SLC39A4

Summary

SLC39A4 (solute carrier family 39 member 4, HGNC:17129) is a protein-coding gene on chromosome 8q24.3, encoding Zinc transporter ZIP4 (Q6P5W5). Selective transporter that mediates the uptake of Zn(2+).

This gene encodes a member of the zinc/iron-regulated transporter-like protein (ZIP) family. The encoded protein localizes to cell membranes and is required for zinc uptake in the intestine. Mutations in this gene result in acrodermatitis enteropathica. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 55630 — RefSeq curated summary.

At a glance

• Gene–disease (curated): acrodermatitis enteropathica (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 1,089 total — 68 pathogenic, 63 likely-pathogenic
• Phenotypes (HPO): 52
• MANE Select transcript: NM_130849

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17129
Approved symbol	SLC39A4
Name	solute carrier family 39 member 4
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	ZIP4, ZIP-4, AWMS2
Ensembl gene	ENSG00000147804
Ensembl biotype	protein_coding
OMIM	607059
Entrez	55630

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding_CDS_not_defined, 3 protein_coding, 1 retained_intron

ENST00000276833, ENST00000301305, ENST00000526658, ENST00000527148, ENST00000529462, ENST00000530807, ENST00000531013, ENST00000531789, ENST00000532718

RefSeq mRNA: 4 — MANE Select: NM_130849 NM_001280557, NM_001374839, NM_017767, NM_130849

CCDS: CCDS43782, CCDS6424

Canonical transcript exons

ENST00000301305 — 12 exons

Exon	Start	End
ENSE00001055591	144415227	144415419
ENSE00001278550	144414725	144414896
ENSE00001278584	144416598	144416844
ENSE00001300286	144415810	144416091
ENSE00001317741	144414262	144414434
ENSE00001324645	144414974	144415110
ENSE00001325297	144413958	144414095
ENSE00003521533	144413513	144413567
ENSE00003576961	144413750	144413881
ENSE00003644704	144413237	144413389
ENSE00003656783	144412759	144412946
ENSE00003903394	144412414	144412666

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.8645 / max 486.5990, expressed in 1747 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95669	40.4867	1704
95668	0.6094	312
95677	0.4933	89
95679	0.1582	55
95674	0.0485	13
95676	0.0295	17
95678	0.0280	14
95675	0.0108	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
duodenum	UBERON:0002114	98.58	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.04	gold quality
small intestine	UBERON:0002108	95.66	gold quality
mucosa of transverse colon	UBERON:0004991	95.63	gold quality
transverse colon	UBERON:0001157	93.97	gold quality
adult mammalian kidney	UBERON:0000082	93.96	gold quality
lower esophagus mucosa	UBERON:0035834	93.29	gold quality
cortex of kidney	UBERON:0001225	92.48	gold quality
body of stomach	UBERON:0001161	90.76	gold quality
intestine	UBERON:0000160	90.73	gold quality
metanephros cortex	UBERON:0010533	90.68	gold quality
kidney	UBERON:0002113	90.01	gold quality
colon	UBERON:0001155	89.62	gold quality
left lobe of thyroid gland	UBERON:0001120	89.30	gold quality
thyroid gland	UBERON:0002046	88.68	gold quality
fundus of stomach	UBERON:0001160	88.65	gold quality
right ovary	UBERON:0002118	88.24	gold quality
right lobe of thyroid gland	UBERON:0001119	88.15	gold quality
skin of abdomen	UBERON:0001416	87.87	gold quality
esophagus mucosa	UBERON:0002469	87.61	gold quality
stomach	UBERON:0000945	87.54	gold quality
left ovary	UBERON:0002119	87.43	gold quality
zone of skin	UBERON:0000014	86.97	gold quality
ovary	UBERON:0000992	86.90	gold quality
skin of leg	UBERON:0001511	86.74	gold quality
upper lobe of left lung	UBERON:0008952	86.58	gold quality
body of pancreas	UBERON:0001150	86.47	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.31	gold quality
granulocyte	CL:0000094	85.61	gold quality
right lung	UBERON:0002167	85.50	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	1882.94
E-ANND-3	yes	9.05

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF4A, KLF4

miRNA regulators (miRDB)

24 targeting SLC39A4, 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-4713-3P	100.00	65.92	505
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-4464	98.95	67.73	820
HSA-MIR-4748	98.95	67.53	810
HSA-MIR-1294	98.91	69.26	1030
HSA-MIR-9986	98.91	69.28	1024
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-5087	98.01	69.09	965
HSA-MIR-4675	97.69	64.82	774
HSA-MIR-4741	97.69	64.14	883
HSA-MIR-450B-3P	97.56	66.12	512
HSA-MIR-3620-5P	97.42	63.95	792
HSA-MIR-769-3P	97.06	64.83	464
HSA-MIR-1587	96.95	64.03	932
HSA-MIR-6085	96.57	64.11	621
HSA-MIR-4654	95.86	65.72	751
HSA-MIR-4769-5P	95.37	66.09	570
HSA-MIR-6813-5P	94.68	64.20	588
HSA-MIR-638	83.93	64.46	66

Literature-anchored findings (GeneRIF, showing 40)

• A novel member of a zinc transporter family, hZIP4, is defective in acrodermatitis enteropathica. (PMID:12032886)
• SLC39A4 is centrally involved in the pathogenesis of acrodermatitis enteropathica. (PMID:12068297)
• Three novel mutations, 1017ins53, which creates premature termination codon, and two mis-sense mutations, R95C and Q303H. (PMID:12787121)
• temporal and spatial patterns of expression of the mouse ZIP1, 3, 4, and 5 genes in the developing intestine and the effects of maternal dietary zinc deficiency on these patterns of expression were examined (PMID:16682017)
• Zinc can regulate the mRNA expression of ZIP4 in Caco2 cells. (PMID:16986515)
• ubiquitin-mediated degradation of the ZIP4 protein is critical for regulating zinc homeostasis in response to the upper tier of physiological zinc concentrations. (PMID:17202136)
• therapeutic strategy whereby ZIP4 is targeted to control pancreatic cancer growth (PMID:18003899)
• Acrodermatitis enteropathica is a rare autosomal recessive disorder caused by mutations in SLC39A4, which encodes the tissue-specific zinc transporter ZIP4. (PMID:18328205)
• the clinical manifestations in three acrodermatitis enteropathica patients with a novel mutation (PMID:19416242)
• results suggest that exon 9 in the SLC39A4 gene encompassing c.1438G should be screened first in the molecular diagnosis of Japanese patients with Acrodermatitis Enteropathic. (PMID:19416256)
• Knocking down ZIP4 by short hairpin RNA might be a novel treatment strategy for pancreatic cancers with ZIP4 overexpression. (PMID:19755388)
• Overexpression of ZIP4 caused significantly increased expression of NRP-1, VEGF, MMP-2 and MMP-9 and is associated with angiogenesis, invasion and metastasis pathways in pancreatic cancer. (PMID:20023433)
• ZIP4 overexpression causes increased IL-6 transcription through CREB, which in turn activates STAT3 and leads to increased cyclin D1 expression (PMID:20160059)
• GSPE and EGCG enhance the expression of cellular zinc importers ZIP4 (SLC39A4). (PMID:20471814)
• Cell migration assays revealed that RNAi knockdown of Zip4 in Hepa cells depressed in vitro migration whereas forced over-expression in Hepa cells and MCF-7 cells enhanced in vitro migration (PMID:20957146)
• The transporter ZIP4 is expressed along the entire gastrointestinal tract and acts as a major processor of dietary zinc (PMID:21462106)
• Expression of two Zn(2+) influx transporters, ZIP2 and ZIP4, is reduced as a function of retinal pigment epithelium age. (PMID:21603979)
• The results suggest that ZIP4 may be a tumor suppressor gene and down-regulation of ZIP4 may be a critical early event in the development of prostate carcinoma (PMID:21803616)
• Zinc, copper(II), and nickel can be transported by human ZIP4 when the cation concentration is in the micromolar range; nickel can bind to but is not transported by human ZIP4. (PMID:22242765)
• resulkts indicate ZIP4 is the only zinc transporter that is significantly up-regulated in pancreatic cancer and might be the major zinc transporter that plays an important role in pancreatic cancer growth (PMID:23331012)
• High ZIP4 expression is associated with glioma. (PMID:23595627)
• ZIP4 activates the zinc-dependent transcription factor CREB and requires this transcription factor to increase miR-373 expression through the regulation of its promoter. (PMID:23857777)
• The results described a previously uncharacterized role of ZIP4 in apoptosis resistance and elucidated a novel pathway through which ZIP4 regulates pancreatic cancer growth. (PMID:24553114)
• Both acrodermatitis mutations cause absence of the ZIP4 transporter cell surface expression and nearly absent zinc uptake. (PMID:24586184)
• SLC39A4 mutations have roles in zinc deficiency (PMID:25391167)
• Studied the zinc binding properties of the large intracellular loop of hZIP4. (PMID:25882556)
• In glioma tumors, high ZIP4 expression was significantly associated with higher grade. (PMID:25921144)
• Developed is a structural model of ZIP4 by combining protein prediction methods with in situ experiments. Insight into the permeation pathway of ZIP4 is provided. (PMID:25971965)
• Data sho that silencing of zinc transporter ZIP4 resulted in increased bone tissue mineral density, and restoration of bone strength. (PMID:26305676)
• Case Report: heterozygote mutation in SLC39A4 resulting in acrodermatitis enteropathica. (PMID:26351177)
• Structural insights of ZIP4 extracellular domain critical for optimal zinc transport have been uncovered. (PMID:27321477)
• ZIP4 regulates human epidermal homeostasis in patients with acrodermatitis enteropathica. (PMID:27940220)
• ZIP4 and intracellular zinc have essential roles in tumoral growth in oral squamous cell carcinoma (PMID:28017725)
• The authors present the first report of SLC39A4 mutation in an acrodermatitis enteropathica family from the Middle East. (PMID:28188634)
• Results showed decreased expression of Zn uptake transporters ZIP2 and ZIP4 on mRNA and protein level correlating with SHANK3 expression levels, and found reduced levels of ZIP4 protein co-localizing with SHANK3 at the plasma membrane. ZIP4 exists in a complex with SHANK3. Further results confirmed a link between enterocytic SHANK3, ZIP2 and ZIP4. (PMID:28345660)
• SLC39A4 is overexpressed in NSCLC and correlates with increased staging and diminished patient survival. Moreover, silencing of SLC39A4 induced an epithelial-like phenotype, decreased cancer stem cell marker expression, and increased cisplatin sensitivity. (PMID:28775359)
• These findings suggest a novel pathway activated by ZIP4-controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease. (PMID:29615456)
• Expression of zinc transporters ZIP4, ZIP14 and ZnT9 in hepatic carcinogenesis-An immunohistochemical study (PMID:29895370)
• exosomal ZIP4 promotes cancer growth and is a novel diagnostic biomarker for pancreatic cancer. (PMID:30007115)
• Results demonstrate that the hZIP4 ICL2 domain is conformationally heterogeneous in the apo- and metal-bound states. No signi fi cant structural differences between the apo- and zinc-bound protein forms were discernable. The histidine-rich region in the apoprotein makes transient tertiary contacts with predicted post-translational modification sites. (PMID:30793391)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc39a4	ENSDARG00000059361
mus_musculus	Slc39a4	ENSMUSG00000063354
rattus_norvegicus	Slc39a4	ENSRNOG00000014314
drosophila_melanogaster	foi	FBGN0024236
caenorhabditis_elegans		WBGENE00021936

Paralogs (6): SLC39A14 (ENSG00000104635), SLC39A8 (ENSG00000138821), SLC39A5 (ENSG00000139540), SLC39A6 (ENSG00000141424), SLC39A12 (ENSG00000148482), SLC39A10 (ENSG00000196950)

Protein

Protein identifiers

Zinc transporter ZIP4 — Q6P5W5 (reviewed: Q6P5W5)

Alternative names: Solute carrier family 39 member 4, Zrt- and Irt-like protein 4

All UniProt accessions (2): Q6P5W5, E9PQ16

UniProt curated annotations — full annotation on UniProt →

Function. Selective transporter that mediates the uptake of Zn(2+). Plays an essential role for dietary zinc uptake from small intestine. The Zn(2+) uniporter activity is regulated by zinc availability. Also exhibits polyspecific binding and transport of Cu(2+), Cd(2+) and possibly Ni(2+) but at higher concentrations.

Subunit / interactions. Homodimer; homodimerization is mediated by the transmembrane domain.

Subcellular location. Cell membrane. Recycling endosome membrane. Apical cell membrane.

Tissue specificity. Highly expressed in kidney, small intestine, stomach, colon, jejunum and duodenum.

Post-translational modifications. The extracellular N-terminal ectodomain is cleaved when cells are Zn(2+) deficient, N-terminally cleaved SLC39A4 is internalized at a faster rate. Under excess Zn(2+) conditions, SLC39A4 on the cell surface is rapidly endocytosed, ubiquitinated and degraded. Glycosylated.

Disease relevance. Acrodermatitis enteropathica, zinc-deficiency type (AEZ) [MIM:201100] A rare autosomal recessive disease caused by the inability to absorb sufficient zinc. The clinical features are growth retardation, immune-system dysfunction, alopecia, severe dermatitis, diarrhea and occasionally mental disorders. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The Zn(2+) uniporter activity is regulated by zinc availability. Extracellular acidification stimulated SLC39A4-dependent Zn(2+) uptake.

Domain organisation. The N-terminal extracellular domain is required for high efficient zinc transport. The two metal binding sites M1 and M2 that are halfway through the membrane form a binuclear metal center. M1 is essential to Zn(2+) transport, while the other, M2 appears to have an auxiliary role presumably by acting as an additional transport site that can modulate the properties of the primary transport site. The binuclear metal center plays a key role in Zn(2+) sensing.

Similarity. Belongs to the ZIP transporter (TC 2.A.5) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6P5W5-1	1	yes
Q6P5W5-2	2

RefSeq proteins (3): NP_001361768, NP_060237, NP_570901* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003689	ZIP	Family
IPR041137	ZIP4_N	Domain
IPR049406	ZIP4_12_EF-hand	Domain
IPR050799	ZIP_Transporter	Family

Pfam: PF02535, PF18292, PF21116

Catalyzed reactions (Rhea), 1 shown:

• Zn(2+)(in) = Zn(2+)(out) (RHEA:29351)

UniProt features (94 total): mutagenesis site 36, sequence variant 20, topological domain 9, transmembrane region 8, binding site 7, disulfide bond 4, region of interest 2, splice variant 2, signal peptide 1, chain 1, short sequence motif 1, compositionally biased region 1, site 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6P5W5-F1	75.05	0.28

Functional residue map

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

Catalytic / active sites (1): 511 (essential role in zn(2+) sensing)

Ligand- & substrate-binding residues (7): 507 (m1 metal binding site); 508 (m2 metal binding site); 511 (m1 metal binding site); 511 (m2 metal binding site); 536 (m1 metal binding site); 537 (m2 metal binding site); 540 (m1 metal binding site)

Disulfide bonds (4): 57–62, 65–111, 160–195, 270–309

Glycosylation sites (1): 261

Mutagenesis-validated functional residues (36):

Position	Phenotype
62	decreases location at cell membrane. retained in the er. loss of zinc transport activity.
99	loss of zinc transport activity.
202	does not affect location at cell membrane. does not affect zinc transport activity.
238	decreases zinc transport activity; when associated with s-241; s-243; s-245. decreases vmax for zn(2+) by 20% but does n
241	decreases zinc transport activity; when associated with s-238; s-243 and s-245. decreases vmax for zn(2+) by 20% does no
243	decreases zinc transport activity; when associated with s-238; s-241 and s-245. decreases vmax for zn(2+) by 20% does no
245	decreases zinc transport activity; when associated with s-238; s-241 and s-243. decreases vmax for zn(2+) by 20% but doe
261	decreases location at cell membrane; retained in the er.
266	no glycosylated. very low cell surface expression. decreases zinc uptake activity.
275	decreases zinc uptake activity.
303	reduces glycosylation level. reduces cell surface expression. decreases zinc uptake activity.
375	reduces zinc transport activity; when associated with a-379.
379	reduces zinc transport activity; when associated with a-375.
388	does not affect zinc sensing.
390	does not affect zinc sensing.
452–454	abrogates endocytosis of the a-511 mutant which undergoes zinc-independent endocytosis.
452	abrogates endocytosis.
453	reduces endocytosis.
454	abrogates endocytosis.
463	no effect on slc39a4 endocytosis. no effect on slc39a4 endocytosis; when associated with r-611.
481	no effect on slc39a4 endocytosis. no effect on slc39a4 endocytosis; when associated with a-482.
482	no effect on slc39a4 endocytosis. no effect on slc39a4 endocytosis; when associated with a-481.
507	moderately reduces zinc transport activity. completely abrogated zinc transport activity; when associated with a-536 and
507	abolishes zinc transport activity.
508	moderately reduces zinc transport activity. reduced zinc transmembrane transporter activity; when associated with a-537.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-442380	Zinc influx into cells by the SLC39 gene family
R-HSA-5619088	Defective SLC39A4 causes acrodermatitis enteropathica, zinc-deficiency type (AEZ)
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-425366
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-425410	Metal ion SLC transporters
R-HSA-435354	Zinc transporters
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters

MSigDB gene sets: 319 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_TRANSITION_METAL_ION_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GGGTGGRR_PAX4_03, GOBP_MONOATOMIC_CATION_TRANSPORT, GOLDRATH_ANTIGEN_RESPONSE, ONKEN_UVEAL_MELANOMA_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM2, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_BICARBONATE_TRANSPORT, LIAO_METASTASIS

GO Biological Process (10): intracellular zinc ion homeostasis (GO:0006882), intracellular monoatomic cation homeostasis (GO:0030003), cellular response to zinc ion starvation (GO:0034224), zinc ion transmembrane transport (GO:0071577), zinc ion import across plasma membrane (GO:0071578), monoatomic ion transport (GO:0006811), zinc ion transport (GO:0006829), bicarbonate transport (GO:0015701), metal ion transport (GO:0030001), transmembrane transport (GO:0055085)

GO Molecular Function (8): zinc ion transmembrane transporter activity (GO:0005385), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), metal ion binding (GO:0046872), zinc ion sensor activity (GO:0106219), monoatomic cation:bicarbonate symporter activity (GO:0140410), zinc ion sequestering activity (GO:0140486), metal ion transmembrane transporter activity (GO:0046873)

GO Cellular Component (6): plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), cytoplasmic vesicle (GO:0031410), recycling endosome membrane (GO:0055038), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Zinc transporters	1
SLC transporter disorders	1
Transport of small molecules	1
SLC-mediated transmembrane transport	1
Metal ion SLC transporters	1
Disorders of transmembrane transporters	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	3
zinc ion transmembrane transport	2
zinc ion binding	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
intracellular monoatomic ion homeostasis	1
monoatomic cation homeostasis	1
cellular response to starvation	1
response to zinc ion starvation	1
zinc ion transport	1
monoatomic cation transmembrane transport	1
inorganic cation import across plasma membrane	1
transition metal ion transport	1
monoatomic cation transport	1
cellular process	1
transition metal ion transmembrane transporter activity	1
transition metal ion binding	1
protein binding	1
cation binding	1
metal ion sensor activity	1
bicarbonate transmembrane transporter activity	1
solute:monoatomic cation symporter activity	1
metal ion sequestering activity	1
monoatomic cation transmembrane transporter activity	1
metal ion transport	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
cytoplasm	1
intracellular vesicle	1
endosome membrane	1
recycling endosome	1
endomembrane system	1
cytoplasmic vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

898 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC39A4	SLC30A4	O14863	957
SLC39A4	SLC39A1	Q9NY26	744
SLC39A4	SLC30A2	Q9BRI3	742
SLC39A4	SLC39A3	Q9BRY0	716
SLC39A4	SLC39A9	Q9NUM3	715
SLC39A4	SLC30A1	Q9Y6M5	708
SLC39A4	SLC39A2	Q9NP94	706
SLC39A4	SLC39A11	Q8N1S5	699
SLC39A4	SLC30A6	Q6NXT4	656
SLC39A4	SLC30A5	Q8TAD4	635
SLC39A4	SLC30A9	Q6PML9	560
SLC39A4	SLC30A7	Q8NEW0	543
SLC39A4	SLC30A10	Q6XR72	531
SLC39A4	SLC30A3	Q99726	496
SLC39A4	ADCK5	Q3MIX3	460

IntAct

23 interactions, top by confidence:

A	B	Type	Score
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
GPR17	IPO8	psi-mi:“MI:0914”(association)	0.530
SLC39A4	ADRB2	psi-mi:“MI:0915”(physical association)	0.370
C5AR1	SLC12A8	psi-mi:“MI:0914”(association)	0.350
FFAR1	SLC12A8	psi-mi:“MI:0914”(association)	0.350
COMTD1	TARS3	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
GPR45	VWA8	psi-mi:“MI:0914”(association)	0.350
SPPL2B	HAS3	psi-mi:“MI:0914”(association)	0.350
FZD7	EI24	psi-mi:“MI:0914”(association)	0.350
LPAR2	EI24	psi-mi:“MI:0914”(association)	0.350
VIPR2	EI24	psi-mi:“MI:0914”(association)	0.350
GPR173	CDIPT	psi-mi:“MI:0914”(association)	0.350
S1PR1	TNPO2	psi-mi:“MI:0914”(association)	0.350
P2RY2	SCAMP3	psi-mi:“MI:0914”(association)	0.350
P2RY8	BTAF1	psi-mi:“MI:0914”(association)	0.350
S1PR4	NPC1	psi-mi:“MI:0914”(association)	0.350
SLC39A4	GPR39	psi-mi:“MI:0914”(association)	0.350
SLC39A4	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (461): DHRS13 (Affinity Capture-MS), SLC46A1 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), METTL9 (Affinity Capture-MS), SCCPDH (Affinity Capture-MS), GOLIM4 (Affinity Capture-MS), ALG8 (Affinity Capture-MS), ATP13A2 (Affinity Capture-MS), TMEM192 (Affinity Capture-MS), HADHB (Affinity Capture-MS), SREBF2 (Affinity Capture-MS), FAR2 (Affinity Capture-MS), MGAT1 (Affinity Capture-MS), C1orf43 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2KQY6, A0A6I8PMZ8, A0JPN2, A2RU67, A4IGY6, A5D7L5, D3ZWJ9, L5KLU7, O08644, O08721, O08722, O15197, P0C0K7, P0DX17, Q08E40, Q15043, Q1KZG0, Q4V887, Q504Y0, Q58Y75, Q5FVQ0, Q5FWH7, Q5M936, Q5RAB7, Q640M6, Q642A7, Q6L8F3, Q6P5W5, Q6PEH9, Q6ZN44, Q75N73, Q76MJ5, Q78IQ7, Q7TNJ2, Q8BYI8, Q8C0Z1, Q8IZJ1, Q8IZY2, Q8K1S4, Q8WTR4

Diamond homologs: A0A0G2KQY6, A0A6I8PMZ8, A0JPN2, A4IGY6, A5D7H1, A5D7L5, A8X482, L5KLU7, Q08E40, Q15043, Q1KZG0, Q29175, Q2M1K6, Q4V887, Q504Y0, Q55FL1, Q5FWH7, Q5R6I6, Q5RAB7, Q6L8F3, Q6P5F6, Q6P5W5, Q6PEH9, Q75N73, Q78IQ7, Q8BZH0, Q95KA5, Q96H72, Q9M647, Q9ULF5, Q9V3A4, Q9VSL7, Q9XTQ7, P0DX17, Q31125, Q5FVQ0, Q5RFD5, Q5TJF6, Q6MGB4, Q6ZMH5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Class A/1 (Rhodopsin-like receptors)	6	22.2×	1e-05
GPCR ligand binding	5	16.0×	3e-04
G alpha (q) signalling events	5	14.3×	3e-04
Signaling by GPCR	5	10.0×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
G protein-coupled receptor signaling pathway	9	10.2×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

1089 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	68
Likely pathogenic	63
Uncertain significance	213
Likely benign	632
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068496	NM_130849.4(SLC39A4):c.1308C>A (p.Cys436Ter)	Pathogenic
1069887	NM_130849.4(SLC39A4):c.1203G>A (p.Trp401Ter)	Pathogenic
1070005	NM_130849.4(SLC39A4):c.674C>A (p.Ser225Ter)	Pathogenic
1076820	NM_130849.4(SLC39A4):c.853C>T (p.Gln285Ter)	Pathogenic
1373036	NM_130849.4(SLC39A4):c.646G>T (p.Glu216Ter)	Pathogenic
1377966	NM_130849.4(SLC39A4):c.534_546del (p.Ala179fs)	Pathogenic
1383544	NM_130849.4(SLC39A4):c.155_156dup (p.Asp53fs)	Pathogenic
1386590	NM_130849.4(SLC39A4):c.1202G>A (p.Trp401Ter)	Pathogenic
1392271	NM_130849.4(SLC39A4):c.908dup (p.Gln304fs)	Pathogenic
1393732	NM_130849.4(SLC39A4):c.948del (p.Val317fs)	Pathogenic
1406250	NM_130849.4(SLC39A4):c.88del (p.Ser30fs)	Pathogenic
1407218	NM_130849.4(SLC39A4):c.254dup (p.Val87fs)	Pathogenic
1407940	NM_130849.4(SLC39A4):c.1396del (p.His466fs)	Pathogenic
1412167	NM_130849.4(SLC39A4):c.1132del (p.Leu378fs)	Pathogenic
1423556	NM_130849.4(SLC39A4):c.413del (p.Pro138fs)	Pathogenic
1448897	NM_130849.4(SLC39A4):c.1357C>T (p.Gln453Ter)	Pathogenic
1451263	NM_130849.4(SLC39A4):c.309C>A (p.Tyr103Ter)	Pathogenic
1452203	NM_130849.4(SLC39A4):c.1462_1474+1del	Pathogenic
1458442	NM_130849.4(SLC39A4):c.983_992del (p.Leu328fs)	Pathogenic
1989349	NM_130849.4(SLC39A4):c.867_886del (p.Pro290fs)	Pathogenic
2013185	NM_130849.4(SLC39A4):c.1464dup (p.Leu489fs)	Pathogenic
2018854	NM_130849.4(SLC39A4):c.796_797dup (p.Trp266fs)	Pathogenic
2029541	NM_130849.4(SLC39A4):c.106dup (p.Gln36fs)	Pathogenic
2118724	NM_130849.4(SLC39A4):c.1397dup (p.His466fs)	Pathogenic
2120845	NM_130849.4(SLC39A4):c.1248_1249insA (p.Glu417fs)	Pathogenic
2141319	NM_130849.4(SLC39A4):c.1224del (p.Leu410fs)	Pathogenic
2229680	NM_130849.4(SLC39A4):c.1023_1475-7del	Pathogenic
2427204	NC_000008.10:g.(?145639206)(145643123_?)del	Pathogenic
2427205	NC_000008.10:g.(?145637954)(145644386_?)del	Pathogenic
2709237	NM_130849.4(SLC39A4):c.1334del (p.Gly445fs)	Pathogenic

SpliceAI

1647 predictions. Top by Δscore:

Variant	Effect	Δscore
8:144412743:C:A	donor_gain	1.0000
8:144412752:T:TA	donor_gain	1.0000
8:144412779:A:AC	donor_gain	1.0000
8:144412823:T:A	donor_gain	1.0000
8:144412942:GTCCC:G	acceptor_gain	1.0000
8:144412943:TCCC:T	acceptor_gain	1.0000
8:144412944:CCC:C	acceptor_gain	1.0000
8:144412944:CCCC:C	acceptor_gain	1.0000
8:144412945:CC:C	acceptor_gain	1.0000
8:144412945:CCC:C	acceptor_gain	1.0000
8:144412946:CC:C	acceptor_gain	1.0000
8:144412947:C:CC	acceptor_gain	1.0000
8:144412947:CTGC:C	acceptor_loss	1.0000
8:144413232:CTCA:C	donor_loss	1.0000
8:144413233:TCAC:T	donor_loss	1.0000
8:144413234:CACC:C	donor_loss	1.0000
8:144413235:A:AC	donor_gain	1.0000
8:144413235:AC:A	donor_gain	1.0000
8:144413235:ACCC:A	donor_loss	1.0000
8:144413236:C:CC	donor_gain	1.0000
8:144413236:C:G	donor_loss	1.0000
8:144413236:CC:C	donor_gain	1.0000
8:144413236:CCCAG:C	donor_gain	1.0000
8:144413240:G:C	donor_gain	1.0000
8:144413358:C:CT	acceptor_gain	1.0000
8:144413358:C:T	acceptor_gain	1.0000
8:144413385:CAACT:C	acceptor_gain	1.0000
8:144413388:CT:C	acceptor_gain	1.0000
8:144413390:C:CC	acceptor_gain	1.0000
8:144413508:CTCA:C	donor_loss	1.0000

AlphaMissense

4127 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:144414810:G:C	S297R	0.988
8:144414810:G:T	S297R	0.988
8:144414812:T:G	S297R	0.988
8:144413307:G:C	F519L	0.985
8:144413307:G:T	F519L	0.985
8:144413309:A:G	F519L	0.985
8:144414892:C:G	C270S	0.980
8:144414893:A:T	C270S	0.980
8:144414313:G:C	S366R	0.979
8:144414313:G:T	S366R	0.979
8:144414315:T:G	S366R	0.979
8:144414824:A:G	W293R	0.979
8:144414824:A:T	W293R	0.979
8:144412588:A:G	W632R	0.976
8:144412588:A:T	W632R	0.976
8:144415279:G:C	F205L	0.975
8:144415279:G:T	F205L	0.975
8:144415281:A:G	F205L	0.975
8:144412783:G:C	F597L	0.974
8:144412783:G:T	F597L	0.974
8:144412785:A:G	F597L	0.974
8:144415107:A:G	L224P	0.972
8:144413330:C:A	G512W	0.968
8:144414893:A:G	C270R	0.966
8:144415993:A:C	S97R	0.966
8:144415993:A:T	S97R	0.966
8:144415995:T:G	S97R	0.966
8:144415280:A:C	F205C	0.965
8:144415264:G:C	F210L	0.964
8:144415264:G:T	F210L	0.964

dbSNP variants (sampled 300 via entrez): RS1000446530 (8:144417027 C>G,T), RS1001699456 (8:144418029 G>A), RS1001881338 (8:144414127 G>A,T), RS1002171564 (8:144417777 G>A), RS1002550857 (8:144415727 G>A,C), RS1002604581 (8:144415542 G>A), RS1004230257 (8:144416538 G>C), RS1005903753 (8:144417488 G>A,T), RS1005955553 (8:144417318 C>T), RS1006592881 (8:144413631 G>A,C), RS1007578305 (8:144418445 C>G), RS1007832704 (8:144414530 G>A,C), RS1008508319 (8:144416041 C>G), RS1009045935 (8:144412325 G>A), RS1010184171 (8:144417051 C>T)

Disease associations

OMIM: gene MIM:607059 | disease phenotypes: MIM:201100

GenCC curated gene-disease

Disease	Classification	Inheritance
acrodermatitis enteropathica	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
acrodermatitis enteropathica	Definitive	AR

Mondo (1): acrodermatitis enteropathica (MONDO:0008713)

Orphanet (1): Acrodermatitis enteropathica (Orphanet:37)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000135	Hypogonadism
HP:0000157	Abnormality of the tongue
HP:0000206	Glossitis
HP:0000221	Furrowed tongue
HP:0000224	Hypogeusia
HP:0000492	Abnormal eyelid morphology
HP:0000498	Blepharitis
HP:0000505	Visual impairment
HP:0000509	Conjunctivitis
HP:0000534	Abnormal eyebrow morphology
HP:0000613	Photophobia
HP:0000712	Emotional lability
HP:0000737	Irritability
HP:0000958	Dry skin
HP:0001251	Ataxia
HP:0001254	Lethargy
HP:0001337	Tremor
HP:0001508	Failure to thrive
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001744	Splenomegaly
HP:0001807	Ridged nail
HP:0001818	Paronychia
HP:0001824	Weight loss
HP:0002014	Diarrhea
HP:0002024	Malabsorption
HP:0002028	Chronic diarrhea
HP:0002039	Anorexia
HP:0002120	Cerebral cortical atrophy

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008163_8	Height	4.000000e-06
GCST90013406_88	Liver enzyme levels (alkaline phosphatase)	6.000000e-70

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538178	Acrodermatitis enteropathica (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC39 family of metal ion transporters

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Zinc	affects expression, decreases expression, increases ubiquitination, decreases reaction, increases degradation (+2 more)	4
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	increases methylation, affects methylation, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Cyclosporine	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
bisphenol A	affects expression	1
deoxynivalenol	decreases expression	1
potassium perchlorate	decreases expression	1
beta-lapachone	increases expression	1
zinc chloride	decreases reaction, increases expression, decreases expression	1
cobaltous chloride	decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
epigallocatechin gallate	increases expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases degradation	1
methyl-beta-cyclodextrin	decreases reaction, increases degradation	1
Grape Seed Proanthocyanidins	increases expression, decreases reaction	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
licochalcone B	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Ammonium Chloride	decreases reaction, increases degradation	1
Arsenic	affects methylation	1
Calcitriol	decreases expression	1
Cisplatin	increases expression	1
Coumestrol	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	affects expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4NK	HCT116-SLC39A4-KO-c16	Cancer cell line	Male
CVCL_D4NL	HCT116-SLC39A4-KO-c5	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02870166	Not specified	COMPLETED	Genetic Study of Severe Zinc Deficiencies
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns