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Glen K. Andrews - One of the best experts on this subject based on the ideXlab platform.
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Extreme Population Differences in the Human Zinc Transporter ZIP4 (SLC39A4) Are Explained by Positive Selection in Sub-Saharan Africa
2016Co-Authors: Johannes Engelken, Elena Carnero-montoro, Marc Pybus, Glen K. Andrews, Carles Lalueza-fox, David Comas, Israel Sekler, Marco De La Rasilla, Antonio Rosas, Mark StonekingAbstract:Extreme differences in allele frequency between West Africans and Eurasians were observed for a leucine-to-valine substitution (Leu372Val) in the human intestinal zinc uptake transporter, ZIP4, yet no further evidence was found for a selective sweep around the ZIP4 gene (SLC39A4). By interrogating allele frequencies in more than 100 diverse human populations and resequencing Neanderthal DNA, we confirmed the ancestral state of this locus and found a strong geographical gradient for the derived allele (Val372), with near fixation in West Africa. In extensive coalescent simulations, we show that the extreme differences in allele frequency, yet absence of a classical sweep signature, can be explained by the effect of a local recombination hotspot, together with directional selection favoring the Val372 allele in Sub-Saharan Africans. The possible functional effect of the Leu372Val substitution, together with two pathological mutations at the same codon (Leu372Pro and Leu372Arg) that cause acrodermatitis enteropathica (a disease phenotype characterized by extreme zinc deficiency), was investigated by transient overexpression of human ZIP4 protein in HeLa cells. Both acrodermatiti
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4Department of Integrative and Molecular Physiology
2015Co-Authors: Jodi Dufner-beattie, Jim Geiser, Benjamin P Weaver, Mehmet Bilgen, Glen K. AndrewsAbstract:The mouse acrodermatitis enteropathica gene SLC39A4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficienc
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slc39a9 zip9 regulates zinc homeostasis in the secretory pathway characterization of the zip subfamily i protein in vertebrate cells
Bioscience Biotechnology and Biochemistry, 2009Co-Authors: Wataru Matsuura, Glen K. Andrews, Tomohiro Yamazaki, Yuko Yamaguchiiwai, Seiji Masuda, Masaya Nagao, Taiho KambeAbstract:The SLC39A family of zinc transporters can be divided into four subfamilies (I, II, LIV-1, and gufA) in vertebrates, but studies of their functions have been restricted exclusively to members of subfamilies II and LIV-1. In this study, we characterized SLC39A9 (ZIP9), the only member of subfamily I in vertebrates. Confocal microscopy demonstrated that transiently expressed, HA-tagged human ZIP9 (hZIP9-HA) was localized to the trans-Golgi network regardless of zinc status. Disruption of the ZIP9 gene in DT40 cells did not change the growth rate, sensitivity to high zinc and manganese concentrations during long-term culture, or cellular zinc status after short-term incubation with zinc. The alkaline phosphatase activity of ZIP9 −⁄− cells did not change in cells cultured in medium containing normal zinc levels. In contrast, the activity of this enzyme decreased in wild-type cells cultured in zinc deficient medium but less so in ZIP9 −⁄− cells under these conditions. Stable over-expression of hZIP9-HA moderat...
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novel proteolytic processing of the ectodomain of the zinc transporter zip4 SLC39A4 during zinc deficiency is inhibited by acrodermatitis enteropathica mutations
Molecular and Cellular Biology, 2009Co-Authors: Taiho Kambe, Glen K. AndrewsAbstract:Zinc deficiency during pregnancy impairs embryonic, fetal, and postnatal development, leading to growth retardation, abnormal morphogenesis, immune system dysfunction, skin lesions, and neurological disorders in mammals (reviewed in references 8 and 22). Therefore, the ability to acquire zinc from the diet via the intestine and transfer it to the embryonic environment via the visceral yolk sac ([VYS] in mice) plays a critical role in the growth and morphogenesis of the embryo and subsequent health status of offspring. The zinc transporter SLC39A4 (ZIP4) is an essential component for the acquisition of zinc. Mutations in the human SLC39A4 gene cause a rare autosomal recessive genetic disorder of zinc deficiency called acrodermatitis enteropathica (AE) (10, 32); in mice the SLC39A4 gene is essential during early embryogenesis, and homozygous embryos die soon after implantation (5). Furthermore, heterozygous SLC39A4 knockout mice are significantly underrepresented after birth and are hypersensitive to dietary zinc deficiency (5). Recent studies reveal that the expression of SLC39A4 is regulated at multiple posttranscriptional levels in response to changes in zinc availability (2, 9, 15, 33). For example, during zinc deficiency this mRNA is stabilized, leading to increased accumulation of SLC39A4 mRNA and ZIP4 protein and the localization of ZIP4 at the apical surfaces of enterocytes and visceral endoderm cells (4, 33). In contrast, repletion of zinc to normal levels causes the rapid endocytosis and degradation of ZIP4 and destabilization of SLC39A4 mRNA (33). Similar results were obtained with in vitro transfection studies of recombinant ZIP4, which demonstrated that ZIP4 was degraded via a process that requires both the proteasomal and lysosomal compartments (9, 15). Thus, dynamic posttranscriptional control of ZIP4 in response to zinc plays an important role in regulating zinc homeostasis. Previous studies from our laboratory revealed that during prolonged zinc deficiency, apparently full-length ZIP4 and its glycosylated forms (∼75 kDa and larger) are detectable in membrane preparations from the intestine and VYS, but by far the major immunoreactive ZIP4 peptide detected by Western blotting was ∼37 kDa in apparent molecular mass, or about half the predicted size of full-length ZIP4 (2, 7, 33). This observation was explored further herein, and our results demonstrate that the ∼37-kDa peptide represents ZIP4 lacking the N-terminal extracellular domain or ectodomain. This novel processing of ZIP4 occurs in response to zinc deficiency in polarized epithelial cells like MDCK and CaCo2 as well as in mouse Hepa cells, mimicking the results obtained in mice. The evidence suggests that the ectodomain of ZIP4 accumulates as a peripheral membrane protein, whereas the remainder of the processed protein is apparently recycled back to the apical membrane. Overexpression of processed ZIP4 or ZIP4 with ectodomain truncations correlated with hypersensitivity to zinc, as shown by a dramatic reduction in the dose response for induction of Mt1 (metallothionein 1) gene expression. Furthermore, AE mutations near the predicted cleavage site of the ectodomain block processing of ZIP4. Thus, this novel regulation of ZIP4 may be an additional and important regulatory mechanism controlling zinc transport or other activities of this critical zinc transporter.
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novel zinc responsive post transcriptional mechanisms reciprocally regulate expression of the mouse SLC39A4 and slc39a5 zinc transporters zip4 and zip5
Biological Chemistry, 2007Co-Authors: Benjamin P Weaver, Jodi Dufnerbeattie, Taiho Kambe, Glen K. AndrewsAbstract:Dietary zinc deficiency in mice is accompanied by enhanced expression of the zinc uptake transporter SLC39A4 (Zip4) and repressed expression of Slc39a5 (Zip5) in tissues which regulate zinc homeostasis (intestine, pancreas and visceral yolk sac). Herein, mechanisms controlling this differential expression were investigated. The induction of Zip4 mRNA during zinc deficiency, and its repression in response to zinc repletion were found to reflect changes in Zip4 mRNA stability and not changes in the relative rate of transcription of this gene. During zinc deficiency, ZIP4 protein levels are increased and this protein is localized on the apical membranes. Administration of an oral gavage of zinc caused ZIP4 internalization and degradation in enterocytes and visceral endoderm cells. Similarly, ZIP4 is induced by zinc deficiency in cultured mouse Hepa cells and is rapidly degraded in response to added zinc. Zip5 mRNA abundance does not change in response to zinc, but the translation of this mRNA was found to be zinc-responsive. During zinc deficiency, Zip5 mRNA remains associated with polysomes, while the protein is internalized and degraded in enterocytes, acinar cells and endoderm cells. After zinc-gavage, ZIP5 is rapidly resynthesized and targeted to the basolateral membranes of these cell types.
S Kury - One of the best experts on this subject based on the ideXlab platform.
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clinical utility gene card for acrodermatitis enteropathica update 2015
European Journal of Human Genetics, 2016Co-Authors: S Kury, Monia Kharfi, Eric Blouin, Sebastien Schmitt, Stephane BezieauAbstract:1. Name of the disease (synonyms) Acrodermatitis enteropathica (AEZ). 2. OMIM# of the disease 201100. 3. Name of the analyzed genes or DNA/chromosome segments SLC39A4. 4. OMIM# of the gene(s) 607059. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the SLC39A4 gene in diagnostic settings and for risk assessment in relatives.
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identification of a novel mutation in the SLC39A4 gene in a case of acrodermatitis enteropathica
Acta Dermato-venereologica, 2016Co-Authors: Rudiger Panzer, S Kury, Sebastien Schmitt, Regina FolsterholstAbstract:Acrodermatitis enteropathica is an autosomal recessive disorder with hypozincaemia due to impaired intestinal absorption of zinc. It is the result of a mutation in the SLC39A4 gene encoding the zinc transporter protein ZIP4. The symptoms develop shortly after weaning. Dermatological signs include highly exudative periorificial and acral lesions. The lesions are typically accompanied by alopecia, diarrhoea and impaired development. We report here a case of an infant with typical dermatological signs of zinc deficiency. Zinc substitution resulted in rapid resolution of the symptoms. Genetic analysis revealed compound heterozygosity of a novel mutation c.1130_1140dup (p.Thr381Serfs*4) in the SLC39A4 gene, inducing a premature stop codon at position 384, and the well-known mutation c.1120G>A (p.Gly374Arg).
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autosomal recessive intellectual disability with cerebellar atrophy syndrome caused by mutation of the manganese and zinc transporter gene slc39a8
American Journal of Human Genetics, 2015Co-Authors: Kym M Boycott, Chandree L Beaulieu, Kristin D Kernohan, Ola H Gebril, Aziz Mhanni, Albert E Chudley, David Redl, Wen Qin, Sarah Hampson, S KuryAbstract:Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development.
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acrodermatitis enteropathica a novel SLC39A4 gene mutation in a patient with normal zinc levels
Pediatric Dermatology, 2015Co-Authors: Veronica Garzarodriguez, S Schmitt, S Kury, Alberto De La Fuentegarcia, Carmen Liywong, Ijaz S Jamall, Jorge OcampocandianiAbstract:Acrodermatitis enteropathica (AE) is a rare disease that results from a defective gene, SLC39A4, and is characterized by dermatitis, alopecia, and diarrhea. We report a case of AE presenting with only periorificial and acral dermatitis in which genetic testing revealed two novel compound heterozygous missense mutations for SLC39A4. This case demonstrates that not all AE mutations alter zinc transporters in the same manner and highlights the phenotypic variability of AE.
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a zinc sulphate resistant acrodermatitis enteropathica patient with a novel mutation in SLC39A4 gene
JIMD reports, 2011Co-Authors: Mustafa Kilic, M Taskesen, Turgay Coskun, F Gurakan, A Tokatli, Hatice Serap Sivri, Ali Dursun, S Schmitt, S KuryAbstract:Acrodermatitis enteropathica (AE) is a rare autosomal recessive disorder of zinc deficiency due to an abnormal intestinal zinc transporter. It is characterized by the triad of acral dermatitis, alopecia, and diarrhoea. Once AE is correctly diagnosed, patients are treated with orally administered zinc sulphate. In some patients, relapses occur during adolescence, despite the regular treatment. Here, we discuss the clinical and molecular features of a 13-year-old adolescent girl with acrodermatitis enteropathica who was resistant to high-dose zinc sulphate therapy. We successfully treated the patient with zinc gluconate and vitamin C, and we detected a novel homozygous c.541_551dup (p.Leu186fsX38) mutation in the exon 3 of her SLC39A4 gene.
Jodi Dufnerbeattie - One of the best experts on this subject based on the ideXlab platform.
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novel zinc responsive post transcriptional mechanisms reciprocally regulate expression of the mouse SLC39A4 and slc39a5 zinc transporters zip4 and zip5
Biological Chemistry, 2007Co-Authors: Benjamin P Weaver, Jodi Dufnerbeattie, Taiho Kambe, Glen K. AndrewsAbstract:Dietary zinc deficiency in mice is accompanied by enhanced expression of the zinc uptake transporter SLC39A4 (Zip4) and repressed expression of Slc39a5 (Zip5) in tissues which regulate zinc homeostasis (intestine, pancreas and visceral yolk sac). Herein, mechanisms controlling this differential expression were investigated. The induction of Zip4 mRNA during zinc deficiency, and its repression in response to zinc repletion were found to reflect changes in Zip4 mRNA stability and not changes in the relative rate of transcription of this gene. During zinc deficiency, ZIP4 protein levels are increased and this protein is localized on the apical membranes. Administration of an oral gavage of zinc caused ZIP4 internalization and degradation in enterocytes and visceral endoderm cells. Similarly, ZIP4 is induced by zinc deficiency in cultured mouse Hepa cells and is rapidly degraded in response to added zinc. Zip5 mRNA abundance does not change in response to zinc, but the translation of this mRNA was found to be zinc-responsive. During zinc deficiency, Zip5 mRNA remains associated with polysomes, while the protein is internalized and degraded in enterocytes, acinar cells and endoderm cells. After zinc-gavage, ZIP5 is rapidly resynthesized and targeted to the basolateral membranes of these cell types.
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the mouse acrodermatitis enteropathica gene SLC39A4 zip4 is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency
Human Molecular Genetics, 2007Co-Authors: Jodi Dufnerbeattie, Benjamin P Weaver, Jim Geiser, Mehmet Bilgen, Melissa C Larson, Wenhao Xu, Glen K. AndrewsAbstract:The human Zip4 gene (SLC39A4) is mutated in the rare recessive genetic disorder of zinc metabolism acrodermatitis enteropathica, but the physiological functions of Zip4 are not well understood. Herein we demonstrate that homozygous Zip4-knockout mouse embryos die during early morphogenesis and heterozygous offspring are significantly underrepresented. At mid-gestation, an array of developmental defects including exencephalia, anophthalmia and severe growth retardation were noted in heterozygous embryos, and at weaning, many (63/280) heterozygous offspring were hydrocephalic, growth retarded and missing one or both eyes. Maternal dietary zinc deficiency during pregnancy exacerbated these effects, whereas zinc excess ameliorated these effects and protected embryonic development of heterozygotes but failed to rescue homozygous embryos. Heterozygous Zip4 embryos were not underrepresented in litters from wild-type mothers, but were ∼10 times more likely to develop abnormally than were their wild-type littermates during zinc deficiency. Thus, both embryonic and maternal Zip4 gene expressions are critical for proper zinc homeostasis. These studies suggest that heterozygous mutations in the acrodermatitis gene Zip4 may be associated with a wider range of developmental defects than was previously appreciated, particularly when dietary zinc is limiting.
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the mouse acrodermatitis enteropathica gene SLC39A4 zip4 is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency
Human Molecular Genetics, 2007Co-Authors: Jodi Dufnerbeattie, Benjamin P Weaver, Jim Geiser, Mehmet Bilgen, Melissa C Larson, Glen K. AndrewsAbstract:The human Zip4 gene (SLC39A4) is mutated in the rare recessive genetic disorder of zinc metabolism acrodermatitis enteropathica, but the physiological functions of Zip4 are not well understood. Herein we demonstrate that homozygous Zip4-knockout mouse embryos die during early morphogenesis and heterozygous offspring are significantly underrepresented. At mid-gestation, an array of developmental defects including exencephalia, anophthalmia and severe growth retardation were noted in heterozygous embryos, and at weaning, many (63/280) heterozygous offspring were hydrocephalic, growth retarded and missing one or both eyes. Maternal dietary zinc deficiency during pregnancy exacerbated these effects, whereas zinc excess ameliorated these effects and protected embryonic development of heterozygotes but failed to rescue homozygous embryos. Heterozygous Zip4 embryos were not underrepresented in litters from wild-type mothers, but were approximately 10 times more likely to develop abnormally than were their wild-type littermates during zinc deficiency. Thus, both embryonic and maternal Zip4 gene expressions are critical for proper zinc homeostasis. These studies suggest that heterozygous mutations in the acrodermatitis gene Zip4 may be associated with a wider range of developmental defects than was previously appreciated, particularly when dietary zinc is limiting.
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targeting of the mouse slc39a2 zip2 gene reveals highly cell specific patterns of expression and unique functions in zinc iron and calcium homeostasis
Genesis, 2007Co-Authors: Jennifer L Peters, Jodi Dufnerbeattie, Jim Geiser, Brett Lahner, David E Salt, Glen K. AndrewsAbstract:Fourteen members of the Slc39a superfamily of metal ion uptake transporters have been identified in mice and humans, but the physiological functions of most remain obscure. Herein, we created mice with Zip2 (Slc39a2) genes in which the open reading frame was replaced with that of the enhanced green fluorescent protein (EGFP), to study temporal and spatial patterns of Zip2 gene expression and examine the physiological roles of this transporter. Expression of this gene was remarkably cell-type specific and developmentally regulated in pericentral hepatocytes, developing keratinocytes, and a subset of immature dendritic cells in the immune system. In addition, the Zip2 gene was transiently expressed in giant trophoblast cells in the placenta. Although the Zip2 gene was not essential under conditions of normal dietary zinc, it played an important role in adapting to dietary zinc deficiency during pregnancy, and in the homeostasis of iron in the liver as well as iron and calcium in developing embryos. These studies suggest that active expression of the Zip2 gene in these few specific cell types, aforementioned, plays a particularly important role during zinc deficiency. These studies further reveal novel interactions between zinc transporter function and the homeostasis of other essential metals.
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acrodermatitis enteropathica mutations affect transport activity localization and zinc responsive trafficking of the mouse zip4 zinc transporter
Human Molecular Genetics, 2004Co-Authors: Fudi Wang, Glen K. Andrews, Byungeun Kim, Jodi Dufnerbeattie, Michael J Petris, David J. EideAbstract:The Zip4 protein is involved in dietary zinc uptake from the intestinal lumen. The human ZIP4 gene (SLC39A4) was identified because of its association with acrodermatitis enteropathica (AE), a genetic disorder of zinc absorption. To date, several SLC39A4 mutations have been identified in AE patients. To investigate the effects of these mutations on function of the Zip4 transporter, we introduced six AE-associated missense mutations into the orthologous mouse ZIP4 gene for functional expression in cultured cells. All mutations decreased 65Zn uptake activity of mZip4, thereby providing a causal link to AE. The mutants fell into two groups based on their phenotypic effects. Several alleles (G340D, L382P, G384R, G643R) failed to localize on the cell surface at high levels. These defects were attributable to misfolding and/or mislocalization in the secretory pathway. Two other alleles (P200L and G539R) accumulated to high levels in the plasma membrane and had wild-type apparent Km values for 65Zn uptake. However, these mutations decreased the Vmax of uptake to approximately 30% of wild-type. We showed previously that wild-type mZip4 is regulated post-translationally in response to zinc status. In zinc-replete cells, mZip4 is found largely in intracellular compartments. In zinc-limited cells, surface levels increase markedly because the rate of endocytosis decreases. Surprisingly, endocytosis of both P200L and G539R is no longer zinc responsive; these proteins are endocytosed at a slow rate regardless of zinc status. These effects suggest a zinc sensing mechanism for regulating Zip4 trafficking in response to zinc.
Toshiyuki Fukada - One of the best experts on this subject based on the ideXlab platform.
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An Acrodermatitis Enteropathica-Associated Zn Transporter, ZIP4, Regulates Human Epidermal Homeostasis
Journal of Investigative Dermatology, 2017Co-Authors: Bum Ho Bin, Su Hyon Lee, Nan Hyung Kim, Juyeon Seo, Dae Kyum Kim, Jinhyuk Bhin, Haeng Sun Jung, Daehee Hwang, Toshiyuki Fukada, Ai Young LeeAbstract:Acrodermatitis enteropathica is an autosomal recessive disorder characterized by scaly eczematous dermatosis accompanied by alopecia and diarrhea. Various mutations in the SLC39A4 gene (ZIP4), which encodes a zinc transporter, are responsible for this disorder. However, the molecular mechanism underlying the involvement of ZIP4 in the pathogenesis of this condition has yet to be established. In this study, we report the role of ZIP4 in human epidermis. ZIP4 is predominantly expressed in human keratinocytes, and its expression is dramatically reduced on epidermal differentiation. ZIP4 knockdown in human keratinocytes down-regulates zinc (Zn) levels and the transcriptional activity of a key epidermal Zn-binding protein, ΔNp63, and dysregulates epidermal differentiation in a reconstituted human skin model, resulting in the appearance of proliferating keratinocytes even in the uppermost layers of the skin. We verified that, among the amino acid residues in its Zn-binding motif, Cys205 is critical for the processing and nuclear distribution of ΔNp63 and, therefore, Zn-dependent transcriptional activity. Our results suggest that ZIP4 is essential for maintaining human epidermal homeostasis through the regulation of Zn-dependent ΔNp63 activity and can provide insight into the molecular mechanisms responsible for the cutaneous symptoms observed in Acrodermatitis enteropathica patients.
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slc39a14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis
Cell Metabolism, 2015Co-Authors: Supak Jenkitkasemwong, Toshiyuki Fukada, Shintaro Hojyo, Chiayu Wang, Richard Coffey, Wei Zhang, Alan Chan, Thomas G Biel, Jaesung KimAbstract:Nearly all forms of hereditary hemochromatosis are characterized by pathological iron accumulation in the liver, pancreas, and heart. These tissues preferentially load iron because they take up non-transferrin-bound iron (NTBI), which appears in the plasma during iron overload. Yet, how tissues take up NTBI is largely unknown. We report that ablation of Slc39a14, the gene coding for solute carrier SLC39A14 (also called ZIP14), in mice markedly reduced the uptake of plasma NTBI by the liver and pancreas. To test the role of SLC39A14 in tissue iron loading, we crossed Slc39a14(-/-) mice with Hfe(-/-) and Hfe2(-/-) mice, animal models of type 1 and type 2 (juvenile) hemochromatosis, respectively. Slc39a14 deficiency in hemochromatotic mice greatly diminished iron loading of the liver and prevented iron deposition in hepatocytes and pancreatic acinar cells. The data suggest that inhibition of SLC39A14 may mitigate hepatic and pancreatic iron loading and associated pathologies in iron overload disorders.
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the zinc transporter slc39a14 zip14 controls g protein coupled receptor mediated signaling required for systemic growth
PLOS ONE, 2011Co-Authors: Shintaro Hojyo, Bum Ho Bin, Toshiyuki Fukada, Shinji Shimoda, Wakana Ohashi, Haruhiko Koseki, Toshio HiranoAbstract:Aberrant zinc (Zn) homeostasis is associated with abnormal control of mammalian growth, although the molecular mechanisms of Zn's roles in regulating systemic growth remain to be clarified. Here we report that the cell membrane-localized Zn transporter SLC39A14 controls G-protein coupled receptor (GPCR)-mediated signaling. Mice lacking Slc39a14 (Slc39a14-KO mice) exhibit growth retardation and impaired gluconeogenesis, which are attributable to disrupted GPCR signaling in the growth plate, pituitary gland, and liver. The decreased signaling is a consequence of the reduced basal level of cyclic adenosine monophosphate (cAMP) caused by increased phosphodiesterase (PDE) activity in Slc39a14-KO cells. We conclude that SLC39A14 facilitates GPCR-mediated cAMP-CREB signaling by suppressing the basal PDE activity, and that this is one mechanism for Zn's involvement in systemic growth processes. Our data highlight SLC39A14 as an important novel player in GPCR-mediated signaling. In addition, the Slc39a14-KO mice may be useful for studying the GPCR-associated regulation of mammalian systemic growth.
Benjamin P Weaver - One of the best experts on this subject based on the ideXlab platform.
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4Department of Integrative and Molecular Physiology
2015Co-Authors: Jodi Dufner-beattie, Jim Geiser, Benjamin P Weaver, Mehmet Bilgen, Glen K. AndrewsAbstract:The mouse acrodermatitis enteropathica gene SLC39A4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficienc
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novel zinc responsive post transcriptional mechanisms reciprocally regulate expression of the mouse SLC39A4 and slc39a5 zinc transporters zip4 and zip5
Biological Chemistry, 2007Co-Authors: Benjamin P Weaver, Jodi Dufnerbeattie, Taiho Kambe, Glen K. AndrewsAbstract:Dietary zinc deficiency in mice is accompanied by enhanced expression of the zinc uptake transporter SLC39A4 (Zip4) and repressed expression of Slc39a5 (Zip5) in tissues which regulate zinc homeostasis (intestine, pancreas and visceral yolk sac). Herein, mechanisms controlling this differential expression were investigated. The induction of Zip4 mRNA during zinc deficiency, and its repression in response to zinc repletion were found to reflect changes in Zip4 mRNA stability and not changes in the relative rate of transcription of this gene. During zinc deficiency, ZIP4 protein levels are increased and this protein is localized on the apical membranes. Administration of an oral gavage of zinc caused ZIP4 internalization and degradation in enterocytes and visceral endoderm cells. Similarly, ZIP4 is induced by zinc deficiency in cultured mouse Hepa cells and is rapidly degraded in response to added zinc. Zip5 mRNA abundance does not change in response to zinc, but the translation of this mRNA was found to be zinc-responsive. During zinc deficiency, Zip5 mRNA remains associated with polysomes, while the protein is internalized and degraded in enterocytes, acinar cells and endoderm cells. After zinc-gavage, ZIP5 is rapidly resynthesized and targeted to the basolateral membranes of these cell types.
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the mouse acrodermatitis enteropathica gene SLC39A4 zip4 is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency
Human Molecular Genetics, 2007Co-Authors: Jodi Dufnerbeattie, Benjamin P Weaver, Jim Geiser, Mehmet Bilgen, Melissa C Larson, Wenhao Xu, Glen K. AndrewsAbstract:The human Zip4 gene (SLC39A4) is mutated in the rare recessive genetic disorder of zinc metabolism acrodermatitis enteropathica, but the physiological functions of Zip4 are not well understood. Herein we demonstrate that homozygous Zip4-knockout mouse embryos die during early morphogenesis and heterozygous offspring are significantly underrepresented. At mid-gestation, an array of developmental defects including exencephalia, anophthalmia and severe growth retardation were noted in heterozygous embryos, and at weaning, many (63/280) heterozygous offspring were hydrocephalic, growth retarded and missing one or both eyes. Maternal dietary zinc deficiency during pregnancy exacerbated these effects, whereas zinc excess ameliorated these effects and protected embryonic development of heterozygotes but failed to rescue homozygous embryos. Heterozygous Zip4 embryos were not underrepresented in litters from wild-type mothers, but were ∼10 times more likely to develop abnormally than were their wild-type littermates during zinc deficiency. Thus, both embryonic and maternal Zip4 gene expressions are critical for proper zinc homeostasis. These studies suggest that heterozygous mutations in the acrodermatitis gene Zip4 may be associated with a wider range of developmental defects than was previously appreciated, particularly when dietary zinc is limiting.
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the mouse acrodermatitis enteropathica gene SLC39A4 zip4 is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency
Human Molecular Genetics, 2007Co-Authors: Jodi Dufnerbeattie, Benjamin P Weaver, Jim Geiser, Mehmet Bilgen, Melissa C Larson, Glen K. AndrewsAbstract:The human Zip4 gene (SLC39A4) is mutated in the rare recessive genetic disorder of zinc metabolism acrodermatitis enteropathica, but the physiological functions of Zip4 are not well understood. Herein we demonstrate that homozygous Zip4-knockout mouse embryos die during early morphogenesis and heterozygous offspring are significantly underrepresented. At mid-gestation, an array of developmental defects including exencephalia, anophthalmia and severe growth retardation were noted in heterozygous embryos, and at weaning, many (63/280) heterozygous offspring were hydrocephalic, growth retarded and missing one or both eyes. Maternal dietary zinc deficiency during pregnancy exacerbated these effects, whereas zinc excess ameliorated these effects and protected embryonic development of heterozygotes but failed to rescue homozygous embryos. Heterozygous Zip4 embryos were not underrepresented in litters from wild-type mothers, but were approximately 10 times more likely to develop abnormally than were their wild-type littermates during zinc deficiency. Thus, both embryonic and maternal Zip4 gene expressions are critical for proper zinc homeostasis. These studies suggest that heterozygous mutations in the acrodermatitis gene Zip4 may be associated with a wider range of developmental defects than was previously appreciated, particularly when dietary zinc is limiting.
