Novel mutations in SLC30A2 involved in the pathogenesis of transient neonatal zinc deficiency
Novel mutations in SLC30A2 involved in the pathogenesis of transient neonatal zinc deficiency
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DOI：
10.1038/pr.2016.108
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发表时间：
2016-10-01
影响因子：
3.6
通讯作者：
Kambe, Taiho
中科院分区：
文献类型：
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作者：
Itsumura, Naoya;Kibihara, Yoshie;Kambe, Taiho
背景：婴儿易患缺锌。因此，母乳锌水平异常低会导致母乳喂养婴儿的暂时性新生儿缺锌(TNZD)。TNZD一直被认为是罕见的，因为在已发表的文献中引用的很少。然而，最近对受影响母亲的研究发现，编码锌转运蛋白ZnT2的溶质携带者家族30成员2基因(SLC30A2)有4个错义突变。方法：对3名分泌低锌牛奶的日本母亲(其婴儿患有TNZD)进行了SLC30A2/ZnT2的基因分析。已确定的突变的影响在基于细胞的测试中进行了检验。此外，对SLC30A2/ZnT2中的31个单核苷酸多态(SNPs)进行了评估，以了解它们与牛奶中低锌水平的关系。结果：每个母亲在SLC30A2/ZnT2中都有不同的新杂合子突变。一个突变降低了SLC30A2/ZnT2转录本的剪接效率，所有的突变株在锌转运方面都存在缺陷，并且在细胞中不稳定。此外，4个SNPs导致锌转运活性的显著丧失，与致病的ZnT2突变相似。结论：我们的结果表明许多SLC30A2/ZnT2突变导致或可能导致TNZD。关于TNZD发病机制的遗传信息有限，我们的结果表明，TNZD的频率可能比先前认为的更高。
BACKGROUND: Infants are vulnerable to zinc deficiency. Thus, abnormally low breast milk zinc levels cause transient neonatal zinc deficiency (TNZD) in breast-fed infants. TNZD has been considered to be rare because of a paucity of citations in the published literature. However, recent studies of affected mothers identified four missense mutations in the solute carrier family 30 member 2 gene (SLC30A2), which encodes the zinc transporter, ZnT2.METHODS: Genetic analyses of SLC30A2/ZnT2 in three Japanese mothers secreting low-zinc milk (whose infants developed TNZD) were performed. The effects of identified mutations were examined in a cell-based assay. Furthermore, 31 single-nucleotide polymorphisms (SNPs) in SLC30A2/ZnT2 were evaluated for their potential involvement in low-zinc levels in milk.RESULTS: Each mother had a different novel heterozygous mutation in SLC30A2/ZnT2. One mutation reduced splicing efficiency of the SLC30A2/ZnT2 transcript, and all ZnT2 mutants were defective in zinc transport and were unstable in cells. Moreover, four SNPs caused a significant loss of zinc-transport activity, similar to that in disease-causing ZnT2 mutants.CONCLUSION: Our results indicate that many SLC30A2/ZnT2 mutations cause or potentially cause TNZD. Genetic information concerning TNZD pathogenesis is limited, and our results suggest that the TNZD frequency may be higher than previously thought.