SLC39A14 — Solute Carrier Family 39 Member 14 (Zip14)

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><b>Gene Symbol</b></td><td>SLC39A14</td></tr>
<tr><td><b>Full Name</b></td><td>Solute Carrier Family 39 Member 14</td></tr>
<tr><td><b>Also Known As</b></td><td>ZIP14, Zrt- and Irt-like Protein 14</td></tr>
<tr><td><b>Chromosomal Location</b></td><td>8p22</td></tr>
<tr><td><b>NCBI Gene ID</b></td><td>[91252](https://www.ncbi.nlm.nih.gov/gene/91252)</td></tr>
<tr><td><b>OMIM</b></td><td>[608767](https://www.omim.org/entry/608767)</td></tr>
<tr><td><b>Ensembl ID</b></td><td>ENSG00000146373</td></tr>
<tr><td><b>UniProt ID</b></td><td>[Q5HYNY4](https://www.uniprot.org/uniprot/Q5HYNY4)</td></tr>
<tr><td><b>Protein Class</b></td><td>Solute carrier, ZIP transporter family</td></tr>
<tr><td><b>Associated Diseases</b></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><b>Gene Symbol</b></td><td>SLC39A14</td></tr>
<tr><td><b>Full Name</b></td><td>Solute Carrier Family 39 Member 14</td></tr>
<tr><td><b>Also Known As</b></td><td>ZIP14, Zrt- and Irt-like Protein 14</td></tr>
<tr><td><b>Chromosomal Location</b></td><td>8p22</td></tr>
<tr><td><b>NCBI Gene ID</b></td><td>[91252](https://www.ncbi.nlm.nih.gov/gene/91252)</td></tr>
<tr><td><b>OMIM</b></td><td>[608767](https://www.omim.org/entry/608767)</td></tr>
<tr><td><b>Ensembl ID</b></td><td>ENSG00000146373</td></tr>
<tr><td><b>UniProt ID</b></td><td>[Q5HYNY4](https://www.uniprot.org/uniprot/Q5HYNY4)</td></tr>
<tr><td><b>Protein Class</b></td><td>Solute carrier, ZIP transporter family</td></tr>
<tr><td><b>Associated Diseases</b></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

Transport Mechanism

ZIP14 operates as a proton-coupled metal symporter:

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)

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

• 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

• Zinc modulates synaptic transmission
• ZIP14 contributes to synaptic zinc
• Affects glutamate receptor 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)

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

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

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

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

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

• 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

• Broader metal dysregulation in AD
• ZIP14 may contribute
• Therapeutic targeting possibilities

• 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

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

• 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 |

See Also

• [Genes Directory](/genes/)
• [Metal Transporters](/proteins/metal-transporters)
• [Zinc Homeostasis](/mechanisms/zinc-homeostasis)
• [Manganese Metabolism](/mechanisms/manganese-metabolism)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Manganism](/diseases/manganism)

References