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

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          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 Mn 2+, Zn 2+, Fe 2+, Se 4+, and Co 2+ 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 Mn 2+-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.

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          Genetic compensation triggered by mutant mRNA degradation

          Genetic robustness, or the ability of an organism to maintain fitness in the presence of mutations, can be achieved via protein feedback loops. Recent evidence suggests that organisms may also respond to mutations by upregulating related gene(s) independently of protein feedback loops, a phenomenon called transcriptional adaptation. However, the prevalence of transcriptional adaptation and its underlying molecular mechanisms are unknown. Here, by analyzing several models of transcriptional adaptation in zebrafish and mouse, we show a requirement for mRNA degradation. Alleles that fail to transcribe the mutated gene do not display transcriptional adaptation and exhibit more severe phenotypes than alleles displaying mutant mRNA decay. Transcriptome analysis reveals the upregulation of a substantial proportion of the genes that exhibit sequence similarity with the mutated gene’s mRNA, suggesting a sequence dependent mechanism. Besides implications for our understanding of disease-causing mutations, these findings will help design mutant alleles with minimal transcriptional adaptation-derived compensation.
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            A single-cell molecular map of mouse gastrulation and early organogenesis

            Across the animal kingdom, gastrulation represents a key developmental event during which embryonic pluripotent cells diversify into lineage-specific precursors that will generate the adult organism. Here we report the transcriptional profiles of 116,312 single cells from mouse embryos collected at nine sequential time-points ranging from 6.5 to 8.5 days post-fertilisation. We reconstruct a molecular map of cellular differentiation from pluripotency towards all major embryonic lineages, and explore the complex events involved in the convergence of visceral and primitive streak-derived endoderm. Furthermore, we demonstrate how combining temporal and transcriptional information illuminates gene function by single-cell profiling of Tal1 −/− chimeric embryos, with our analysis revealing defects in early mesoderm diversification. Taken together, this comprehensive delineation of mammalian cell differentiation trajectories in vivo represents a baseline for understanding the effects of gene mutations during development as well as a baseline for the optimisation of in vitro differentiation protocols for regenerative medicine.
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              Human ATP-binding cassette (ABC) transporter family

              There exist four fundamentally different classes of membrane-bound transport proteins: ion channels; transporters; aquaporins; and ATP-powered pumps. ATP-binding cassette (ABC) transporters are an example of ATP-dependent pumps. ABC transporters are ubiquitous membrane-bound proteins, present in all prokaryotes, as well as plants, fungi, yeast and animals. These pumps can move substrates in (influx) or out (efflux) of cells. In mammals, ABC transporters are expressed predominantly in the liver, intestine, blood-brain barrier, blood-testis barrier, placenta and kidney. ABC proteins transport a number of endogenous substrates, including inorganic anions, metal ions, peptides, amino acids, sugars and a large number of hydrophobic compounds and metabolites across the plasma membrane, and also across intracellular membranes. The human genome contains 49 ABC genes, arranged in eight subfamilies and named via divergent evolution. That ABC genes are important is underscored by the fact that mutations in at least I I of these genes are already known to cause severe inherited diseases (eg cystic fibrosis and X-linked adrenoleukodystrophy [X-ALD]). ABC transporters also participate in the movement of most drugs and their metabolites across cell surface and cellular organelle membranes; thus, defects in these genes can be important in terms of cancer therapy, pharmacokinetics and innumerable pharmacogenetic disorders.
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                Author and article information

                Contributors
                dan.nebert@uc.edu
                Journal
                Hum Genomics
                Hum. Genomics
                Human Genomics
                BioMed Central (London )
                1473-9542
                1479-7364
                14 September 2019
                14 September 2019
                2019
                : 13
                : Suppl 1
                : 51
                Affiliations
                [1 ]ISNI 0000 0000 9881 9161, GRID grid.413561.4, Department of Environmental Health and Center for Environmental Genetics, , University of Cincinnati Medical Center, ; Cincinnati, OH 45267-0056 USA
                [2 ]ISNI 0000 0000 9025 8099, GRID grid.239573.9, Division of Human Genetics, Department of Pediatrics & Molecular Developmental Biology, , Cincinnati Children’s Hospital, ; Cincinnati, OH 45229-2899 USA
                [3 ]ISNI 0000 0001 2219 916X, GRID grid.261277.7, Department of Biological Sciences, , Oakland University, ; Rochester, MI 48309 USA
                Article
                233
                10.1186/s40246-019-0233-3
                6744627
                31521203
                2610752c-186f-43b7-8247-995fd5547760
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 24 May 2019
                : 14 August 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000066, National Institute of Environmental Health Sciences;
                Award ID: R01 ES010416
                Award ID: P30 ES006096
                Award Recipient :
                Funded by: Oakland University
                Award ID: Research Excellence Fund
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Genetics
                zip8 transporter,slc39a8 gene,manganese uptake,zinc uptake,iron uptake,selenium uptake,genome-wide association studies,cardiovascular disease,schizophrenia,type ii congenital disorder of glycosylation,leigh syndrome-like mitochondrial redox deficiency,parkinson disease,crohn disease,pleiotropy

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