Journal Article

The mouse acrodermatitis enteropathica gene Slc39a4 (<i>Zip4</i>) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency

Jodi Dufner-Beattie, Benjamin P. Weaver, Jim Geiser, Mehmet Bilgen, Melissa Larson, Wenhao Xu and Glen K. Andrews

in Human Molecular Genetics

Volume 16, issue 12, pages 1391-1399
Published in print June 2007 | ISSN: 0964-6906
Published online May 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm088
The mouse acrodermatitis enteropathica gene Slc39a4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency

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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.

Journal Article.  5361 words.  Illustrated.

Subjects: Genetics and Genomics

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