The mouse acrodermatitis enteropathica gene Slc39a4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency
The mouse acrodermatitis enteropathica gene Slc39a4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency
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DOI：
10.1093/hmg/ddm088
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发表时间：
2007-06-15
影响因子：
3.5
通讯作者：
Andrews, Glen K.
中科院分区：
文献类型：
--
作者：
Dufner-Beattie, Jodi;Weaver, Benjamin P.;Andrews, Glen K.
人类ZIP4基因(Slc39a4)在罕见的隐性遗传性锌代谢肠病肢端皮炎中发生突变，但ZIP4的生理功能尚不清楚。在这里，我们证明了纯合子ZIP4基因敲除的小鼠胚胎在早期形态发生过程中死亡，而杂合子后代的比例明显偏低。在妊娠中期，杂合子胚胎出现一系列发育缺陷，包括外脑畸形、眼球缺失和严重的生长迟缓，断奶时，许多杂合子后代(63/280)出现脑积水、生长迟缓和一侧或双眼缺失。母亲孕期膳食缺锌加剧了这些影响，而过量的锌则改善了这些影响，保护了杂合子的胚胎发育，但未能挽救纯合子胚胎。杂合子ZIP4胚胎在野生型母鼠的窝产仔中的比例并不低，但在缺锌期间发育异常的可能性是野生型母鼠的10倍。因此，胚胎和母体ZIP4基因的表达对锌的正常稳态都是至关重要的。这些研究表明，肢端皮炎基因ZIP4的杂合突变可能与比之前认识到的更广泛的发育缺陷有关，特别是在饮食锌有限的情况下。
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 wildtype mothers, but were similar to 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.