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Molecular and pathophysiological aspects of metal ion uptake by the zinc transporter ZIP8 (SLC39A8).

ABSTRACT: Zinc ion (Zn2+) is essential for life; its deficiency in the human body could cause stunted growth, anemia and susceptibility to infection. The Zn transporter ZIP8 (also known as SLC39A8) is an important Zn2+ importer; aberrant Zn2+ influx mediated by ZIP8 can lead to the pathogenesis of osteoarthritis and inflammatory diseases. ZIP8 also mediates the cellular uptake of divalent metal ions including iron, manganese, and the toxic heavy metal cadmium. Individuals with SLC39A8 mutations and transgenic mouse models are starting to reveal the critical role that this gene plays in embryonic development and the metabolism of essential metal ions. Here we summarize our current understanding of ZIP8's function and regulation, at both the molecular and biological levels. We also review the association of ZIP8 with various diseases and its linkage with complex disorders like obesity, hypertension, and schizophrenia as revealed by several large genome-wide association studies.

SUBMITTER: Zang ZS

PROVIDER: S-EPMC6062374 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Molecular and pathophysiological aspects of metal ion uptake by the zinc transporter ZIP8 (SLC39A8).

Zang Zhong-Sheng ZS Xu Yan-Ming YM Lau Andy T Y ATY

Toxicology research 20160218 4

Zinc ion (Zn2+) is essential for life; its deficiency in the human body could cause stunted growth, anemia and susceptibility to infection. The Zn transporter ZIP8 (also known as SLC39A8) is an important Zn2+ importer; aberrant Zn2+ influx mediated by ZIP8 can lead to the pathogenesis of osteoarthritis and inflammatory diseases. ZIP8 also mediates the cellular uptake of divalent metal ions including iron, manganese, and the toxic heavy metal cadmium. Individuals ...[more]

PMID: 30090406

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Project description:Abstract Objectives The SLC39A8 gene encodes a divalent metal transporter, ZIP8. ZIP8 polymorphisms are associated with pleiotropic effects including altered risks for schizophrenia. Our objective is to determine the different brain MRI phenotypes associated at or near the SLC39A8 (ZIP8) genetic locus using a phenome-wide association (PheWAS) approach followed by joint and conditional association analysis. Methods Using the summary statistics database containing brain MRI genome-wide association study (GWAS) data, we systematically selected all brain MRI phenotypes which were associated with single-nucleotide polymorphisms (SNPs) within 1 million bp of the SLC39A8 genetic locus, as defined as reaching a P-value significance cutoff of P < 5.0 × 10–8. For all brain MRI phenotypes reaching significance, we used GCTA-COJO to determine the number of independent association signals using settings of P < 1.0 × 10–5 and a window of 10 million base pairs. Using SNPclip and the European 1000 Genomes linkage panel with a linkage disequilibrium cutoff of r2 > 0.8, we identified SNP candidates at each index SNP. Linkage equilibrium for brain phenotypes with multiple independent signals was confirmed by LDpair. Results We identified 25 brain MRI phenotypes that vary due to MRI type and brain region that all contain a SNP associated with the SLC39A8 locus. All of these datasets have at least 1 index SNP directly labeling or in high linkage disequilibrium with rs13107325, which encodes a missense mutation in the SLC39A8 (ZIP8). Among the 25 datasets, an additional 4 association signals were identified by GCTA-COJO and confirmed to be in linkage equilibrium with rs13107325 using LDpair. For these additional association signals, probable causative SNPs were identified from the index SNP using SNPclip. Conclusions From the 25 brain MRI phenotypes, we identified new probable causative SNPs in addition to a previously reported missense SNP (rs13107325) associated with schizophrenia. This study provides leads into how SNPs in genes involved in trace metal transport influence brain structures and affect risks for schizophrenia. Funding Sources This work was funded by grants from the Oklahoma Center for the Advancement of Science and Technology and the Oklahoma Agricultural Experiment Station.

Project description:SLC39A8 is an evolutionarily highly conserved gene that encodes the ZIP8 metal cation transporter in all vertebrates. SLC39A8 is ubiquitously expressed, including pluripotent embryonic stem cells; SLC39A8 expression occurs in every cell type examined. Uptake of ZIP8-mediated Mn2+, Zn2+, Fe2+, Se4+, and Co2+ represents endogenous functions-moving these cations into the cell. By way of mouse genetic differences, the phenotype of "subcutaneous cadmium-induced testicular necrosis" was assigned to the Cdm locus in the 1970s. This led to identification of the mouse Slc39a8 gene, its most closely related Slc39a14 gene, and creation of Slc39a8-overexpressing, Slc39a8(neo/neo) knockdown, and cell type-specific conditional knockout mouse lines; the Slc39a8(-/-) global knockout mouse is early-embryolethal. Slc39a8(neo/neo) hypomorphs die between gestational day 16.5 and postnatal day 1-exhibiting severe anemia, dysregulated hematopoiesis, hypoplastic spleen, dysorganogenesis, stunted growth, and hypomorphic limbs. Not surprisingly, genome-wide association studies subsequently revealed human SLC39A8-deficiency variants exhibiting striking pleiotropy-defects correlated with clinical disorders in virtually every organ, tissue, and cell-type: numerous developmental and congenital disorders, the immune system, cardiovascular system, kidney, lung, liver, coagulation system, central nervous system, musculoskeletal system, eye, and gastrointestinal tract. Traits with which SLC39A8-deficiency variants are currently associated include Mn2+-deficient hypoglycosylation; numerous birth defects; Leigh syndrome-like mitochondrial redox deficiency; decreased serum high-density lipoprotein-cholesterol levels; increased body mass index; greater risk of coronary artery disease, hypotension, cardiovascular death, allergy, ischemic stroke, schizophrenia, Parkinson disease, inflammatory bowel disease, Crohn disease, myopia, and adolescent idiopathic scoliosis; systemic lupus erythematosus with primary Sjögren syndrome; decreased height; and inadvertent participation in the inflammatory progression of osteoarthritis.

Dataset Information

Molecular and pathophysiological aspects of metal ion uptake by the zinc transporter ZIP8 (SLC39A8).

Publications

Molecular and pathophysiological aspects of metal ion uptake by the zinc transporter ZIP8 (SLC39A8).

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