Novel mutations in SLC30A2 involved in the pathogenesis of transient neonatal zinc deficiency

Itsumura, Naoya; Kibihara, Yoshie; Fukue, Kazuhisa; Miyata, Akiko; Fukushima, Kenji; Tamagawa‐Mineoka, Risa; Katoh, Norito; Nishito, Yukina; Ishida, Riko; Narita, Hiroshi; Kodama, Hiroko; Kambe, Taiho

doi:10.1038/pr.2016.108

Cited by 33 publications

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References 36 publications

(70 reference statements)

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“…This zinc deficiency can lead to death in the absence of adequate zinc supplementation (13). To date, eight loss of function mutations were identified in the SLC30A2 (ZnT2) gene, which cause TNZD (6 -11) (OMIM number 608118) and at least 20 cases of infants with TNZD were reported in the past eight years in Japan (11). Current data suggest that 36% of 54 women who were tested had an exon variation in the SLC30A2 gene, and exhibit inadequate or excess zinc levels in their breast milk (15).…”

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“…Here we employed this BiFC technique along with an advanced bioinformatics analysis, using three-dimensional modeling, which is based upon the crystal structure of the bacterial YiiP, a ZnT homologue from Escherichia coli, to functionally characterize three novel mutations in the ZnT2 (SLC30A2) gene, which were recently shown to cause TNZD in Japanese infants (11). These novel ZnT2 mutations provide new insight into the structure and function of the C terminus of ZnT2 transporter with emphasis on the disruption of zinc binding and zinc permeation capacity.…”

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Molecular Basis of Transient Neonatal Zinc Deficiency

Golan¹,

Itsumura

Glaser³

et al. 2016

Journal of Biological Chemistry

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A gradually increasing number of transient neonatal zinc deficiency (TNZD) cases was recently reported, all of which were associated with inactivating ZnT2 mutations. Here we characterized the impact of three novel heterozygous ZnT2 mutations G280R, T312M, and E355Q, which cause TNZD in exclusively breastfed infants of Japanese mothers. We used the bimolecular fluorescence complementation (BiFC) assay to provide direct visual evidence for the in situ dimerization of these ZnT2 mutants, and to explore their subcellular localization. Moreover, using three complementary functional assays, zinc accumulation using BiFC-Zinquin and Zinpyr-1 fluorescence as well as zinc toxicity assay, we determined the impact of these ZnT2 mutations on vesicular zinc accumulation. Although all three mutants formed homodimers with the wild type (WT) ZnT2 and retained substantial vesicular localization, as well as vesicular zinc accumulation, they had no dominant-negative effect over the WT ZnT2. Furthermore, using advanced bioinformatics, structural modeling, and site-directed mutagenesis we found that these mutations localized at key residues, which play an important physiological role in zinc coordination (G280R and E355Q) and zinc permeation (T312M). Collectively, our findings establish that some heterozygous loss of function ZnT2 mutations disrupt zinc binding and zinc permeation, thereby suggesting a haploinsufficiency state for the unaffected WT ZnT2 allele in TNZD pathogenesis. These results highlight the burning need for the development of a suitable genetic screen for the early diagnosis of TNZD to prevent morbidity.In the past 50 years, the key role of zinc in human health was established (1). Zinc is crucial for central physiological processes including DNA and protein synthesis, enzyme activity, intracellular signaling, immune function, fertility, as well as growth and development (1-3). Zinc homeostasis is primarily regulated by two zinc transporter families as well as by zincbinding proteins. The SLC39A gene family encodes for ZIP1-14 transporters, which are responsible for zinc uptake into the cytosol from the extracellular fluid or from intracellular vesicles (4). In contrast, the SLC30A gene family encodes for the transporters ZnT1-10, which are responsible for zinc secretion from the cytosol to intracellular organelles or through the plasma membrane outside the cells (2, 4).The recent position of the Academy of Nutrition and Dietetics (5) is that breastfeeding in the first 6 months of life can provide adequate micronutrients and macronutrients for optimal growth and development. This statement is correct for the vast majority of infants around the world. However, recent reports indicate that some exclusively breastfed infants suffer from severe zinc deficiency due to lack of zinc in the breast milk they consume (6 -11). These cases were referred to as transient neonatal zinc deficiency (TNZD), 4 as the symptoms can be treated with zinc supplementation to the diet of the infant (12, 13). In contrast to TNZD, which appe...

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Molecular Basis of Transient Neonatal Zinc Deficiency

Golan¹,

Itsumura

Glaser³

et al. 2016

Journal of Biological Chemistry

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“…This suggestion was based on three different heterozygous mutations that caused TNZD without exerting a dominant negative effect over the WT ZnT2 protein [3,5] . In the current paper, we provide direct support for this hypothesis as shown in the TNZD case we characterized here.…”

Section: Discussionmentioning

confidence: 99%

“…Cumulative evidence indicates that some exclusively breastfed infants suffer from severe zinc deficiency due to lack of zinc in the breast milk they consume [1][2][3][4][5][6][7][8]. The main initial symptoms of zinc deficiency are dermatitis, diarrhea, alopecia, and loss of appetite [9].…”

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Identification of Genetic Diseases Using Breast Milk Cell Analysis: The Case of Transient Neonatal Zinc Deficiency (TNZD)

Golan¹,

Yerushalmi²,

Efrati³

et al. 2017

Cell Mol Med

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Novel SLC30A2 mutations in the pathogenesis of transient neonatal zinc deficiency

Muto

Kawase

Aiba

et al. 2023

Pediatric Investigation

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Importance Transient neonatal zinc deficiency (TNZD) occurs in breastfed infants due to abnormally low breast milk zinc levels. Mutations in the solute carrier family 30 member 2 ( SLC30A2 ) gene, which encodes the zinc transporter ZNT2, cause low zinc concentration in breast milk. Objective This study aimed to provide further insights into TNZD pathophysiology. Methods SLC30A2 sequencing was performed in three unrelated Japanese mothers, whose infants developed TNZD due to low‐zinc milk consumption. The effects of the identified mutations were examined using cell‐based assays and luciferase reporter analysis. Results Novel SLC30A2 mutations were identified in each mother. One harbored a heterozygous missense mutation in the ZNT2 zinc‐binding site, which resulted in defective zinc transport. The other two mothers exhibited multiple heterozygous mutations in the SLC30A2 promoter, the first mutations in the SLC30A2 regulatory region reported to date. Interpretation This report provides new genetic insights into TNZD pathogenesis in breastfed infants.

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Novel mutations in SLC30A2 involved in the pathogenesis of transient neonatal zinc deficiency

Abstract: 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.

Cited by 33 publications

References 36 publications

Molecular Basis of Transient Neonatal Zinc Deficiency

Molecular Basis of Transient Neonatal Zinc Deficiency

Identification of Genetic Diseases Using Breast Milk Cell Analysis: The Case of Transient Neonatal Zinc Deficiency (TNZD)

Novel SLC30A2 mutations in the pathogenesis of transient neonatal zinc deficiency

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