The mouse acrodermatitis enteropathica gene Slc39a4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency
| Autor: | Mehmet Bilgen, Melissa C. Larson, Benjamin P. Weaver, Glen K. Andrews, Jodi Dufner-Beattie, Jim Geiser, Wenhao Xu |
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| Rok vydání: | 2007 |
| Předmět: |
Male
medicine.medical_specialty Heterozygote Offspring Embryonic Development Mice Inbred Strains Biology Loss of heterozygosity Mice Internal medicine Genetics medicine Animals Allele Molecular Biology Cation Transport Proteins Genetics (clinical) Alleles Cells Cultured Mice Knockout Models Genetic Acrodermatitis Acrodermatitis enteropathica Endoderm Homozygote Genetic disorder Heterozygote advantage General Medicine medicine.disease Embryo Mammalian Mice Inbred C57BL Zinc Endocrinology Microscopy Fluorescence Zinc deficiency Female |
| Zdroj: | Human molecular genetics. 16(12) |
| ISSN: | 0964-6906 |
| Popis: | 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 approximately 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. |
| Databáze: | OpenAIRE |
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