Human Molecular Genetics Advance Access published online on May 4, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm088
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The mouse acrodermatitis enteropathica gene Slc39a4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency
1 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160-7421 4 Department of Integrative and Molecular Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160-7421 5 Hoglund Brain Imaging Center, University of Kansas Medical Center, Kansas City, Kansas 66160-7421
* Correspondence should be addressed to Dr. G.K. Andrews, Department of Biochemistry and Molecular Biology, Mail Stop 3030, University of Kansas Medical Center, 39th and Rainbow Blvd., Kansas City, KS. 66160-7421 Tel. (913) 588-6935; Fax (913) 588-3920 E-mail: gandrews{at}kumc.edu
Received February 28, 2007; Revised March 31, 2007; Accepted March 31, 2007
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 midgestation, 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, embryonic and maternal Zip4 gene expression are both 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.
2 Current address is: Apath, LLC, 893 North Warson Road Saint Louis, MO 63141. E-mail: beattie{at}apath.com
3 These authors contributed equally to this work.
6 Current address is: Department of Microbiology, PO Box 800734, University of Virginia School of Medicine, Charlottesville, VA 22908. E-mail: ewx8n{at}virginia.edu
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