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

Abstract

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.

Emerging Links between Cadmium Exposure and Insulin Resistance: Human, Animal, and Cell Study Data

“…There is evidence that mitochondria can transport Cd via the calcium uniporter, resulting in interference of the K+/H+ exchanger [93]. Nearly forty years ago, a transport-specific deficiency was identified due to changes in Cd sensitivity encoded by the SLC39A8 gene [94]. The transporter encoded by this gene is highly conserved across species and has been shown to encode a specific element cation transporter referred to as ZIP8.…”

N‐glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency

“…5,6 Few detailed reports exist of SLC39A8-CDG (OMIM: 616721). 1,2,7 The pleiotropic effects of manganese deficiency are likely related to its function as a cofactor for a multitude of enzymes including arginase, glutamine synthetase, pyruvate carboxylase, manganese superoxide dismutase (MnSOD, SOD2) 8,9 and many Golgi glycosyltransferases. 10 Severe hypoglycosylation was among the initial observations in individuals with SLC39A8 deficiency, leading to the characterization of the disease as a type II congenital disorder of glycosylation (CDG).…”

A missense variant in SLC39A8 confers risk for Crohn’s disease by disrupting manganese homeostasis and intestinal barrier integrity

“…Due to its central role in Mn homeostasis and the requirement for Mn in a wide range of physiological processes, SLC39A8 has been associated with several clinical traits and diseases. The common SLC39A8 A391T missense variant is unique in its prevalence in European ancestry [8% minor-allele frequency (24)] and its unusual extent of pleiotropy (25,26). The minor allele A391T is associated with reduced Mn levels relative to the Significance SLC39A8 A391T exhibits remarkable pleiotropic effects on multiple conditions, including cardiovascular diseases, Parkinson's disease, and Crohn's disease.…”