Table 1.
Properties and phenotypes reported, to date, for mammalian SLC39A8 gene.
| Organ or system | Properties/Phenotypes of mammalian SLC39A8 gene (and its encoded ZIP8 transporter) | References |
|---|---|---|
| Systemic | Mouse ZIP8 transports Zn2+, Mn2+, Cd2+/and probably Fe2+ and Co2+ — each presumanly as a M++/(HCO3−)2 electroneutral complex, moving ions into the cell; Slc39a8(neo/neo) knockdown fetus exhibits stunted growth, and neonatal lethality; Human SLC39A8 regulates manganese homeostasis and manganese-dependent enzyme activities, posttranslational glycosylation, and causes mitochondrial disorders; Mouse ZIP8 is required for Mn2+-dependent enzyme activities; Human SLC39A8 variant associated with increased body mass index | 2, 4, 5, 7, 13, 14, 19, 20, 32, 79 |
| Developmental | Mouse Slc39a8 expressed in visceral endoderm at gestational day (GD)7.5, in the gastrula at earlier development, and expressed in pluripotent embryonic stem cells; Mouse Slc39a8(neo/neo) global knockout is early embryo-lethal; Slc39a8(neo/neo) knockdown fetus exhibits multi-organ dysmorphogenesis and decreases in size of placenta | 9– 13, 18– 20, 80 |
| Liver | Mouse Slc39a8(neo) allele is associated with highly significantly decreased liver size; Mouse ZIP8 transports selenium, presumably as a Zn2+/(HCO3−)(HSeO3−) electroneutral complex; Mouse hepatic ZIP8 rescues Mn2+ from bile, regulates whole-body Mn2+ homeostasis, and modulates activity of Mn2+-dependent enzymes | 6, 13, 14, 18, 19 |
| Kidney | Mouse Slc39a8(neo) allele is associated with highly significantly decreased kidney size; Human SLC39A8 variant associated with blood pressure | 13, 21 |
| Lung | Mouse Slc39a8(neo) allele is associated with highly significantly decreased lung size; Human ZIP8 participates in Zn2+-mediated cytoprotection in lung inflammation | 13, 22, 23 |
| Cardiovascular system | Mouse Slc39a8(neo/neo) knockdown fetus shows trenda toward enlarged heart size; Human SLC39A8 variant associated with increased serum lipid levels, regulation of blood pressure, and risk of coronary artery disease; Human SLC39A8 variant associated with increased risk of acute coronary syndrome; Human SLC39A8 variant associated with increased risk of increased atherosclerosis in smokers; Mouse Slc39a8 is essential for cardiac ventricular compaction | 13, 15, 21, 26– 31 |
| Blood chemistry | Mouse Slc39a8(neo/neo) neonate shows significantly decreased total iron, total iron-binding capacity, serum ALT & AST levels,b and serum triglyceride levels; Human SLC39A8 variant associated with blood levels of toxic metals | 13, 32 |
| Hematological system | Mouse Slc39a8(neo/neo) knockdown fetus exhibits severe anemia and dysregulation of hematopoiesis; Slc39a8(neo/neo) GD13.5 yolk sac and placenta shows smaller size and number of hematopoietic islands; Slc39a8(neo/neo) GD16.5 liver reveals decreased size and number of hematopoietic islands | 13 |
| Immune system | ZIP8 originally discovered in human monocytes; Human ZIP8 participates in Zn2+-mediated immune response to inflammation, participates in innate immune response to endotoxin-induced macrophage inflammation, and host response in macrophages to Mycbacterium tuberculosis | 17, 22– 25 |
| Central nervous system | Mouse Slc39a8(neo/neo) knockdown fetus shows trenda in smaller size of cerebrum and cerebellum; Human SLC39A8 variant associated with increased risk of schizophrenia; Human SLC39A8 variant associated with impaired intellectual ability and cerebellar atrophy | 13, 18– 20, 33, 34 |
| Eye | Human SLC39A8 variant associated with retinal iron accumulation | 35 |
| Spleen | Mouse Slc39a8(neo) allele is associated with highly significantly decreased spleen size | 13 |
| Gastrointestinal tract | Human SLC39A8 variant associated with Crohn disease and human gut microbiome composition | 36 |
| Musculoskeletal system | Mouse Slc39a8(neo/neo) knockdown fetus exhibits shortened limbs, and deformed skull; Human SLC39A8 variant associated with pathogenesis of osteoarthritis; Human SLC39A8 variant associated with severe limb malformations | 13, 18, 19, 37, 38 |
| Reproductive system | Mouse Slc39a8 variant is associated with Cd2+-induced testicular necrosis | 1– 3, 16 |
aThe term “trend’” denotes P-value > 0.05 < 0.10.
bALT, alanine aminotransferase (common measurement used to assess damage largely in liver); AST, aspartate aminotransferase (common measurement used to assess damage in heart, skeletal muscle, kidney and brain, as well as liver.