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

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession
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
SLC39A4-related disorder	Likely pathogenic; Pathogenic	rs121434287, rs782563835	RCV003415640 RCV003399039

Associations from Text Mining
Disease Name	Relationship Type	References
Acrodermatitis	Associate	24586184, 26684640
Acrodermatitis enteropathica	Associate	12787121, 17202136, 18328205, 21165302, 24586184, 27940220, 31164399, 31979155, 33837739
Adenocarcinoma of Lung	Associate	33535184
Breast Neoplasms	Associate	32744318
Carcinogenesis	Associate	27611948
Carcinoma Hepatocellular	Associate	24643086
Carcinoma Pancreatic Ductal	Associate	24345208
Carcinoma Squamous Cell	Associate	33535184
Fibrocartilaginous embolism	Associate	38217540
Genetic Diseases Inborn	Associate	31164399
Glioma	Stimulate	23595627
Glioma	Associate	25921144
Immunologic Deficiency Syndromes	Associate	31979155
Inflammation	Stimulate	38217540
Inflammatory Bowel Diseases	Associate	32410873
Intervertebral Disc Degeneration	Associate	37700277
Intervertebral Disc Degeneration	Stimulate	38217540
Lung Neoplasms	Stimulate	27611948
Lymphatic Metastasis	Associate	24643086
Neoplasm Metastasis	Associate	38477086
Neoplasms	Associate	23595627, 24345208, 24643086, 25921144, 38477086
Neoplasms	Stimulate	27611948
Pancreatic Neoplasms	Associate	23331012, 24345208, 24643086
Prostatic Neoplasms	Associate	24643086
Signs and Symptoms	Associate	27940220
Thyroid Neoplasms	Associate	38477086
Uveal melanoma	Associate	34630418
Zinc Deficiency Neonatal due to Low Breast Milk Zinc	Associate	21165302, 24586184