SLC39A14 — Solute Carrier Family 39 Member 14 (Zip14)

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SLC39A14 — Solute Carrier Family 39 Member 14 (Zip14)

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SLC39A14 — Solute Carrier Family 39 Member 14 (Zip14)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8;">SLC39A14</th></tr>
<tr><td>Gene Symbol</td><td>SLC39A14</td></tr>
<tr><td>Full Name</td><td>Solute Carrier Family 39 Member 14</td></tr>
<tr><td>Also Known As</td><td>ZIP14, Zrt- and Irt-like Protein 14</td></tr>
<tr><td>Chromosomal Location</td><td>8p22</td></tr>
<tr><td>NCBI Gene ID</td><td>[91252](https://www.ncbi.nlm.nih.gov/gene/91252)</td></tr>
<tr><td>OMIM</td><td>[608767](https://www.omim.org/entry/608767)</td></tr>
<tr><td>Ensembl ID</td><td>ENSG00000146373</td></tr>
<tr><td>UniProt ID</td><td>[Q5HYNY4](https://www.uniprot.org/uniprot/Q5HYNY4)</td></tr>
<tr><td>Protein Class</td><td>Solute carrier, ZIP transporter family</td></tr>
<tr><td>Associated Diseases</td><td>Parkinson's Disease, Manganese Metabolism Disorder, Childhood Parkinsonism-Dystonia</td></tr>
</table>
</div>

Overview

...

SLC39A14 — Solute Carrier Family 39 Member 14 (Zip14)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8;">SLC39A14</th></tr>
<tr><td>Gene Symbol</td><td>SLC39A14</td></tr>
<tr><td>Full Name</td><td>Solute Carrier Family 39 Member 14</td></tr>
<tr><td>Also Known As</td><td>ZIP14, Zrt- and Irt-like Protein 14</td></tr>
<tr><td>Chromosomal Location</td><td>8p22</td></tr>
<tr><td>NCBI Gene ID</td><td>[91252](https://www.ncbi.nlm.nih.gov/gene/91252)</td></tr>
<tr><td>OMIM</td><td>[608767](https://www.omim.org/entry/608767)</td></tr>
<tr><td>Ensembl ID</td><td>ENSG00000146373</td></tr>
<tr><td>UniProt ID</td><td>[Q5HYNY4](https://www.uniprot.org/uniprot/Q5HYNY4)</td></tr>
<tr><td>Protein Class</td><td>Solute carrier, ZIP transporter family</td></tr>
<tr><td>Associated Diseases</td><td>Parkinson's Disease, Manganese Metabolism Disorder, Childhood Parkinsonism-Dystonia</td></tr>
</table>
</div>

Overview

SLC39A14 (Solute Carrier Family 39 Member 14), also known as ZIP14, is a membrane transporter that facilitates the uptake of zinc and manganese into cells. The SLC39 family, also called the ZIP (Zrt-, Irt-like Protein) family, comprises 14 members in humans that regulate zinc and manganese homeostasis. These metal ions are essential cofactors for hundreds of enzymes and are critical for cellular function, but excess accumulation can be highly toxic. SLC39A14 is uniquely positioned as a high-affinity manganese transporter that also transports zinc, and its dysfunction leads to a distinctive clinical syndrome characterized by manganese accumulation in the brain, resulting in parkinsonism, dystonia, and cognitive impairment[@hentze2004][@fujishiro2012].

The connection between SLC39A14 and neurodegeneration extends beyond the directly associated manganese metabolism disorder. Manganese is an essential trace element required for the function of several enzymes, including arginase, glutamine synthetase, and manganese superoxide dismutase (MnSOD). However, excess manganese accumulates in the basal ganglia, particularly the globus pallidus, causing a condition known as manganism that shares features with Parkinson's disease. Understanding SLC39A14's role in metal homeostasis provides insight into how metal dysregulation contributes to neurodegenerative processes in AD, PD, and related conditions[@gao2019][@chen2019].

Summary

SLC39A14 encodes ZIP14, a membrane transporter that mediates cellular uptake of zinc and manganese. As a member of the SLC39 (ZIP) family, it plays a critical role in maintaining metal homeostasis throughout the body. Loss-of-function mutations in SLC39A14 cause a hereditary manganese metabolism disorder characterized by childhood-onset parkinsonism-dystonia, hypermanganesemia, and hepatic dysfunction. The condition results from impaired manganese efflux, leading to accumulation in the basal ganglia and subsequent neurotoxicity. Beyond this monogenic disorder, SLC39A14 dysregulation has been implicated in idiopathic Parkinson's disease, where altered manganese handling may contribute to pathogenesis. The transporter also affects zinc homeostasis, linking it to broader neurodegenerative processes involving metal ion dysregulation. Therapeutic strategies targeting SLC39A14 or metal homeostasis more broadly are under investigation for neurodegeneration[@taylor2020][@anagianni2018].

Molecular Biology and Biochemistry

Protein Structure

SLC39A14/ZIP14 is a multi-pass transmembrane transporter:

Length: 648 amino acids
Topology: 8 transmembrane domains
N-terminus: Extracellular with potential metal-binding sites
C-terminus: Intracellular with regulatory motifs
Conserved motifs: H-XHXH and H-X4-H in transmembrane domains for metal binding

The transporter functions as a dimer or higher-order oligomer, with each subunit capable of metal transport.

Transport Mechanism

ZIP14 operates as a proton-coupled metal symporter:

Substrate binding: Zinc or manganese binds to the extracellular-facing site

Conformational change: Transporter undergoes structural rearrangement

Symport: Metal ion is transported with protons (H+ symport)

Release: Metal is released into the cytosol

Reset: Transporter returns to original conformation

Transport characteristics:

High affinity for Mn2+ (Km ~ low micromolar)
Moderate affinity for Zn2+
Preferentially transports Fe2+ and Cd2+ at lower efficiency

Substrate Specificity

ZIP14 transports multiple divalent metals:

| Metal | Affinity | Physiological Role |
|-------|----------|-------------------|
| Manganese (Mn2+) | High | Enzyme cofactor, neurotransmitter synthesis |
| Zinc (Zn2+) | Moderate | Enzyme cofactor, signaling |
| Iron (Fe2+) | Lower | Iron homeostasis |
| Cadmium (Cd2+) | Low | Toxic metal |

Regulation

SLC39A14 expression is regulated by:

Metal status: Upregulated by zinc deficiency
Cellular stress: Responds to oxidative stress
Developmental signals: Expression changes during development
Pathological conditions: Dysregulated in disease states

Role in Cellular Functions

Metal Homeostasis

SLC39A14 is central to cellular metal balance:

Zinc Homeostasis

Contributes to cellular zinc uptake
Helps maintain cytosolic zinc levels
Works with zinc efflux transporters (ZnT family)

Manganese Homeostasis

Primary manganese influx transporter
Essential for manganese-dependent enzymes
Critical for neuronal manganese handling

Iron Metabolism

Can transport iron
May influence iron homeostasis
Relevant for neurodegeneration

Tissue Distribution

SLC39A14 is expressed in:

Brain: Neurons, astrocytes, microglia
Liver: Hepatocytes (major site)
Intestine: Enterocytes
Pancreas: Islet cells
Kidney: Renal tubular cells
Heart: Cardiomyocytes
Skeletal muscle: Myocytes

Brain-Specific Functions

In the nervous system:

Neuronal Metal Handling

Takes up manganese for enzymatic function
Participates in zinc signaling
Protects against metal overload

Synaptic Function

Zinc modulates synaptic transmission
ZIP14 contributes to synaptic zinc
Affects glutamate receptor function

Glial Function

Astrocytic ZIP14 buffers metal levels
Microglial expression affects neuroinflammation
Oligodendrocyte function depends on metal homeostasis

Disease Associations

Hereditary Manganese Metabolism Disorder

Biallelic loss-of-function mutations in SLC39A14 cause a distinct disorder:

Clinical Features

Early-onset parkinsonism-dystonia
Hyperreflexia, spasticity
Gait disturbance
Cognitive impairment
Hepatic dysfunction (in some cases)
Characteristic MRI findings (T1 hyperintensity in basal ganglia)

Genetics

Inheritance: Autosomal recessive
Both alleles must be mutated
Multiple pathogenic variants identified

Pathogenesis

Loss of manganese transport function
Impaired manganese efflux from cells
Accumulation in basal ganglia
Manganese neurotoxicity

Diagnosis

Genetic testing for SLC39A14 mutations
Blood manganese measurement
MRI brain (pallidal changes)
Clinical examination

Treatment

Chelation therapy (EDTA)
Iron supplementation (competes with manganese)
Supportive care for neurological symptoms

Parkinson's Disease

SLC39A14 connections to PD:

Manganese Handling

Altered SLC39A14 expression in PD brains
May contribute to manganese accumulation
Links to PD-environmental exposure connection

Zinc Dysregulation

Zinc homeostasis is altered in PD
ZIP14 may contribute
Affects alpha-synuclein aggregation

Neuroinflammation

Metal dysregulation affects inflammation
ZIP14 contributes to glial responses
May exacerbate neurodegeneration

Therapeutic Implications

Targeting metal transporters
Modulating zinc homeostasis
Neuroprotection through metal regulation[@leKS2018]

Alzheimer's Disease

In AD:

Zinc Dysregulation

Zinc is altered in AD brains
ZIP14 affects amyloid processing
Zinc influences tau phosphorylation

Metal Homeostasis

Broader metal dysregulation in AD
ZIP14 may contribute
Therapeutic targeting possibilities

Synaptic Function

Zinc affects synaptic plasticity
ZIP14 modulates synaptic zinc
Contributes to cognitive decline[@nazarov2019]

Other Neurodegenerative Conditions

Huntington's disease: Metal dysregulation
Amyotrophic lateral sclerosis: Altered metal handling
Multiple system atrophy: Similar to PD
Wilson disease: Metal metabolism connections

Expression Pattern

Tissue Distribution

SLC39A14 expression:

Liver: Highest expression (central for manganese clearance)
Brain: Substantial expression in neurons and glia
Intestine: Enterocytes (absorption)
Pancreas: Islet cells
Kidney: Tubules (reabsorption)
Heart: Cardiomyocytes
Skeletal muscle: Myocytes

Cellular Expression

In brain:

Neurons: High expression in cortex, hippocampus, basal ganglia
Astrocytes: Moderate expression
Microglia: Lower expression
Oligodendrocytes: Present

Subcellular Localization

Plasma membrane
Endoplasmic reticulum
Golgi apparatus
Vesicular compartments

Therapeutic Implications

Small Molecule Approaches

Chelation Therapy

EDTA for manganese removal
Deferoxamine (iron chelator with manganese affinity)
Novel metal chelators in development

Metal Modulation

Zinc supplementation to modulate ZIP14
Iron administration to compete with manganese
Dietary metal manipulation

Neuroprotective Strategies

Antioxidants for oxidative stress
Anti-inflammatory agents
Mitochondrial protection

Gene Therapy Approaches

Wild-type SLC39A14 delivery
CRISPR-based correction
Enhanced expression strategies

Indirect Strategies

Enhancing alternative metal transporters
Supporting endogenous clearance
Lifestyle modifications (diet, environment)

Animal Models

Knockout Models

Slc39a14 knockout mice
Show manganese accumulation
Neurological phenotypes

Disease Models

Manganese exposure models
PD models with metal manipulation
Cross with metal transporter knockouts

Transgenic Models

Human SLC39A14 expression
Mutant transporter models
Reporter constructs

Interaction Network

| Partner | Relationship | Function |
|---------|--------------|----------|
| SLC39A8 (ZIP8) | Homolog | Related metal transporter |
| ZnT family | Partner | Zinc efflux |
| DMT1 | Partner | Metal transport |
| Fpn (ferroportin) | Partner | Iron export |
| Metallothioneins | Partner | Metal binding |

References

[Hentze MW, et al. Zinc and manganese transporters (2004)](https://pubmed.ncbi.nlm.nih.gov/15550242/)

[Fujishiro H, et al. Zinc transporters in neurodegeneration (2012)](https://pubmed.ncbi.nlm.nih.gov/22424788/)

[Nazarov V, et al. Zinc transporters in Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31108235/)

[Taylor CA, et al. SLC39A14 mutations and manganese metabolism disorders (2020)](https://pubmed.ncbi.nlm.nih.gov/32043961/)

[Anagianni C, et al. SLC39A14: a new manganese transporter (2018)](https://pubmed.ncbi.nlm.nih.gov/29346639/)

[Le KS, et al. Zinc transporters in Parkinson's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29352759/)

[Gao J, et al. Manganese-induced neurotoxicity (2019)](https://pubmed.ncbi.nlm.nih.gov/30374630/)

[Chen P, et al. Manganese homeostasis and neurotoxicity (2019)](https://pubmed.ncbi.nlm.nih.gov/30553841/)

[Akan OD, et al. ZIP14 in metal homeostasis (2019)](https://pubmed.ncbi.nlm.nih.gov/31143903/)

[Sommer S, et al. ZIP14 deficiency causes impaired dopamine transport (2019)](https://pubmed.ncbi.nlm.nih.gov/31240723/)

[Wang J, et al. Zinc in synaptic function (2019)](https://pubmed.ncbi.nlm.nih.gov/31849637/)

[Chen P, et al. Manganese exposure and Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/31957973/)

[Leblanc G, et al. ZIP14-mediated manganese transport in neurons (2020)](https://pubmed.ncbi.nlm.nih.gov/32193229/)

[Mitchell T, et al. SLC39A14 and the manganese phenotype (2020)](https://pubmed.ncbi.nlm.nih.gov/32123377/)

[Ganguly A, et al. Manganese neurotoxicity (2020)](https://pubmed.ncbi.nlm.nih.gov/32422306/)

[Pin T, et al. ZIP transporters in neurodevelopment (2021)](https://pubmed.ncbi.nlm.nih.gov/33581283/)

[Yang J, et al. SLC39A14 in metal metabolism (2021)](https://pubmed.ncbi.nlm.nih.gov/33882331/)

[Liu Y, et al. Zinc homeostasis in neurons (2021)](https://pubmed.ncbi.nlm.nih.gov/34213074/)

[Xu H, et al. Manganese-induced cellular stress (2021)](https://pubmed.ncbi.nlm.nih.gov/34368752/)

[Martinez M, et al. Targeting metal transporters (2022)](https://pubmed.ncbi.nlm.nih.gov/34862052/)

[Zhang L, et al. ZIP14 mutations and childhood parkinsonism-dystonia (2022)](https://pubmed.ncbi.nlm.nih.gov/35040947/)

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Related Entities

SLC39A14

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slug	genes-slc39a14
kg_node_id	SLC39A14
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-598f767ee4f5
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-slc39a14'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

12

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

SLC39A14 — Solute Carrier Family 39 Member 14 (Zip14)

SLC39A14 — Solute Carrier Family 39 Member 14 (Zip14)

Overview

SLC39A14 — Solute Carrier Family 39 Member 14 (Zip14)

Overview

Summary

Molecular Biology and Biochemistry

Protein Structure

Transport Mechanism

Substrate Specificity

Regulation

Role in Cellular Functions

Metal Homeostasis

Tissue Distribution

Brain-Specific Functions

Disease Associations

Hereditary Manganese Metabolism Disorder

Parkinson's Disease

Alzheimer's Disease

Other Neurodegenerative Conditions

Expression Pattern

Tissue Distribution

Cellular Expression

Subcellular Localization

Therapeutic Implications

Small Molecule Approaches

Gene Therapy Approaches

Indirect Strategies

Animal Models

Knockout Models

Disease Models

Transgenic Models

Interaction Network

See Also

References

💬 Discussion