Human Molecular Genetics Advance Access originally published online on May 4, 2007
Human Molecular Genetics 2007 16(12):1391-1399; 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
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1 Department of Biochemistry and Molecular Biology, 2 Department of Integrative and Molecular Physiology and 3 Hoglund Brain Imaging Center, University of Kansas Medical Center, Kansas City, KS 66160-7421, USA and 4 Department of Microbiology, University of Virginia School of Medicine, PO Box 800734, Charlottesville, VA 22908, USA
* To whom correspondence should be addressed at: Department of Biochemistry and Molecular Biology, Mail Stop 3030, University of Kansas Medical Center, 39th and Rainbow Boulevard, Kansas City, KS 66160-7421, USA. Tel: +1 9135886935; Fax: +1 9135883920; Email: gandrews{at}kumc.edu
Received February 28, 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 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.
Present address: Apath, LLC, 893 North Warson Road, St Louis, MO 63141, USA. Email: beattie{at}apath.com.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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