans_sf	Homologous_superfamily
IPR045915	S22A4/5	Family

Pfam: PF00083

Catalyzed reactions (Rhea), 4 shown:

• (R)-carnitine(out) + Na(+)(out) = (R)-carnitine(in) + Na(+)(in) (RHEA:72091)
• glycine betaine(out) + Na(+)(out) = glycine betaine(in) + Na(+)(in) (RHEA:72115)
• acetylcholine(in) = acetylcholine(out) (RHEA:74663)
• ergothioneine(out) + Na(+)(out) = ergothioneine(in) + Na(+)(in) (RHEA:75843)

UniProt features (33 total): topological domain 13, transmembrane region 12, glycosylation site 3, sequence variant 3, chain 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H015-F1	85.07	0.53

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 218–225

Glycosylation sites (3): 57, 64, 91

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-549127	SLC-mediated transport of organic cations
R-HSA-6798163	Choline catabolism
R-HSA-382551	Transport of small molecules
R-HSA-425366
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-549132

MSigDB gene sets: 306 (showing top): MODULE_416, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_MODIFIED_AMINO_ACID_TRANSPORT, MODULE_64, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_REGENERATION, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GOBP_AMINO_ACID_BETAINE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GNF2_ANK1, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_GLYCEROLIPID_METABOLIC_PROCESS

GO Biological Process (18): sulfur amino acid transport (GO:0000101), triglyceride metabolic process (GO:0006641), sodium ion transport (GO:0006814), lactation (GO:0007595), carnitine metabolic process (GO:0009437), quaternary ammonium group transport (GO:0015697), carnitine transport (GO:0015879), response to lipopolysaccharide (GO:0032496), response to vitamin D (GO:0033280), xenobiotic transport (GO:0042908), response to exogenous dsRNA (GO:0043330), acetylcholine uptake (GO:0051630), amino acid import across plasma membrane (GO:0089718), liver regeneration (GO:0097421), monoatomic ion transport (GO:0006811), neurotransmitter transport (GO:0006836), transmembrane transport (GO:0055085), carnitine transmembrane transport (GO:1902603)

GO Molecular Function (13): acetylcholine transmembrane transporter activity (GO:0005277), ATP binding (GO:0005524), obsolete secondary active organic cation transmembrane transporter activity (GO:0008513), amino acid transmembrane transporter activity (GO:0015171), amino-acid betaine transmembrane transporter activity (GO:0015199), carnitine transmembrane transporter activity (GO:0015226), symporter activity (GO:0015293), quaternary ammonium group transmembrane transporter activity (GO:0015651), PDZ domain binding (GO:0030165), nucleotide binding (GO:0000166), protein binding (GO:0005515), obsolete organic cation transmembrane transporter activity (GO:0015101), transmembrane transporter activity (GO:0022857)

GO Cellular Component (7): mitochondrion (GO:0005739), plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), apical plasma membrane (GO:0016324), mitochondrial membrane (GO:0031966), neuronal cell body (GO:0043025), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
SLC-mediated transmembrane transport	1
Metabolism of amino acids and derivatives	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	4
nitrogen compound transport	2
amino-acid betaine transport	2
response to lipid	2
response to oxygen-containing compound	2
amino acid transmembrane transport	2
transmembrane transport	2
transmembrane transporter activity	2
quaternary ammonium group transmembrane transporter activity	2
modified amino acid transmembrane transporter activity	2
plasma membrane region	2
carboxylic acid transport	1
sulfur compound transport	1
acylglycerol metabolic process	1
metal ion transport	1
body fluid secretion	1
mammary gland development	1
milk ejection reflex	1
amino-acid betaine metabolic process	1
response to molecule of bacterial origin	1
response to vitamin	1
response to dsRNA	1
acetylcholine transport	1
import across plasma membrane	1
liver development	1
animal organ regeneration	1
cellular process	1
carnitine transport	1
neurotransmitter transmembrane transporter activity	1
acetate ester transmembrane transporter activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
carnitine transmembrane transport	1
secondary active transmembrane transporter activity	1
quaternary ammonium group transport	1
protein domain specific binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transporter activity	1

Protein interactions and networks

STRING

1372 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC22A4	NOD2	Q9HC29	838
SLC22A4	RUNX1	Q01196	772
SLC22A4	PADI4	Q9UM07	772
SLC22A4	SLC47A1	Q96FL8	734
SLC22A4	SLC47A2	Q86VL8	711
SLC22A4	SLC15A2	Q16348	663
SLC22A4	DLG5	Q8TDM6	655
SLC22A4	SLCO4C1	Q6ZQN7	640
SLC22A4	SLC15A1	P46059	621
SLC22A4	SLCO1A2	P46721	617
SLC22A4	P4HA2	O15460	612
SLC22A4	NHERF4	Q86UT5	601
SLC22A4	SLC29A4	Q7RTT9	596
SLC22A4	PTPN22	Q9Y2R2	594
SLC22A4	SLCO2B1	O94956	591

IntAct

4 interactions, top by confidence:

A	B	Type	Score
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
CES2	SERPINF2	psi-mi:“MI:0914”(association)	0.350
SLC22A4	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (239): SLC22A4 (Reconstituted Complex), SLC22A4 (Proximity Label-MS), SLC22A4 (Two-hybrid), SLC22A4 (Affinity Capture-MS), DERL2 (Affinity Capture-MS), TMEM120A (Affinity Capture-MS), RIPK4 (Affinity Capture-MS), C17orf62 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), AGPAT3 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), CSNK1G3 (Affinity Capture-MS), TMEM11 (Affinity Capture-MS), FADS1 (Affinity Capture-MS), VMP1 (Affinity Capture-MS)

ESM2 similar proteins: A6NK97, A6QLW8, A7MBE0, A9CB25, B2GV36, O15245, O35956, O57379, O75751, O88446, O88909, Q1RPP5, Q3YAW7, Q4U2R8, Q4W8A2, Q4W8A3, Q5NCM1, Q5R540, Q5R9C4, Q5RCH6, Q5RLM2, Q66J52, Q66J54, Q6A4L0, Q6DFR1, Q6NUB3, Q6NWF1, Q6NYN7, Q70BM6, Q80UJ1, Q863T6, Q864Z3, Q86VW1, Q8HY24, Q8MK48, Q8R0S9, Q8TCC7, Q8VC69, Q91WU2, Q9H015

Diamond homologs: A0A3Q2IDB4, A0A8B7HA97, A6NK97, A6QLW8, A7MBE0, A9CB25, B2GV36, G1SZD9, J9VLA6, O02713, O08966, O15244, O15245, O35956, O57379, O70577, O70594, O75751, O76082, O77504, O88446, O88909, Q1RPP5, Q28ES4, Q2KIV1, Q3YAW7, Q3ZAV1, Q4U2R8, Q4W8A2, Q4W8A3, Q504N2, Q5R540, Q5R5H7, Q5R9C4, Q5RC45, Q5RCH6, Q5RLM2, Q63089, Q63ZE4, Q66J52

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

54 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	28
Likely benign	16
Benign	5

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
832924	NC_000005.9:g.(?131436897)(131729974_?)del	Pathogenic

SpliceAI

1677 predictions. Top by Δscore:

Variant	Effect	Δscore
5:132294980:G:GT	donor_gain	1.0000
5:132312159:A:AG	acceptor_gain	1.0000
5:132312159:AGT:A	acceptor_gain	1.0000
5:132312159:AGTG:A	acceptor_gain	1.0000
5:132312160:G:GG	acceptor_gain	1.0000
5:132312160:GT:G	acceptor_gain	1.0000
5:132312160:GTG:G	acceptor_gain	1.0000
5:132312160:GTGG:G	acceptor_gain	1.0000
5:132312160:GTGGA:G	acceptor_gain	1.0000
5:132312260:GACAG:G	donor_gain	1.0000
5:132312263:AGG:A	donor_loss	1.0000
5:132312264:GGT:G	donor_loss	1.0000
5:132312265:G:GA	donor_loss	1.0000
5:132312266:T:A	donor_loss	1.0000
5:132313752:G:GA	donor_gain	1.0000
5:132321227:T:A	acceptor_gain	1.0000
5:132324555:C:G	donor_gain	1.0000
5:132331747:T:TA	acceptor_gain	1.0000
5:132331748:G:A	acceptor_gain	1.0000
5:132331750:TTACA:T	acceptor_loss	1.0000
5:132331751:TACAG:T	acceptor_loss	1.0000
5:132331753:CA:C	acceptor_loss	1.0000
5:132331753:CAGG:C	acceptor_gain	1.0000
5:132331754:A:AG	acceptor_gain	1.0000
5:132331754:AG:A	acceptor_gain	1.0000
5:132331754:AGGA:A	acceptor_gain	1.0000
5:132331755:G:A	acceptor_loss	1.0000
5:132331755:G:GG	acceptor_gain	1.0000
5:132331755:GG:G	acceptor_gain	1.0000
5:132331755:GGA:G	acceptor_gain	1.0000

AlphaMissense

3577 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:132294764:T:A	C50S	0.997
5:132294765:G:C	C50S	0.997
5:132294737:T:C	F41L	0.996
5:132294739:C:A	F41L	0.996
5:132294739:C:G	F41L	0.996
5:132294802:G:C	W62C	0.996
5:132294802:G:T	W62C	0.996
5:132294738:T:C	F41S	0.995
5:132313623:G:C	R169S	0.995
5:132313623:G:T	R169S	0.995
5:132335970:A:C	S472R	0.995
5:132335972:C:A	S472R	0.995
5:132335972:C:G	S472R	0.995
5:132294953:T:A	C113S	0.994
5:132294954:G:C	C113S	0.994
5:132313622:G:C	R169T	0.994
5:132322299:G:C	W256C	0.994
5:132322299:G:T	W256C	0.994
5:132335926:G:T	R457M	0.994
5:132335980:C:A	A475D	0.994
5:132294738:T:G	F41C	0.993
5:132313622:G:T	R169M	0.993
5:132335926:G:C	R457T	0.993
5:132335967:G:C	G471R	0.993
5:132340600:G:C	G494R	0.993
5:132294764:T:C	C50R	0.992
5:132312221:G:C	G152R	0.992
5:132322255:G:C	G242R	0.992
5:132327303:T:C	L284P	0.992
5:132334822:C:A	A384D	0.992

dbSNP variants (sampled 300 via entrez): RS1000040643 (5:132297586 G>A), RS1000104835 (5:132304547 G>A), RS1000104919 (5:132341341 C>T), RS1000157868 (5:132293252 G>A,T), RS1000324609 (5:132327020 C>T), RS1000325348 (5:132312063 G>A,C,T), RS1000468639 (5:132318433 C>A), RS1000659423 (5:132299277 C>T), RS1000677220 (5:132319474 C>A), RS1000813248 (5:132293180 C>A), RS1000968983 (5:132339939 A>G), RS1001078850 (5:132306635 A>T), RS1001089260 (5:132298447 C>G,T), RS1001120648 (5:132305487 A>G), RS1001124026 (5:132340070 T>G)

Disease associations

OMIM: gene MIM:604190 | disease phenotypes: MIM:180300, MIM:212140

GenCC curated gene-disease

Disease	Classification	Inheritance
hearing loss, autosomal recessive	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hearing loss, autosomal recessive	Limited	AR

Mondo (3): rheumatoid arthritis (MONDO:0008383), systemic primary carnitine deficiency disease (MONDO:0008919), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (2): Systemic primary carnitine deficiency (Orphanet:158), NON RARE IN EUROPE: Rheumatoid arthritis (Orphanet:284130)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0001370	Rheumatoid arthritis
HP:0001386	Joint swelling
HP:0001387	Joint stiffness
HP:0001824	Weight loss
HP:0001945	Fever
HP:0002633	Vasculitis
HP:0002829	Arthralgia
HP:0002923	Rheumatoid factor positive
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0005764	Polyarticular arthritis
HP:0006150	Swan neck-like deformities of the fingers
HP:0006252	Interphalangeal joint erosions
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0012276	Digital flexor tenosynovitis
HP:0012378	Fatigue
HP:0033034	Anti-citrullinated protein antibody positivity

GWAS associations

46 associations (top):

Study	Trait	p-value
GCST000368_1	Fibrinogen	1.000000e-06
GCST000368_5	Fibrinogen	1.000000e-12
GCST000879_15	Crohn’s disease	1.000000e-20
GCST001217_35	Metabolic traits	7.000000e-16
GCST001438_16	Crohn’s disease	4.000000e-08
GCST001725_83	Inflammatory bowel disease	1.000000e-52
GCST002445_1	Asthma (sex interaction)	9.000000e-07
GCST003194_40	Fibrinogen levels	9.000000e-27
GCST004063_119	Waist circumference adjusted for body mass index	2.000000e-07
GCST004063_164	Waist circumference adjusted for body mass index	7.000000e-10
GCST004131_32	Inflammatory bowel disease	4.000000e-27
GCST004132_10	Crohn’s disease	6.000000e-36
GCST004133_36	Ulcerative colitis	2.000000e-06
GCST004500_47	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	2.000000e-08
GCST004501_133	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	2.000000e-08
GCST004504_98	Waist circumference adjusted for BMI in non-smokers	2.000000e-07
GCST004599_34	Mean platelet volume	3.000000e-33
GCST004610_1	White blood cell count	7.000000e-26
GCST004613_140	Sum neutrophil eosinophil counts	4.000000e-22
GCST004614_82	Granulocyte count	8.000000e-23
GCST004620_153	Sum basophil neutrophil counts	2.000000e-16
GCST004625_14	Monocyte count	4.000000e-15
GCST004626_47	Myeloid white cell count	5.000000e-25
GCST004628_75	Immature fraction of reticulocytes	3.000000e-10
GCST004629_68	Neutrophil count	8.000000e-16
GCST004861_67	Itch intensity from mosquito bite	8.000000e-38
GCST005195_71	Coronary artery disease	5.000000e-10
GCST005196_88	Coronary artery disease	3.000000e-10
GCST006249_8	Serum metabolite levels	9.000000e-15
GCST006249_92	Serum metabolite levels	2.000000e-11

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0008343	sex interaction measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004318	smoking behavior
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0005091	monocyte count
EFO:0007986	reticulocyte count
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0007778	urinary albumin to creatinine ratio
EFO:0004346	neuroimaging measurement
EFO:0004587	lymphocyte count
EFO:0004309	platelet count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001172	Arthritis, Rheumatoid	C05.550.114.154; C05.799.114; C17.300.775.099; C20.111.199
C564609	Deafness, Autosomal Recessive (supp.)
C536778	Systemic carnitine deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2073668 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1050152	Efficacy	3	imatinib	Chronic myelogenous leukemia;BCR-ABL1 positive;Gastrointestinal Stromal Tumors

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1050152	SLC22A4	3	3.75	1	imatinib
rs272893	SLC22A4		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — Organic zwitterions/cation transporters (OCTN)

CTD chemical–gene interactions

67 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	4
Tetrachlorodibenzodioxin	decreases reaction, increases expression, affects cotreatment	4
Doxorubicin	decreases expression, decreases reaction, increases abundance	3
Estradiol	affects cotreatment, increases expression	3
Tetraethylammonium	decreases reaction, increases uptake, increases transport	3
perfluorooctane sulfonic acid	increases expression	2
Acetaminophen	increases expression, decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Carnitine	increases uptake	2
Metformin	decreases reaction, increases abundance	2
Smoke	increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	increases expression	2
Valproic Acid	increases expression	2
Aflatoxin B1	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	decreases reaction, affects binding, decreases activity	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	increases expression	1
lead acetate	increases expression	1
tetrahydropalmatine	decreases reaction, increases import	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	increases expression	1
cupric chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
methanethiosulfonate ethylammonium	decreases activity	1
trans-10,cis-12-conjugated linoleic acid	increases expression	1

ChEMBL screening assays

29 unique, capped per target: 26 functional, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2076015	Functional	TP_TRANSPORTER: uptake in OCTN1-expressing HEK 293 cells	Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. — J Pharmacol Exp Ther
CHEMBL3531367	ADMET	Inhibition of OCTN1 (unknown origin) expressed in HEK293 cells assessed as reduction of [3H]ergothioneine substrate uptake at 100 uM by liquid scintillation counting	Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods. — Drug Metab Dispos

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D4EN	1321N1-SLC22A4-KO-c10	Cancer cell line	Male
CVCL_D4EP	1321N1-SLC22A4-KO-c11	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00056667	PHASE4	COMPLETED	Relaxation Response Training for the Treatment of Rheumatoid Arthritis
NCT00094341	PHASE4	COMPLETED	Preference of Rheumatoid Arthritis (RA) Patients of Enbrel® (Etanercept) Auto-Injector Versus Enbrel® Pre-Filled Syringes
NCT00099554	PHASE4	COMPLETED	Effectiveness and Safety of Enbrel® (Etanercept) in Rheumatoid Arthritis Subjects Who Have Failed Remicade® (Infliximab)
NCT00111410	PHASE4	COMPLETED	Evaluating the Effect of Anakinra (r-metHuIL-1ra) on Vaccine AntibodyResponse in Subjects With Rheumatoid Arthritis (RA)
NCT00115219	PHASE4	COMPLETED	Evaluating Efficacy and Safety of Etanercept 50 mg Twice Weekly (BIW) in Rheumatoid Arthritis (RA) Subjects Who Are Sub-Optimal Responders to Etanercept 50 mg Once Weekly (QW)
NCT00121043	PHASE4	COMPLETED	Evaluating Kineret® (Anakinra) in Rheumatoid Arthritis (RA) Subjects Using aSelf-Reported Questionnaire
NCT00132418	PHASE4	COMPLETED	Study of Enbrel in Rheumatoid Arthritis (RA) Subjects With Comorbid Disorders
NCT00157872	PHASE4	COMPLETED	A Study of Rofecoxib Versus Naproxen in the Treatment of Chinese Patient With Rheumatoid Arthritis (0966-231)
NCT00195494	PHASE4	COMPLETED	Study Comparing Etanercept and Methotrexate vs. Methotrexate Alone in Rheumatoid Arthritis
NCT00208364	PHASE4	TERMINATED	A Two Centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Metal-on-Metal Bearing in Primary Total Hip Replacement
NCT00208377	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy ASR™ System in Primary Hip Resurfacing Surgery
NCT00208390	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the Summit™ Hip in Primary Total Hip Replacement
NCT00208429	PHASE4	WITHDRAWN	A Multi-centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Polyethylene-on-metal Bearing in Primary Total Hip Replacement
NCT00208455	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy PROXIMA™ Hip in Primary Total Hip Replacement
NCT00209859	PHASE4	COMPLETED	Methotrexate and Cyclosporine in Treatment of Early Rheumatoid Arthritis
NCT00216177	PHASE4	UNKNOWN	Comparison of Adalimumab and Infliximab Treatment of Rheumatoid Arthritis
NCT00233558	PHASE4	TERMINATED	Open-Label Steroid Reduction Study of Adalimumab With Methotrexate in Patients With Active Rheumatoid Arthritis
NCT00234234	PHASE4	COMPLETED	Predictors of the Response to Adalimumab in Rheumatoid Arthritis
NCT00234897	PHASE4	COMPLETED	Efficacy of HUMIRA in Subjects With Active Rheumatoid Arthritis
NCT00244556	PHASE4	COMPLETED	Study Comparing Enbrel (Etanercept) Plus Methotrexate Versus Enbrel Alone in Active Rheumatoid Arthritis Despite Current Methotrexate Therapy
NCT00252668	PHASE4	COMPLETED	Study Evaluating the Combination of Etanercept and Methotrexate in Rheumatoid Arthritis Subjects
NCT00259610	PHASE4	COMPLETED	Treatment of Early Aggressive Rheumatoid Arthritis (TEAR)
NCT00291915	PHASE4	UNKNOWN	Multicenter Randomized Prospective Trial Comparing Methotrexate Alone or in Combination With Adalimumab in Early Arthritis
NCT00319917	PHASE4	COMPLETED	A Double Blind Placebo Controlled Study to Assess the Efficacy on Joint Damage in RA Patients
NCT00334620	PHASE4	COMPLETED	Effectiveness of Radon Spa Therapy in Multimodal Rehabilitative Treatment of Rheumatoid Arthritis
NCT00346294	PHASE4	COMPLETED	An Open-Label Study to Assess the Rate of Failure of an Enbrel® (Etanercept) SureClick™ Auto-injector in Subjects With Rheumatoid Arthritis
NCT00356473	PHASE4	COMPLETED	Effects of Atorvastatin on Disease Activity and HDL Cholesterol Function in Patients With Rheumatoid Arthritis
NCT00369187	PHASE4	COMPLETED	Study of a Large Protein Molecule Administered With Escalating Doses of Recombinant Human Hyaluronidase
NCT00385528	PHASE4	COMPLETED	Effects of a Multi-Faceted Psychiatric Intervention Targeted at the Complex Medically Ill: a Randomized Controlled Trial
NCT00396747	PHASE4	COMPLETED	A Comparison of Methotrexate Alone or Combined to Infliximab or to Pulse Methylprednisolone in Early Rheumatoid Arthritis: A Magnetic Resonance Imaging Study
NCT00420927	PHASE4	COMPLETED	Study of the Optimal Protocol for Methotrexate and Adalimumab Combination Therapy in Early Rheumatoid Arthritis
NCT00422227	PHASE4	COMPLETED	Study Comparing Etanercept With Usual DMARD Therapy in Subjects With Rheumatoid Arthritis in the Asia Pacific Region
NCT00424502	PHASE4	COMPLETED	A Study of MabThera (Rituximab) in Patients With Rheumatoid Arthritis Who Have Had an Inadequate Response to a TNF-Blocker.
NCT00434200	PHASE4	UNKNOWN	Rheumatoid Arthritis Patients in Training
NCT00439062	PHASE4	COMPLETED	Treatment of Rheumatoid Arthritis With Roxithromycin
NCT00447759	PHASE4	COMPLETED	The Standard Care Versus Celecoxib Outcome Trial
NCT00462072	PHASE4	COMPLETED	Centocor Microarray Study of Patients
NCT00462345	PHASE4	COMPLETED	A Study of MabThera (Rituximab) in Combination With Methotrexate in Patients With Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-TNF Therapies.
NCT00480272	PHASE4	COMPLETED	Prospective Study on Intensive Early Rheumatoid Arthritis Treatment
NCT00502853	PHASE4	COMPLETED	A Pilot Study of MabThera (Rituximab) Evaluated by MRI in Patients With Rheumatoid Arthritis.