ArticleThe Journal of biological chemistry
Zinc transporter mutations linked to acrodermatitis enteropathica disrupt function and cause mistrafficking.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 32 citations in OpenAlex.
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- Functional screening of ZIP8 naturally occurring variants identifies pathogenic mutations and trafficking defects.The Journal of biological chemistry · 2026Article
- Zinc-induced exposure of an LxL motif drives clathrin-mediated endocytosis of the zinc transceptor ZIP4.The Journal of biological chemistry · 2026Article
- Systematic analysis of naturally occurring missense mutations in human manganese transporters: prediction and structural insights.bioRxiv : the preprint server for biology · 2025Article
- Exploring management of acrodermatitis.Asia Pacific journal of clinical nutrition · 2025Article
- Dietary Zinc Restriction and Chronic Restraint Stress Affect Mice Physiology, Immune Organ Morphology, and Liver Function.Nutrients · 2024Article
- Evolution, classification, and mechanisms of transport, activity regulation, and substrate specificity of ZIP metal transporters.Critical reviews in biochemistry and molecular biology · 2024Review
- Determination of metal ion transport rate of human ZIP4 using stable zinc isotopes.The Journal of biological chemistry · 2024Article
- Coordination chemistry suggests that independently observed benefits of metformin and ZnBiometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2024Article
- Modulation of Adverse Health Effects of Environmental Cadmium Exposure by Zinc and Its Transporters.Biomolecules · 2024Review
- Rational engineering of an elevator-type metal transporter ZIP8 reveals a conditional selectivity filter critically involved in determining substrate specificity.Communications biology · 2023Article
- The Molecular Basis for Zinc Bioavailability.International journal of molecular sciences · 2023Review
- Structural insights into the elevator-type transport mechanism of a bacterial ZIP metal transporter.Nature communications · 2023Article
- Cell-based transport assay to study kinetics and substrate specificity of human ZIPs.Methods in enzymology · 2023Article
- The Influence of Dietary Supplementations on Neuropathic Pain.Life (Basel, Switzerland) · 2022Review
- The Integration of Metabolomics with Other Omics: Insights into Understanding Prostate Cancer.Metabolites · 2022Review
- Sophisticated expression responses of ZNT1 and MT in response to changes in the expression of ZIPs.Scientific reports · 2022Article
- Nutritional Supplements for the Treatment of Neuropathic Pain.Biomedicines · 2021Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
ZIP4 is a representative member of the Zrt-/Irt-like protein (ZIP) transporter family and responsible for zinc uptake from diet. Loss-of-function mutations of human ZIP4 (hZIP4) drastically reduce zinc absorption, causing a life-threatening autosomal recessive disorder, acrodermatitis enteropathica (AE). These mutations occur not only in the conserved transmembrane zinc transport machinery, but also in the extracellular domain (ECD) of hZIP4, which is only present in a fraction of mammalian ZIPs. How these AE-causing ECD mutations lead to ZIP4 malfunction has not be fully clarified. In this work, we characterized all seven confirmed AE-causing missense mutations in hZIP4-ECD and found that the variants exhibited completely abolished zinc transport activity in a cell-based transport assay. Although the variants were able to be expressed in HEK293T cells, they failed to traffic to the cell surface and were largely retained in the ER with immature glycosylation. When the corresponding mutations were introduced in the ECD of ZIP4 from Pteropus Alecto, a close homolog of hZIP4, the variants exhibited structural defects or reduced thermal stability, which likely accounts for intracellular mistrafficking of the AE-associated variants and as such a total loss of zinc uptake activity. This work provides a molecular pathogenic mechanism for AE.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.