GeneBe

SLC39A4

protein-coding

solute carrier family 39 member 4, the group of Solute carrier family 39

Gene 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. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2013]

Previous symbols:
  • AEZ

MANE transcript

NM_130849.4

Inheritance

AR

ClinVar variants

P:153U:215B:497

Top phenotype

Acrodermatitis enteropathica, zinc-deficiency type

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr8:144,409,742-144,416,844

External References & Databases

Ensembl (ENSG00000147804)NCBI Gene (55630)OMIM (607059)HGNC:17129GenCCUniProt (Q6P5W5)AlphaFoldClinVar (SLC39A4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~7.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acrodermatitis enteropathicaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008713

Submitter: Ambry Genetics

acrodermatitis enteropathicaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008713

Submitter: PanelApp Australia

acrodermatitis enteropathicaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008713

Submitter: G2P

acrodermatitis enteropathicaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008713

Submitter: Labcorp Genetics (formerly Invitae)

acrodermatitis enteropathicaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008713

Submitter: ClinGen

The SLC39A4 gene encodes the Zrt-/Irt-like protein 4 (ZIP4) that is highly expressed in the small intestine and kidney. ZIP4 transports dietary zinc into enterocytes, and eventually arrive to target tissues and organs through blood circulation system. SLC39A4 was first reported in relation to autosomal recessive acrodermatitis enteropathica (AE) in 2002 (Wang et al., PMID: 11254458). The affected individuals typically present early onset erosive, inflammatory, erythematous and psoriatic skin lesions at periorofacial, perianal and acral regions. They may also exhibit sparse hair or alopecia, diarrhea, irritability, and growth delay. Most patients show reduced serum zinc levels. Twenty-one unique variants including missense, nonsense, frameshift, and splicing variants that have been reported in 19 unrelated probands are included in this curation (PMIDs: 11254458, 12032886, 12787121, 23430849, 26351177, 36479285, 32442281, 34625996, 31987033, 21165302, 21762381, 17573886, 28056538, 19416256, 18684156, 24962159, 30980548). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss-of-function. This gene-disease association is also supported by experimental evidence. Tamoxifen-induced intestine-ZIP4 knockout (KO) mice showed rapid weight loss, growth failure and early death, which could be rescued by addition of zinc in drinking water (PMID: 22737083). Zinc levels in the intestine, pancreas and liver were lower in KO mice than the control littermates. Loss-of-function of intestine ZIP4 leads to progressive and profound disorganization of villus and crypt architecture in intestine (PMID 22737083). Studies in cultured human keratinocytes and reconstituted skin model demonstrated that knockdown ZIP4 decreased the zinc in basal layer of epidermis, disrupted normal skin cell differentiation and epidermis formation, downregulated p63 expression and trafficking. This suggested that ZIP4 is involved in maintaining zinc homeostasis and epidermis development through regulating p63 activity and localization, and p63 downstream target genes (PMID: 27940220). Overexpression of AE-associated ZIP4 variants located in extracellular domain or transmembrane domains led to reduced zinc uptake and diminished membrane surface localization. The dysfunction of the ZIP4 mutant protein resulted from impaired glycosylation and retention in the ER (PMID: 14709598, 33837739). In summary, SLC39A4 is definitively associated with autosomal recessive acrodermatitis enteropathica. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen IEM GCEP on the meeting date September 13, 2024. (SOP Version 10).

acrodermatitis enteropathicaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008713

Submitter: Orphanet

acrodermatitis enteropathicaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008713

Submitter: Genomics England PanelApp

acrodermatitis enteropathicaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008713

Submitter: Natera

Clinical Genomic Database (CGD)

Acrodermatitis enteropathica, zinc-deficiency typeAR

Manifestation: Biochemical; Dermatologic; Gastrointestinal

Intervention: Biochemical

Rationale: The condition may present with failure to thrive, diarrhea, and dermatitis, and, if untreated, may evolve to include other sequelae of zinc deficiency, including immunodeficiency and neurologic manifestations, and medical management (eg, treatment with oral zinc therapy) can be effective

Comments: Heterozygous variants have been reported as disease-associated in some reports

Refs: 4136854; 1090826; 12068297; 19370757; 20883266; 21165302; 21762381; 21906148; 21907902; 22082465; 22166942; 23228939; 23430849Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC39A4 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 817
Hereditary acrodermatitis enteropathicaTotal: 265
Inborn genetic diseasesTotal: 143
not specifiedTotal: 66
SLC39A4-related disorderTotal: 38
Rare genetic inflammatory skin disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_130849.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
14
clinvar
468
clinvar
3
clinvar
 485
missense
4
clinvar
6
clinvar
193
clinvar
26
clinvar
 229
nonsense
17
clinvar
9
clinvar
1
clinvar
 27
start loss
1
clinvar
 1
frameshift
41
clinvar
39
clinvar
2
clinvar
 82
splice donor/acceptor (+/-2bp)
3
clinvar
33
clinvar
5
clinvar
 41
Total65882154943865

Highest pathogenic variant AF is 0.00017728804

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_130849.4RefSeqNP_570901.312MANE Select
ENST00000301305.8EnsemblENSP00000301305.412MANE Select
NM_001280557.2RefSeqNP_001267486.13Standard
NM_001374839.1RefSeqNP_001361768.111Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Mineral absorption - Homo sapiens (human)
  • Nuclear Receptors Meta-Pathway
  • NRF2 pathway
  • Zinc homeostasis
  • Senescence and Autophagy in Cancer

Biological Process

  • cellular zinc ion homeostasis
  • signal transduction
  • cellular response to zinc ion starvation
  • zinc ion import across plasma membrane

Molecular Function

  • zinc ion transmembrane transporter activity

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • apical plasma membrane
  • cytoplasmic vesicle
  • recycling endosome membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000301305
Coding exons
12
Length
7154
Individuals with no LoFs
125662
Homozygous LoFs
0
Heterozygous LoFs
26
Defined
125688
p
0.000103
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.2954123951.040.00002694018
Missense (PolyPhen)100119.410.837481366
Synonymous-3.752732051.330.00001691417
Loss of Function2.661024.10.4150.00000105262

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian0.000120.00011rare
Finnish0.0000550.000046rare
European (Non-Finnish)0.000220.00018rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Plays an important role in cellular zinc homeostasis as a zinc transporter. Regulated in response to zinc availability (By similarity). {ECO:0000250}.;

Recessive Scores

pRec
0.127

Intolerance Scores

LoFtool
0.530
RVIS EVS
1.21
RVIS percentile EVS
93.05

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.231

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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