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Gene
2021 Oct 05;799:145824. doi: 10.1016/j.gene.2021.145824.
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A role for zinc transporter gene SLC39A12 in the nervous system and beyond.
Davis DN, Strong MD, Chambers E, Hart MD, Bettaieb A, Clarke SL, Smith BJ, Stoecker BJ, Lucas EA, Lin D, Chowanadisai W.
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The SLC39A12 gene encodes the zinc transporter protein ZIP12, which is expressed across many tissues and is highly abundant in the vertebrate nervous system. As a zinc transporter, ZIP12 functions to transport zinc across cellular membranes, including cellular zinc influx across the plasma membrane. Genome-wide association and exome sequencing studies have shown that brain susceptibility-weighted magnetic resonance imaging (MRI) intensity is associated with ZIP12 polymorphisms and rare mutations. ZIP12 is required for neural tube closure and embryonic development in Xenopus tropicalis. Frog embryos depleted of ZIP12 by antisense morpholinos develop an anterior neural tube defect and lack viability. ZIP12 is also necessary for neurite outgrowth and mitochondrial function in mouse neural cells. ZIP12 mRNA is increased in brain regions of schizophrenic patients. Outside of the nervous system, hypoxia induces ZIP12 expression in multiple mammalian species, including humans, which leads to endothelial and smooth muscle thickening in the lung and contributes towards pulmonary hypertension. Other studies have associated ZIP12 with other diseases such as cancer. Given that ZIP12 is highly expressed in the brain and that susceptibility-weighted MRI is associated with brain metal content, ZIP12 may affect neurological diseases and psychiatric illnesses such as Parkinson's disease, Alzheimer's disease, and schizophrenia. Furthermore, the induction of ZIP12 and resultant zinc uptake under pathophysiological conditions may be a critical component of disease pathology, such as in pulmonary hypertension. Drug compounds that bind metals like zinc may be able to treat diseases associated with impaired zinc homeostasis and altered ZIP12 function.
Fig. 1. Topology of human ZIP12. N and C indicate N-terminus and C-terminus, respectively. Dashed lines indicate transmembrane domains. Inclusion of exon 9, marked in gray, results in a splice variant with a longer cytoplasmic loop containing a histidine-rich region (motif HXGHXHH, X indicates amino acids not conserved across mammals). Motifs HNF and HEIPHEMGD in transmembrane regions 4 and 5 are fully conserved across different vertebrates and largely conserved across ZIP proteins. Amino acids in light gray are partially conserved between human ZIP4.
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