Journal Article

Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter

Fudi Wang, Byung-Eun Kim, Jodi Dufner-Beattie, Michael J. Petris, Glen Andrews and David J. Eide

in Human Molecular Genetics

Volume 13, issue 5, pages 563-571
Published in print March 2004 | ISSN: 0964-6906
Published online January 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh049
Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter

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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.

Journal Article.  6269 words.  Illustrated.

Subjects: Genetics and Genomics

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