Human Molecular Genetics Advance Access originally published online on January 6, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 5 563-571
DOI: 10.1093/hmg/ddh049
Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter
1Departments of Biochemistry and Nutritional Sciences, University of Missouri, Columbia, MO 65211, USA and 2Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160-7421, USA
Received November 11, 2003; Accepted December 17, 2003
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 
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.
* To whom correspondence should be addressed at: Department of Nutritional Sciences, 217 Gwynn Hall, University of Missouri, Columbia, MO 65211, USA. Tel: +1 5738829686; Fax: +1 5738820185; Email: eided{at}missouri.edu
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