Solute carrier family 39 member 12 is a protein that in humans is encoded by the SLC39A12 gene.

Zinc is an essential cofactor for hundreds of enzymes. It is involved in protein, nucleic acid, carbohydrate, and lipid metabolism, as well as in the control of gene transcription, growth, development, and differentiation. ZIP12 belongs to a subfamily of proteins that show structural characteristics of zinc transporters.

Zinc transporter ZIP12 is a protein that is encoded by the solute carrier 39 member 12 (SLC39A12) gene. ZIP12 is part of a family of Zrt-like, IRT-like proteins (ZIPs) that transport metals. ZIP12 is most closely related to a similar transporter, ZIP4, which is mutated in the genetic disorder acrodermatitis enteropathica. Human ZIP12 shares 31 percent of its amino acids with human ZIP4 between their conserved regions. There are two main splice variants of ZIP12 in humans, which are 691 and 654 amino acids long. The difference in the lengths of these 2 variants of ZIP12 are due to the inclusion or exclusion of an in-frame exon.

The ZIP12 protein contains many elements that are conserved across other ZIP transporters in vertebrates (including mammals and humans). ZIP12 has eight transmembrane domains and contains histidine residues within transmembrane regions four and five that are believed to be necessary for zinc transport across cellular membranes. ZIP12 is present at the plasma membrane and can transport zinc ions from the outside of the cell to the inside.

The SLC39A12 gene is conserved across vertebrates, including humans, non-human primates like rhesus monkeys, cats, dogs, rodents including rats and mice, birds such as chickens, and frogs such as Xenopus laevis and Xenopus tropicalis. The SLC39A12 gene is present in some fish such as Japanese medaka, Nile tilapia, and European seabass, but the SLC39A12 gene is not present in zebrafish. ZIP12 has been shown to transport zinc, and there is currently no evidence that ZIP12 can transport metals other than zinc. ZIP12 is expressed in many tissues and is particularly high in the brain and eye. In mice, ZIP12 mRNA is not detected in pancreas.

In mouse Neuro-2a cells and primary mouse neurons, ZIP12 is necessary for neurite extension. Neurites are projections from the cell body of a neural cell during differentiation, and neurites can refer to either axons or dendrites. To study how ZIP12 is important for a neural cell to extend neurites out from the cell body, researchers used short hairpin RNA (shRNA) to induce RNA interference to degrade ZIP12 mRNA and reduce ZIP12 protein. In Neuro-2a cells and primary mouse neurons transfected with shRNA specifically targeting ZIP12, the neural cells have shorter neurites. Increasing intracellular zinc with a zinc ionophore that can cross the cellular membrane while bypassing ZIP12 can restore neurite extension in cells with targeted ZIP12 depletion.

In a subsequent study, Neuro-2a cells with targeted ZIP12 mutations using CRISPR-mediated genome editing also have shorter neurites during differentiation and mitochondrial dysfunction. In addition, ZIP12-deleted cells have reduced cellular respiration, which is a measure of mitochondrial function. Neurite extension of Neuro-2a is more affected by rotenone and sodium azide, which are inhibitors of the electron transport chain of the mitochondria, in cells without ZIP12. ZIP12-deleted cells also have increased superoxide generation and higher oxidative damage, which are consistent with impaired mitochondrial function. Exposing ZIP12-deleted cells to antioxidants such as alpha-tocopherol (vitamin E), MitoQ, or MitoTEMPO can restore neurite length, which indicates that the oxidative damage present in cells without ZIP12 leads to stunted neurites.

ZIP12 is present in the forebrain, midbrain, and eye of Xenopus tropicalis in nervous system development. ZIP12 is also present at the anterior neuropore during closure of the neural tube. ZIP12 mRNA is concentrated in the neural tube, and ZIP12 expression is higher in the neural tube compared to the rest of the embryo. To study how ZIP12 is necessary for Xenopus tropicalis embryo development, the researchers injected embryos with antisense morpholino oligonucleotides that deplete the embryos of ZIP12. In embryos injected with morpholinos targeting the translation start site of ZIP12, the embryos have incomplete neural tube closure at the anterior neuropore, followed by embryonic death. Embryos injected with morpholinos that alter ZIP12 splicing and impair its function have slower neural tube closure, often lack eyes (called anopia), and undergo embryonic death shortly after neural tube closure.