title: The mouse acrodermatitis enteropathica gene Slc39a4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Virginia School of Medicine, PO Box 800734, Charlottesville, VA 22908, USA. beattie@apath.com
authors.forename: Jodi
authors.initials: J
authors.lastname: Dufner-Beattie
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Weaver
authors.forename: Jim
authors.initials: J
authors.lastname: Geiser
authors.forename: Mehmet
authors.initials: M
authors.lastname: Bilgen
authors.forename: Melissa
authors.initials: M
authors.lastname: Larson
authors.forename: Wenhao
authors.initials: W
authors.lastname: Xu
authors.forename: Glen K
authors.initials: GK
authors.lastname: Andrews
mesh_terms: D000169:Acrodermatitis / Q000235:genetics; D000483:Alleles; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D004707:Endoderm / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D015032:Zinc / Q000172:deficiency* / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; C477530:Slc39a4 protein, mouse; D015032:Zinc