SLC39A4 (solute carrier family 39 member 4)

Gene

• Entrez ID: 55630
• Gene name: Solute carrier family 39 member 4
• Gene symbol: SLC39A4
• Synonyms (NCBI Gene): AEZ, AWMS2, ZIP4
• Chromosome: 8
• Chromosome location: 8q24.3
• Summary: 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. M

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs121434287	G>A	Pathogenic	Upstream transcript variant, genic upstream transcript variant, coding sequence variant, missense variant
rs121434288	C>T	Pathogenic	Intron variant, coding sequence variant, missense variant
rs121434289	C>T	Pathogenic	Upstream transcript variant, genic upstream transcript variant, coding sequence variant, missense variant
rs121434290	G>T	Pathogenic	Coding sequence variant, genic upstream transcript variant, intron variant, missense variant
rs121434291	C>T	Pathogenic	Upstream transcript variant, genic upstream transcript variant, coding sequence variant, missense variant
rs121434292	G>A,T	Pathogenic	Coding sequence variant, genic upstream transcript variant, intron variant, missense variant
rs121434293	C>G	Pathogenic	Upstream transcript variant, genic upstream transcript variant, coding sequence variant, missense variant
rs182506368	C>A,T	Likely-pathogenic	Coding sequence variant, genic upstream transcript variant, missense variant, intron variant
rs1057523837	G>A	Likely-pathogenic	Upstream transcript variant, genic upstream transcript variant, coding sequence variant, stop gained
rs1586652047	->AGAGGCAGATGAGCAGC	Likely-pathogenic	Frameshift variant, upstream transcript variant, coding sequence variant, genic upstream transcript variant

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0005385	Function	Zinc ion transmembrane transporter activity	IBA
GO:0005385	Function	Zinc ion transmembrane transporter activity	IDA	22242765, 31164399
GO:0005385	Function	Zinc ion transmembrane transporter activity	IEA
GO:0005385	Function	Zinc ion transmembrane transporter activity	TAS
GO:0005768	Component	Endosome	IEA
GO:0005886	Component	Plasma membrane	IBA
GO:0005886	Component	Plasma membrane	IDA	14612438, 30874431, 31164399
GO:0005886	Component	Plasma membrane	IEA
GO:0005886	Component	Plasma membrane	TAS
GO:0006811	Process	Monoatomic ion transport	IEA
GO:0006829	Process	Zinc ion transport	IEA
GO:0006882	Process	Intracellular zinc ion homeostasis	IEA
GO:0006882	Process	Intracellular zinc ion homeostasis	ISS
GO:0008270	Function	Zinc ion binding	IMP	25882556
GO:0015701	Process	Bicarbonate transport	IEA
GO:0016020	Component	Membrane	IEA
GO:0016324	Component	Apical plasma membrane	IEA
GO:0016324	Component	Apical plasma membrane	ISS
GO:0030001	Process	Metal ion transport	IEA
GO:0030003	Process	Intracellular monoatomic cation homeostasis	IBA
GO:0031410	Component	Cytoplasmic vesicle	IDA	14612438
GO:0034224	Process	Cellular response to zinc ion starvation	IEA
GO:0042802	Function	Identical protein binding	IDA	30874431
GO:0042802	Function	Identical protein binding	IEA
GO:0046872	Function	Metal ion binding	EXP	30793391
GO:0046872	Function	Metal ion binding	IEA
GO:0046873	Function	Metal ion transmembrane transporter activity	IEA
GO:0055038	Component	Recycling endosome membrane	IDA	14612438
GO:0055038	Component	Recycling endosome membrane	IEA
GO:0055085	Process	Transmembrane transport	IEA
GO:0071577	Process	Zinc ion transmembrane transport	IDA	31164399
GO:0071577	Process	Zinc ion transmembrane transport	TAS
GO:0071578	Process	Zinc ion import across plasma membrane	IBA
GO:0106219	Function	Zinc ion sensor activity	IMP	32348750
GO:0140410	Function	Monoatomic cation:bicarbonate symporter activity	IBA
GO:0140486	Function	Zinc ion sequestering activity	EXP	30793391
GO:0140486	Function	Zinc ion sequestering activity	IMP	25882556

Other IDs

• MIM: 607059
• HGNC: 17129
• e!Ensembl: ENSG00000147804

Protein

• UniProt ID: Q6P5W5
• Protein name: Zinc transporter ZIP4 (Solute carrier family 39 member 4) (Zrt- and Irt-like protein 4) (ZIP-4)
• Protein function: Selective transporter that mediates the uptake of Zn(2+) (PubMed:17202136, PubMed:22242765, PubMed:27321477, PubMed:28875161, PubMed:31164399, PubMed:31914589, PubMed:31979155, PubMed:33837739, PubMed:36473915). Plays an essential role for dieta
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF18292	ZIP4_domain	46 → 196	Zinc transporter ZIP4 domain	Domain
  PF02535	Zip	325 → 639	ZIP Zinc transporter	Family

• Tissue specificity: TISSUE SPECIFICITY: Highly expressed in kidney, small intestine, stomach, colon, jejunum and duodenum. {ECO:0000269|PubMed:12032886, ECO:0000269|PubMed:12068297}.
• Sequence:

  MASLVSLELGLLLAVLVVTATASPPAGLLSLLTSGQGALDQEALGGLLNTLADRVHCANG
  PCGKCLSVEDALGLGEPEGSGLPPGPVLEARYVARLSAAAVLYLSNPEGTCEDARAGLWA
  SHADHLLALLESPKALTPGLSWLLQRMQARAAGQTPKMACVDIPQLLEEAVGAGAPGSAG
  GVLAALLDHVRSGSCFHALPSPQYFVDFVFQQHSSEVPMTLAELSALMQRLGVGREAHSD
  HSHRHRGASSRDPVPLISSSNSSSVWDTVCLSARDVMAAYGLSEQAGVTPEAWAQLSPAL
  LQQQLSGACTSQSRPPVQDQLSQSERYLYGSLATLLICLCAVFGLLLLTCTGCRGVTHYI
  LQTFLSLAVGAVTGDAVLHLTPKVLGLHTHSEEGLSPQPTWRLLAMLAGLYAFFLFENLF
  NLLLPRDPEDLEDGPCGHSSHSHGGHSHGVSLQLAPSELRQPKPPHEGSRADLVAEESPE
  LLNPEPRRLSPELRLLPYMITLGDAVHNFADGLAVGAAFASSWKTGLATSLAVFCHELPH
  ELGDFAALLHAGLSVRQALLLNLASALTAFAGLYVALAVGVSEESEAWILAVATGLFLYV
  ALCDMLPAMLKVRDPRPWLLFLLHNVGLLGGWTVLLLLSLYEDDITF

• Sequence length: 647

Pathways

KEGG:

Mineral absorption
Alzheimer disease
Parkinson disease

Reactome:

Zinc influx into cells by the SLC39 gene family
Defective SLC39A4 causes acrodermatitis enteropathica, zinc-deficiency type (AEZ)

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession	Evidence Score
Hereditary acrodermatitis enteropathica	Pathogenic; Likely pathogenic	rs200482978, rs1285049551, rs781852691, rs1554873649, rs368996660, rs1554872740, rs2130799141, rs2130798128, rs2130796648, rs2130798769, rs781908504, rs121434287, rs121434288, rs121434289, rs121434290, rs121434291, rs2130797713, rs121434292, rs121434293, rs782695425, rs1554871810, rs2537435867, rs2537440685, rs1057523837, rs1255730342, rs782563835	RCV001831381 RCV005040265 RCV001780371 RCV002497946 RCV003485754 RCV005631002 RCV002497883 RCV002492239 RCV000003712 RCV000003713 RCV000003714 RCV000003715 RCV000003716 RCV000003717 RCV000003718 RCV000003720 RCV000003721 RCV000003722 RCV000003723 RCV005045209 RCV003134068 RCV003990494 RCV004594800 RCV005044645 RCV005040065 RCV001836230 RCV002499457	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
SLC39A4-related disorder	Likely pathogenic; Pathogenic	rs121434287, rs782563835	RCV003415640 RCV003399039	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
ACRODERMATITIS ENTEROPATHICA	—	GenCC	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Acrodermatitis	Dermatitis	LHGDN	12032886, 12068297		★☆☆☆☆ Found in Text Mining only
Acrodermatitis	Dermatitis	CTD_human_DG	16714095, 16819703, 16889938, 17190629, 17202136		★☆☆☆☆ Found in Text Mining only
Acrodermatitis	Dermatitis	BEFREE	22082465, 27940220		★☆☆☆☆ Found in Text Mining only
Acrodermatitis enteropathica	Acrodermatitis Enteropathica	BEFREE	12032886, 12068297, 12787121, 12955721, 16714095, 16889938, 18936158, 19370757, 20300938, 21165302, 21906148, 22082465, 22737083, 24015258, 24586184, 25780817, 31164399		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Acrodermatitis enteropathica	Acrodermatitis Enteropathica	UNIPROT_DG	12032886, 12068297, 12787121, 14702039		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Acrodermatitis enteropathica	Acrodermatitis Enteropathica	CTD_human_DG	12068297, 14709598, 15358787, 17483098		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Acrodermatitis enteropathica	Acrodermatitis Enteropathica	GENOMICS_ENGLAND_DG	12068297, 27604308		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Acrodermatitis enteropathica	Acrodermatitis Enteropathica	ORPHANET_DG	12787121, 22082465, 22166942		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Acrodermatitis enteropathica	Acrodermatitis enteropathica	Pubtator	12787121, 17202136, 18328205, 21165302, 24586184, 27940220, 31164399, 31979155, 33837739	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Acrodermatitis enteropathica	Acrodermatitis Enteropathica	Orphanet			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Acrodermatitis enteropathica	Acrodermatitis Enteropathica	CLINVAR_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Alopecia	Alopecia	HPO_DG			★☆☆☆☆ Found in Text Mining only
Anophthalmos	Syndromic microphthalmia	BEFREE	19021533		★☆☆☆☆ Found in Text Mining only
Anorexia	Anorexia	HPO_DG			★☆☆☆☆ Found in Text Mining only
Breast Neoplasms	Breast neoplasm	Pubtator	32744318	Associate	★☆☆☆☆ Found in Text Mining only
Carcinogenesis	Carcinogenesis	Pubtator	27611948	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma Hepatocellular	Hepatocellular carcinoma	Pubtator	24643086	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma of lung	Lung carcinoma	BEFREE	28775359		★☆☆☆☆ Found in Text Mining only
Carcinoma Pancreatic Ductal	Pancreatic ductal carcinoma	Pubtator	24345208	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma Squamous Cell	Squamous cell carcinoma	Pubtator	33535184	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma, Ovarian Epithelial	Ovarian Epithelial carcinoma	BEFREE	29163813, 29927933		★☆☆☆☆ Found in Text Mining only
Cerebral cortical atrophy	Cerebral cortical atrophy	HPO_DG			★☆☆☆☆ Found in Text Mining only
Cheilitis	Cheilitis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Conjunctivitis	Conjunctivitis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Corneal erosion	Corneal erosion	HPO_DG			★☆☆☆☆ Found in Text Mining only
Dermatitis	Dermatitis	BEFREE	25780817		★☆☆☆☆ Found in Text Mining only
Dwarfism	Dwarfism	HPO_DG			★☆☆☆☆ Found in Text Mining only
Epidermodysplasia Verruciformis	Epidermodysplasia Verruciformis	BEFREE	29439479		★☆☆☆☆ Found in Text Mining only
Epithelial ovarian cancer	Ovarian cancer	BEFREE	29163813, 29927933		★☆☆☆☆ Found in Text Mining only
Gianotti-Crosti Syndrome	Gianotti-Crosti Syndrome	CTD_human_DG	16714095, 16819703, 16889938, 17190629, 17202136		★☆☆☆☆ Found in Text Mining only
Glioma	Glioma	BEFREE	23595627		★☆☆☆☆ Found in Text Mining only
Glioma	Glioma	Pubtator	23595627	Stimulate	★☆☆☆☆ Found in Text Mining only
Glioma	Glioma	Pubtator	25921144	Associate	★☆☆☆☆ Found in Text Mining only
Glossitis	Glossitis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Hypogonadism	Hypogonadism	HPO_DG			★☆☆☆☆ Found in Text Mining only
Immune System Diseases	Immune System Diseases	BEFREE	29635109		★☆☆☆☆ Found in Text Mining only
Inflammatory Bowel Diseases	Inflammatory bowel disease	Pubtator	32410873	Associate	★☆☆☆☆ Found in Text Mining only
Intervertebral Disc Degeneration	Intervertebral disc disease	Pubtator	37700277	Associate	★☆☆☆☆ Found in Text Mining only
Intervertebral Disc Degeneration	Intervertebral disc disease	Pubtator	38217540	Stimulate	★☆☆☆☆ Found in Text Mining only
Liver carcinoma	Liver carcinoma	BEFREE	20957146		★☆☆☆☆ Found in Text Mining only
Lung Neoplasms	Lung neoplasms	Pubtator	27611948	Stimulate	★☆☆☆☆ Found in Text Mining only
Lymphatic Metastasis	Lymphatic metastasis	Pubtator	24643086	Associate	★☆☆☆☆ Found in Text Mining only
Malabsorption Syndrome	Malabsorption Syndrome	HPO_DG			★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of liver	Liver Cancer	BEFREE	28017725		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of lung	Lung Cancer	BEFREE	28775359		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of ovary	Ovarian cancer	BEFREE	29163813		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of pancreas	Pancreatic cancer	BEFREE	18003899, 19755388, 20023433, 23331012, 24553114, 26305676, 29615456, 30007115, 31636470, 31711924		★☆☆☆☆ Found in Text Mining only
Malignant Neoplasms	Malignant Neoplasm	BEFREE	20957146, 21803616, 26305676, 28775359, 29163813, 29615456, 30007115		★☆☆☆☆ Found in Text Mining only
Mood swings	Mood swings	HPO_DG			★☆☆☆☆ Found in Text Mining only
Nasopharyngeal carcinoma	Nasopharyngeal Carcinoma	BEFREE	31383854		★☆☆☆☆ Found in Text Mining only
Neoplasms	Neoplasms	BEFREE	18003899, 19755388, 21803616, 23595627, 25921144, 28775359, 29163813, 29615456, 29895370, 30342032, 31383854, 31711924		★☆☆☆☆ Found in Text Mining only
Non-Small Cell Lung Carcinoma	Lung carcinoma	BEFREE	28775359		★☆☆☆☆ Found in Text Mining only
Osteopenia	Osteopenia	BEFREE	26305676		★☆☆☆☆ Found in Text Mining only
ovarian neoplasm	Ovarian neoplasm	BEFREE	29163813		★☆☆☆☆ Found in Text Mining only
Pancreatic carcinoma	Pancreatic carcinoma	BEFREE	18003899, 19755388, 20023433, 23331012, 24553114, 26305676, 29615456, 30007115, 31636470, 31711924		★☆☆☆☆ Found in Text Mining only
Pancreatic Neoplasm	Pancreatic Neoplasm	LHGDN	18003899		★☆☆☆☆ Found in Text Mining only
Pancreatic Neoplasm	Pancreatic Neoplasm	BEFREE	29615456, 30342032		★☆☆☆☆ Found in Text Mining only
Pancreatic Neoplasms	Pancreatic neoplasm	Pubtator	23331012, 24345208, 24643086	Associate	★☆☆☆☆ Found in Text Mining only
Paronychia Inflammation	Paronychia Inflammation	HPO_DG			★☆☆☆☆ Found in Text Mining only
Prostate carcinoma	Prostate cancer	BEFREE	21803616		★☆☆☆☆ Found in Text Mining only
Prostatic Neoplasms	Prostatic neoplasm	Pubtator	24643086	Associate	★☆☆☆☆ Found in Text Mining only
Spina Bifida	Spina Bifida	BEFREE	15172003		★☆☆☆☆ Found in Text Mining only
Thyroid Neoplasms	Thyroid cancer	Pubtator	38477086	Associate	★☆☆☆☆ Found in Text Mining only
Uveal melanoma	Uveal melanoma	Pubtator	34630418	Associate	★☆☆☆☆ Found in Text Mining only