SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside

Daniel W Nebert,Zijuan Liu

doi:10.1186/s40246-019-0233-3

Daniel W Nebert, Zijuan Liu

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https://doi.org/10.1186/s40246-019-0233-3

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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.

Highlights

It could be said that “the SLC39A8 story began in 1919,” when cadmium (Cd2+; Cd2+ cadmium ion (Cd)), administered subcutaneously to the rat, was shown to cause acute testicular necrosisTaking advantage of the latest advances in molecular biology techniques, it became possible to identify unequivocally the mouse gene primarily responsible for the Cd-responsiveness trait
Following incubation with Cd, the Thr-391 variant was found to have lower intracellular Cd levels with accompanying less Cd-induced toxicity, decreased phosphorylation of mitogen-activated protein kinase-1 (MAPK1), and lowered NFκB activation; not surprisingly, the same differences were seen in vascular endothelial cells [68]; the authors suggest that the ZIP8 Thr-391 variant is “ mechanistically responsible for lower serum High-density lipoprotein (HDL)-Chol levels, coronary artery disease, and hypotension”—this connection remains to be elucidated in their study
Expression of the Mouse gene encoding ZIP8 (Slc39a8)-encoded ZIP8 transporter of cation uptake is detectable in mouse gastrula and visceral

Summary

Introduction

It could be said that “the SLC39A8 story began in 1919,” when cadmium (Cd2+; Cd), administered subcutaneously to the rat, was shown to cause acute testicular necrosisTaking advantage of the latest advances in molecular biology techniques, it became possible to identify unequivocally the mouse gene primarily responsible for the Cd-responsiveness trait. Following incubation with Cd, the Thr-391 variant was found to have lower intracellular Cd levels with accompanying less Cd-induced toxicity, decreased phosphorylation of mitogen-activated protein kinase-1 (MAPK1), and lowered NFκB activation; not surprisingly, the same differences were seen in vascular endothelial cells [68]; the authors suggest that the ZIP8 Thr-391 variant is “ mechanistically responsible for lower serum HDL-Chol levels, coronary artery disease, and hypotension”—this connection remains to be elucidated in their study.

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