Regulation and function of Zip4, the acrodermatitis enteropathica gene

Abstract

The SLC39A (solute carrier 39A) [ZIP (Zrt-Irt-like protein)] family consists of 14 members which are thought to control zinc uptake into the cytoplasm. Among these, ZIP4 is known to be particularly important for zinc homoeostasis. Mutations in this gene cause acrodermatitis enteropathica, a rare recessive-lethal human genetic disorder. In the present paper, our studies of the regulation and function of the mouse Zip4 gene are briefly reviewed. Mouse Zip4 is expressed at highest levels in tissues involved in absorption of dietary or maternal zinc, and the gene and protein are dynamically regulated by multiple post-transcriptional mechanisms in response to zinc availability. ZIP4 accumulates at the apical surface of enterocytes and endoderm cells when zinc is deficient, because of increased stability of the mRNA and stabilization of the protein. In contrast, when zinc is replenished, the mRNA is destabilized and the protein is internalized and degraded rapidly. The critical importance of ZIP4 in zinc homoeostasis is revealed in mice with targeted deletions of this gene. Homozygous Zip4-knockout embryos die during early morphogenesis and heterozygous offspring are significantly underrepresented and display an array of developmental defects, including exencephalia, anophthalmia and severe growth retardation. Mice heterozygous for Zip4-knockout are hypersensitive to zinc deficiency, which suggests that humans heterozygous for this gene may also be very sensitive to zinc deficiency.

Figure 1. Mutations in ZIP4 (SLC39A4) cause acrodermatitis enteropathica

A predicted eight-transmembrane domain model of human ZIP4, indicating amino acid substitutions (one letter code) and nonsense mutations (X) identified in patients with AE. Three potential glycosylation sites are indicated in the extracellular N-terminal half of the protein.

Figure 2. Zip4 haploinsufficiency is associated with abnormal development in mice

Wild-type mice and Zip4^+/−-knockout mice (Zip4^+/−) that were obviously abnormal at weaning were examined using high-field MRI. Top row: axial sections through the face at the plane of the eyes. Second row: axial sections through the midbrain region. Third row: sagittal sections near the midline region. White areas in the brain indicate water accumulation. Modified from Dufner-Beattie, J., Weaver, B.P., Geiser, J., Bilgen, M., Larson, M., Xu, W. and Andrews, G.K. The mouse acrodermatitis gene Slc39a4 (ZIP4) is essential for development and heterozygosity causes hypersensitivity to zinc deficiency. Hum. Mol. Genet., 2007, vol. 16(12), pp. 1391–1399 by permission of Oxford University Press.

Figure 3. Heterozygous Zip4-knockout mice are hypersensitive to zinc deficiency

Zip4^+/−-knockout females (Zip4^+/−) or wild-type (WT) females were crossed with Zip4^+/−-knockout males. Pregnant females were fed on a zinc-deficient diet during pregnancy, and embryos were examined at mid-gestation. Severe: embryos were dramatically growth retarded and displayed multiple morphological abnormalities. Mild: embryos exhibited delayed limb development and retarded growth. Results are expressed as the percentage of embryos in each genotype of the total number examined (n). Reproduced from Dufner-Beattie, J., Weaver, B.P., Geiser, J., Bilgen, M., Larson, M., Xu, W. and Andrews, G.K. The mouse acrodermatitis gene Slc39a4 (ZIP4) is essential for development and heterozygosity causes hypersensitivity to zinc deficiency. Hum. Mol. Genet., 2007, vol. 16(12), pp. 1391–1399 by permission of Oxford University Press.