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International Journal of Endocrinology
Volume 2013, Article ID 259189, 8 pages
http://dx.doi.org/10.1155/2013/259189
Research Article

Transient Neonatal Zinc Deficiency Caused by a Heterozygous G87R Mutation in the Zinc Transporter ZnT-2 (SLC30A2) Gene in the Mother Highlighting the Importance of Zn2+ for Normal Growth and Development

1Division of Paediatric Endocrinology, Diabetology and Metabolism and Department of Clinical Research, University Children’s Hospital, Inselspital, 3010 Bern, Switzerland
2Department of Dermatology, University of Bern, 3010 Bern, Switzerland

Received 12 June 2013; Revised 7 August 2013; Accepted 22 August 2013

Academic Editor: Fabio Buzi

Copyright © 2013 Maria Consolata Miletta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Suboptimal dietary zinc (Zn2+) intake is increasingly appreciated as an important public health issue. Zn2+ is an essential mineral, and infants are particularly vulnerable to Zn2+ deficiency, as they require large amounts of Zn2+ for their normal growth and development. Although term infants are born with an important hepatic Zn2+ storage, adequate Zn2+ nutrition of infants mostly depends on breast milk or formula feeding, which contains an adequate amount of Zn2+ to meet the infants’ requirements. An exclusively breast-fed 6 months old infant suffering from Zn2+ deficiency caused by an autosomal dominant negative G87R mutation in the Slc30a2 gene (encoding for the zinc transporter 2 (ZnT-2)) in the mother is reported. More than 20 zinc transporters characterized up to date, classified into two families (Slc30a/ZnT and Slc39a/Zip), reflect the complexity and importance of maintaining cellular Zn2+ homeostasis and dynamics. The role of ZnTs is to reduce intracellular Zn2+ by transporting it from the cytoplasm into various intracellular organelles and by moving Zn2+ into extracellular space. Zips increase intracellular Zn2+ by transporting it in the opposite direction. Thus the coordinated action of both is essential for the maintenance of Zn2+ homeostasis in the cytoplasm, and accumulating evidence suggests that this is also true for the secretory pathway of growth hormone.

1. Introduction

Zinc (Zn2+) is an essential mineral, and infants are particularly vulnerable to Zn2+ deficiency as they require large amounts of Zn2+ for their normal growth and development [14]. Further, suboptimal dietary zinc intake is increasingly appreciated as an important public health issue and has been recently reviewed in a workshop organised by the World Health Organization [5]. The rapid growth experienced by term infants during the first months of life, while they are exclusively breastfed, underscores the appropriateness of breast milk. In particularly in the first three months, Zn2+ occurs in breast milk unlike iron and copper at much higher concentration [6]. Until recently it was not known why some otherwise healthy and normal nourished and nursing mothers may present with low Zn2+ levels in breast milk causing various abnormalities including growth arrest in the baby. Transient neonatal zinc deficiency (TNZD; OMIM number 608118) is one of the disorders well described [711] which is characterized by a low level of Zn2+ found in serum of exclusively breast-fed infants which occurs due to the defective secretion of Zn2+ into mothers milk. This disorder is well distinct, clinically as well as genetically, from the other Zn2+-related entity specified as acrodermatitis enterohepathica (AEZ; OMIM number 201100), where the uptake of Zn2+ is the inborn error of metabolism [1214].

Here we describe the clinical case of an exclusively breast-fed 6 months old infant presented to our outpatient clinic suffering from Zn2+ deficiency caused by an autosomal dominant negative G87R mutation in the zinc transporter ZnT2 gene (SLC30A2) in the mother. In addition, as the mechanism of Zn2+ on growth and development is not well known, we focus further on its impact on growth hormone production/secretion.

2. Case Report/Methods

2.1. Case Report

Following an uneventful pregnancy the baby girl (II.3) was born at term (birth weight 3210 g, 50th centile; birth length 49 cm, 50th centile) [15] (Figure 1). The mother is of Philippine origin and the father of Swiss origin. The family history is uneventful and no genetic diseases are reported. The postnatal adaptation was normal. However, at the age of 6 months the infant was presented to the outpatient clinic of dermatology in the University of Bern, Switzerland. The clinical examination revealed an otherwise healthy, exclusively breast-fed 6 months old infant presented with a 3 weeks history of increasing skin problems, abdominal cramps, and diarrhoea with no obvious malnutrition. The skin lesions involving the face in a perioral distribution (Figure 2(a)), head (Figure 2(b)), and in the anal area (Figure 2(c)) appeared like an acrodermatitis enteropathica while the analysis of serum revealed a significantly low Zn2+ level (Table 1) and decreased level of alkaline phosphatase. Serum Zn2+ level in the mother was measured normal, while Zn2+ concentration in mother’s breast milk was 0.12 mg/kg, which was significantly lower than the normative values (Table 1). Hence, all the clinical parameters were in line with the diagnosis of TNZD. In addition, while analysing length, weight, and length velocity of the infant, a stunted growth (IGF-I and IGF-BP3 levels at −2.3 SDS, −2.9 SDS, resp.) and a failure to thrive became obvious starting at the age of 3 months and progressed further until the age of 6 months, at the time when Zn2+ supplementation was started (Figure 3). At that point the infant also presented with a length that significantly dropped below the 3rd centile on the growth curve (Figure 3). An oral Zn2+ supplementation therapy (administered p.o, 4 mg/kg/day, as zinc sulphate heptahydrate) initiated and thereafter led to disappearance of all the clinical symptoms within the next four weeks.

tab1
Table 1: Laboratory data of the child (II.3) and mother.
259189.fig.001
Figure 1: Pedigree. Full half circle: heterozygosity G87R SLC30A2; hatched circle: clinical signs during infancy while breastfed. , , and were breastfed for 3, 1, and 6 months, respectively. is reported and described.
fig2
Figure 2: Skin lesions. Skin lesions in a perioral region (a), on the head (b), and in the anal region (c).
259189.fig.003
Figure 3: Growth chart of the patient. The solid circles indicate the length measurements. Percentiles are shown on extreme right. The arrows pointing up and down indicate the beginning and the end of the Zn2+ supplementation therapy.
2.2. DNA Isolation

For the genetic studies, written informed consent was obtained from both parents. Genomic DNA was isolated from peripheral leukocytes of the affected subjects using the QIAamp blood extraction kit (Qiagen AG, Basel, Switzerland) and used as a template for analysis of the ZnT2 gene. The concentration of each sample was determined by measuring the optical density of the purified DNA at 260 and 280 nm.

2.3. Amplification and Sequencing of Genomic DNA

The genomic organization of human ZnT2 was determined from published internet data (http://www.ncbi.nlm.nih.gov/), and each one of the 8 coding exons was amplified by PCR amplification using established primers [10]. For PCR, approximately 100 ng of genomic DNA was used as template in a PCR SuperMix High Fidelity (Invitrogen, UK) in a total reaction volume of 50 μL. PCR was carried out in TGradient Thermoblock (Biometra, Germany) under the following conditions: 33 cycles with an initial denaturation step at 94°C for 2 min, thereafter 94°C for 45 s, annealing at 60°C (for exons 1), 55°C (for exon 2 and 4), 61°C (for exon 3), 59°C (for exon 5, 6, 7), 57°C (for exons 8) for 45 s, and with an extension of 72°C for 1 min. Amplification was completed with an additional extension step at 72°C for 5 min. Negative controls included no template control. PCR products were separated on 1.5% agarose gel and stained with ethidium bromide. The bands corresponding to each specific PCR product were purified with QIAquick PCR Purification Kit (Qiagen AG, Basel, Switzerland) and sequenced on an ABI 373 automated DNA sequencing system (Applied Biosystems). The sequences were confirmed by re-PCR and resequencing from the genomic DNA of both strands.

3. Results

3.1. Identification of a Heterozygous G87R ZnT-2 Mutation

We identified a heterozygous G87R ZnT2 mutation in the mother as well as in the baby/girl (Figures 14). To know that does carry the mutation is very much of importance for her possible life as a breastfeeding mother. This mutation has been previously reported and studied in most detail at the functional level [10]. In this study as well in a previous report the authors showed that a functional inactivation of the ZnT2 is the underlying cause of TNZD [10, 11].

259189.fig.004
Figure 4: Heterozygous G87R mutation in the ZnT2 (SLC30A2) gene. At position 87 of the ZnT2 (SLC30A2) gene, a heterozygous mutation G > C (Gly > Arg) is depicted.
3.2. Impairment of Growth and Development

The aim of our study, however, was to focus on the impact of length and length velocity in a Zn2+-deficient environment. Although the mechanisms are not well studied, it is well known and accepted that prolonged Zn2+ deficiency during infancy as well as childhood is not a negligible cause for stunting growth and failure to thrive [15].

3.3. Effect of Zn2+ Supplementation on Growth

As demonstrated in Figure 3, the oral Zn2+ supplementation therapy (administered p.o, 4 mg/kg/day, as zinc sulphate heptahydrate) resulted after 4 months in a complete catch-up growth of the child as well as normalized the IGF-I and IGF-BP3 levels (Table 1). Therefore, a sufficient Zn2+ serum concentration in this infant seems also to be of crucial importance for GH secretion and, thus, normal growth and development.

3.4. Zn2+ Transporters and GH Secretion

By Inoue et al., ZnT5-null mice, as the result of crossing between heterozygous mice according to Mendelian expectations, were cloned and provided some in vivo data about the phenotype caused by the complete deletion of only one zinc transporter, namely, ZnT5 [16]. ZnT5-null mice displayed abnormal bone development, loss of weight, and lethal, male-specific, cardiac arrhythmia. Interestingly, these mice presented with significantly impaired growth when compared to the wild-type animals and with a high degree of osteopenia due to systemic decrease in bone density as the results of the reduced activity of osteoblasts [16]. Although the authors did not focus on growth, it has been nicely described and depicted in this study [16]. Further, Robinson et al. used the advantage of enhanced green fluorescent protein (eGFP), which when expressed from cell-specific promoters in transgenic animals, allows identification of specific cell types in situ and provides a fluorescent tag for their isolation and analysis, using fluorescence-activated cell sorting (FACS) technique [17, 18]. Therefore, eGFP was targeted to the secretory granules of pituitary GH-producing cells in transgenic mice (GH-eGFP transgenic mouse) [18, 19], followed by the FACS sorting of somatotrope cells (eGFP+ cells). Analysis of specific gene expression patterns using microarray technique was performed, and relative expression data of all zinc transporters assessed (Table 2) revealed the expression of ZnT5 to be the strongest in somatotropes. Hence, these data suggest high involvement of ZnT5 in the processes of GH storage and secretion.

tab2
Table 2: Relative expression data of zinc transporters in GFP-sorted somatotrope cells from GH-eGFP transgenic mouse.

4. Discussion

4.1. Zn2+ Deficiency

The initial main symptoms of mild Zn2+ deficiency are growth faltering as well as anorexia. Further prolonged and/or severe zinc deficiency presents with dermatitis and alopecia and is often expressed in growth impairment as well as neuropsychological alterations [20]. Infants are particularly vulnerable to Zn2+ deficiency, as they require large amounts of Zn2+ for their normal growth and development. Although term infants are born with an important hepatic zinc storage, adequate zinc nutrition of infants mostly depends on breast milk (especially in the first 3 months of lactation) or milk formula feeding, which contains an adequate amount of Zn2+ to meet the infants’ requirements [6]. However, there are several causes for Zn2+ deficiency during infancy. First, it may be a result of deficient nutrition due to low level of Zn2+ in the breast milk or to consumption of food that is poor in Zn2+ bioavailability, or second, it is associated with distinct genetic disorders in Zn2+ metabolism [10, 11, 13, 21]. One of those genetic defects is associated with mutations of the intestinal Zn2+-specific transporter Slc39a4/Zip4 [12, 13], which is responsible for Zn2+ absorption in the small intestine and when mutated leads to a rare, autosomal recessive disease called acrodermatitis enteropathica (AEZ) (OMIM number 201100). AEZ manifests in impaired intestinal Zn2+ absorption; hence, patients harbouring AEZ require lifelong zinc supplementation [14, 22]. Without therapy, plasma Zn2+ concentration and serum alkaline phosphatase, as well as urinary excretion of Zn2+, are very low [23]. Another genetic defect is associated with a mutation within Slc30a4/ZnT4 and causes a reduced Zn2+ incorporation into mother’s milk [11, 21]. Mice homozygous for a ZnT4 mutation are known as lethal milk mice (lm/lm mouse) producing milk, which is Zn2+ deficient (OMIM number 602095) [24]. As this phenotype in mice mirrors TNZD (OMIM number 608118) in breast-fed infants [79] Michalczyk et al. investigated whether changes in the ZnT4 gene are responsible for reduced Zn2+ in breast milk in human in two unrelated mothers with low Zn2+ milk levels whose babies had developed Zn2+ deficiency. Their findings suggested that the lm-/lm- mouse is not the corresponding model for the human Zn2+ deficiency condition [25]. Finally, TNZD in humans was found to be associated with mutations in SLC30A2/ZnT2. Gene knockdown of ZnT2 in mammary epithelial cells reduced Zn2+ secretion, suggesting a role for this transporter in Zn2+ secretion from this cell type [11]. ZnT2 was also found to be upregulated and relocalised to vesicles after exposure of mammary epithelial cells to prolactin. Similarly, mammary gland ZnT2 was upregulated and relocalised to the luminal membrane in lactating rats when plasma zinc increased during lactation [26, 27]. Heterozygous H54R and G87R mutations in ZnT2 were recently identified in women presenting with a Zn2+-deficient milk [10, 11]. As there is no impairment in Zn2+ uptake in the gut in affected babies, their infants, consequently, developed TNZD that was resolved after oral Zn2+ supplementation [10, 11]. As previously reported by Lasry et al. [10] we identified and characterized a heterozygous G87R mutation in ZnT2  leading to production of Zn2+-deficient milk in a mother originated from the Philippines; as a result, their exclusively breast-fed infants developed TNZD with low Zn2+ blood levels that resolved upon Zn2+ supplementation. As far as the function is concerned, Lasry et al. showed that the G87R mutation is a loss of function mutation and they provided, therefore, the first evidence for the dominant inheritance of heterozygous ZnT2 mutations via negative dominance due to homodimer formation [10].

4.2. Impact of Zn2+ on Growth Hormone Secretion [28]

The growth hormone-1 (GH-1) gene is mainly expressed as a major 22 kDa isoform in somatotrope cells of the anterior pituitary gland. After being translated, GH protein passes throughout the regulated secretory pathway where it gets packed and stored in concentrated forms in secretory granules enabling a regulated release in circulation upon GHRH stimulation [29, 30].

Zn2+ is considered as the second most abundant “trace” metal in the human body which is required for numerous cellular mechanisms like DNA synthesis, protein synthesis, cell growth, and division [31] as well as for many physiological processes like immune function [32] and reproduction [33, 34]. Hence, cellular Zn2+ homeostasis and dynamics are tightly regulated and maintained by various Zn2+ transporters responsible for transporting these high charge density ions across cellular membranes and various intracellular organelles [35, 36]. Over two decades ago, a high concentration of Zn2+ was reported to be localized mostly in the Golgi complex and GH-containing secretory granules of rat anterior pituitary cells [37], suggesting in that way, an important role of Zn2+ in the regulated secretory pathway of GH. During the process of secretory granule biogenesis, self-association (aggregation) of a hormone destined for secretion facilitates its storage in granules in fairly high amounts, and in the case of GH, it occurs in the presence of Zn2+ [38].

4.3. The Biogenesis of GH Secretory Granules Begins with Zn2+-Mediated GH Aggregation at Acidic pH in the trans-Golgi Lumen

The complex process of secretory granule biogenesis begins with aggregation of proteins (hormones) destined for secretion to form dense cores of granules composed of large insoluble aggregates. Upon appropriate stimulation, aggregates are released into the bloodstream leading to a burst of hormone on a time scale much faster than it could be achieved from increased synthesis.

Protein aggregation takes place in the lumen of trans-Golgi layer where specific environmental factors seem to play an important role in inducing this process. In fact, apart from specific pH requirements [39, 40], aggregation of GH apparently requires high amounts of divalent cations like Zn2+ [37].

A step further towards unravelling the role of Zn2+ in storage of GH in secretory granules came with the study reporting that two Zn2+ associates per GH dimer in a cooperative fashion through binding at high-affinity residues in GH (His18, His21, and Glu174) [41]. Replacement of these residues with alanine caused reductions of dimeric GH formation as demonstrated by size-exclusion chromatography and sedimentation equilibrium analysis. In addition, the data presented also demonstrate that Zn2+ binding to GH would enhance stability of the stored form and that Zn2+-GH complex was more stable to denaturation when compared to monomeric GH ultimately proposing that Zn2+-GH dimer may be the main storage form in the secretory granules [41].

The potential contribution of high-affinity Zn2+-binding residues in GH to the pathogenic mechanisms involved in dominantly transmitted isolated GH deficiency type II (IGHD II) was further studied by Iliev et al. [42]. The production and extracellular secretion of wt-hGH transiently transfected in GH4C1 cells (rat pituitary tumour cells) were compared to that of GH mutants in which the amino acids that bind Zn2+ with high affinity were mutated to alanine in various combinations. When wt-hGH was coexpressed with any of the Zn2+-binding GH mutants, constitutive GH secretion (i.e., without stimulation) and intracellular production remained unaffected. Interestingly, each of the Zn2+-binding GH mutants (single, double, or triple mutants) singly expressed displayed about 50% lower extracellular secretion and intracellular production when compared to the wt-hGH suggesting possible role of these residues in GH stability.

GH and PRL are two hormones that are structurally related, and therefore it is of no surprise that they display many similarities in the process of aggregation as reported in the study mentioned above. However, alanine mutation introduced at His27 in hPRL (topologically corresponding to His18 in hGH) resulted in H27A-PRL mutant reported not to bind Zn2+ [43]. Interestingly, even without the high-affinity Zn2+ binding site, H27A-PRL is still able to aggregate in the presence of Zn2+ with parameters similar to aggregation of wt-PRL [40]. Hence, these data suggest that PRL and GH do not behave similarly in the presence of Zn2+ and that PRL does not form dimer under the conditions that GH does, indicating that the dimer is unlikely to be the storage form of PRL in secretory granules. Zn2+ binding to human PRL and GH can occur through histidine residues (the high-affinity binding sites) [41, 43] or through glutamate, aspartate, and glutamine residues (the low-affinity binding sites) [44]. Acidic pH in the trans-Golgi lumen where the process of aggregation occurs leads to protonation of His residues preventing their binding to Zn2+. Therefore, it is more likely that Zn2+ binding to glutamate and aspartate residues (low-affinity binding) of PRL facilitates the formation of PRL oligomers as the storage form in dense cores of secretory granules.

Finally, as mentioned earlier Zn2+ binding to GH through high-affinity binding sites is proven to be necessary for the formation of GH dimers, but whether this is the final storage form of GH in secretory granules still remains to be elucidated. Alternatively, additional intramolecular cross-linking might occur through low-affinity Zn2+-binding with amino acids other than histidine (as described above for PRL) enhancing in that way GH aggregation and storage in secretory granules.

4.4. Zinc Transporters Mediate Zn2+ Dynamics in the Early Secretory Pathway and Might Play an Important Role in the Formation of GH-Containing Secretory Granules

Out of all proteins synthesized in eukaryotic cells approximately one-third is targeted to the secretory pathway [45] and the first compartment encountered along their road towards secretion is the ER. Together with Golgi complex, ER comprises the early secretory pathway, which plays the key role in regulating the folding, assembly, and transport of newly synthesized proteins and modification and trafficking during the secretory process. There are estimates that between three and ten percent of all proteins in mammalian genomes bind Zn2+ [46], and many zinc-dependent proteins pass through the secretory pathway on their way to other compartments within the cell (e.g., vacuole, lysosomes) or prior to their secretion. Due to its high charge density, Zn2+ requires transporters to move it across the cellular membranes and in and out of each of the organelles participating in the regulated secretory pathway (ER, Golgi complex, and secretory granules). More than 20 zinc transporters identified and characterized up to date, classified into two families (Slc30a/ZnT and Slc39a/Zip), reflect the complexity and importance of maintaining cellular Zn2+ homeostasis and dynamics. The role of ZnTs is to reduce intracellular Zn2+ by transporting it from the cytoplasm into various intracellular organelles and by moving Zn2+ into extracellular space. Zips increase intracellular Zn2+ by transporting it in the opposite direction. Thus the coordinated action of both is essential for the maintenance of Zn2+ homeostasis in the cytoplasm, and accumulating evidence suggests that this is also true for the secretory pathway.

4.5. Conclusion: Where the Mother’s Milk Meets the Baby’s Growth

Having discussed the importance of Zn2+ as well as their individual intracellular transporters it comes without any surprise that an adequate Zn2+ concentration in the child’s plasma is of high importance for normal growth and development [1, 3, 28, 4749].

Acknowledgments

This study was supported by a grant of Swiss National Science Foundation 320000-121998 to P. E. Mullis Further, thanks go to Professor Iain C. Robinson, Division of Molecular Neuroendocrinology (M.S., I.C.R.), National Institute for Medical Research Mill Hill, London NW7 1AA, UK, where P. E. Mullis was on sabbatical leave in 2007.

References

  1. V. H. Moran, A. L. Stammers, M. W. Medina et al., “The relationship between zinc intake and serum/plasma zinc concentration in children: a systematic review and dose-response meta-analysis,” Nutrients, vol. 4, pp. 841–858, 2012. View at Google Scholar
  2. A. S. Prasad, “Zinc deficiency,” British Medical Journal, vol. 326, no. 7386, pp. 409–410, 2003. View at Google Scholar · View at Scopus
  3. R. T. Hamza, A. I. Hamed, and M. T. Sallam, “Effect of zinc supplementation on growth hormone-insulin growth factor axis in short egyptian children with zinc deficiency,” Italian Journal of Pediatrics, vol. 38, article 21, 2012. View at Google Scholar
  4. S. Villalpando, A. García-Guerra, C. I. Ramírez-Silva et al., “Iron, zinc and iodide status in Mexican children under 12 years and women 12–49 years of age. A probabilistic national survey,” Salud Publica de Mexico, vol. 45, no. 4, pp. 520–529, 2003. View at Google Scholar · View at Scopus
  5. WHO, Workshop to review the results of the studies evaluating the impact of zinc supplement on childhood mortality and severe morbidity, http://www.who.int/maternal_child_adolescent/documents/zinc_mortality/en/.
  6. J. G. Dórea, “Zinc deficiency in nursing infants,” Journal of the American College of Nutrition, vol. 21, no. 2, pp. 84–87, 2002. View at Google Scholar · View at Scopus
  7. P. J. Aggett, D. J. Atherton, and J. More, “Symptomatic zinc deficiency in a breast-fed, preterm infant,” Archives of Disease in Childhood, vol. 55, no. 7, pp. 547–550, 1980. View at Google Scholar · View at Scopus
  8. P. H. Parker, G. L. Helinek, and R. L. Meneely, “Zinc deficiency in a premature infant fed exclusively human milk,” American Journal of Diseases of Children, vol. 136, no. 1, pp. 77–78, 1982. View at Google Scholar · View at Scopus
  9. A. W. Zimmerman, K. M. Hambidge, and M. L. Lepow, “Acrodermatitis in breast-fed premature infants: evidence for a defect of mammary zinc secretion,” Pediatrics, vol. 69, no. 2, pp. 176–183, 1982. View at Google Scholar · View at Scopus
  10. I. Lasry, Y. A. Seo, H. Ityel et al., “A dominant negative heterozygous G87R mutation in the zinc transporter, znt-2 (slc30a2), results in transient neonatal zinc deficiency,” The Journal of Biological Chemistry, vol. 287, pp. 29348–29361, 2012. View at Google Scholar
  11. W. Chowanadisai, B. Lönnerdal, and S. L. Kelleher, “Identification of a mutation in SLC30A2 (ZnT-2) in women with low milk zinc concentration that results in transient neonatal zinc deficiency,” The Journal of Biological Chemistry, vol. 281, no. 51, pp. 39699–39707, 2006. View at Publisher · View at Google Scholar · View at Scopus
  12. K. Wang, B. Zhou, Y. Kuo, J. Zemansky, and J. Gitschier, “A novel member of a zinc transporter family is defective in acrodermatitis enteropathica,” American Journal of Human Genetics, vol. 71, no. 1, pp. 66–73, 2002. View at Publisher · View at Google Scholar · View at Scopus
  13. S. Küry, B. Dréno, S. Bézieau et al., “Identification of SLC39A4, a gene involved in acrodermatitis enteropathica,” Nature Genetics, vol. 31, no. 3, pp. 239–240, 2002. View at Publisher · View at Google Scholar · View at Scopus
  14. P. J. Aggett, “Acrodermatitis enteropathica,” Journal of Inherited Metabolic Disease, vol. 6, supplement 1, pp. 39–43, 1983. View at Google Scholar · View at Scopus
  15. A. Prader, R. H. Largo, L. Molinari, and C. Issler, “Physical growth of Swiss children from birth to 20 years of age. First Zurich longitudinal study of growth and development,” Helvetica Paediatrica Acta. Supplementum, vol. 52, pp. 1–125, 1989. View at Google Scholar · View at Scopus
  16. K. Inoue, K. Matsuda, M. Itoh et al., “Osteopenia and male-specific sudden cardiac death in mice lacking a zinc transporter gene, Znt5,” Human Molecular Genetics, vol. 11, no. 15, pp. 1775–1784, 2002. View at Google Scholar · View at Scopus
  17. N. Kawakami, N. Sakane, F. Nishizawa et al., “Green fluorescent protein-transgenic mice: immune functions and their application to studies of lymphocyte development,” Immunology Letters, vol. 70, no. 3, pp. 165–171, 1999. View at Publisher · View at Google Scholar · View at Scopus
  18. C. Magoulas, L. Mcguinness, N. Balthasar et al., “A secreted fluorescent reporter targeted to pituitary growth hormone cells in transgenic mice,” Endocrinology, vol. 141, no. 12, pp. 4681–4689, 2000. View at Publisher · View at Google Scholar · View at Scopus
  19. L. McGuinness, C. Magoulas, A. K. Sesay et al., “Autosomal dominant growth hormone deficiency disrupts secretory vesicles in vitro and in vivo in transgenic mice,” Endocrinology, vol. 144, no. 2, pp. 720–731, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. S. Bhatnagar and S. Taneja, “Zinc and cognitive development,” British Journal of Nutrition, vol. 85, supplement 2, pp. S139–S145, 2001. View at Google Scholar · View at Scopus
  21. D.-Y. Lee, N. F. Shay, and R. J. Cousins, “Altered zinc metabolism occurs in murine lethal milk syndrome,” Journal of Nutrition, vol. 122, no. 11, pp. 2233–2238, 1992. View at Google Scholar · View at Scopus
  22. E. J. Moynahan, “Letter: acrodermatitis enteropathica: a lethal inherited human zinc-deficiency disorder,” The Lancet, vol. 2, no. 7877, pp. 399–400, 1974. View at Google Scholar · View at Scopus
  23. K. H. Neldner and K. M. Hambidge, “Zinc therapy of acrodermatitis enteropathica,” The New England Journal of Medicine, vol. 292, no. 17, pp. 879–882, 1975. View at Google Scholar · View at Scopus
  24. L. Huang and J. Gitschier, “A novel gene involved in zinc transport is deficient in the lethal milk mouse,” Nature Genetics, vol. 17, no. 3, pp. 292–297, 1997. View at Publisher · View at Google Scholar · View at Scopus
  25. A. Michalczyk, G. Varigos, A. Catto-Smith, R. C. Blomeley, and M. L. Ackland, “Analysis of zinc transporter, hZnT4 (SIc30A4), gene expression in a mammary gland disorder leading to reduced zinc secretion into milk,” Human Genetics, vol. 113, no. 3, pp. 202–210, 2003. View at Publisher · View at Google Scholar · View at Scopus
  26. S. L. Kelleher and B. Lönnerdal, “Zn transporter levels and localization change throughout lactation in rat mammary gland and are regulated by zn in mammary cells,” Journal of Nutrition, vol. 133, no. 11, pp. 3378–3385, 2003. View at Google Scholar · View at Scopus
  27. S. L. Kelleher and B. Lönnerdal, “Zip3 plays a major role in zinc uptake into mammary epithelial cells and is regulated by prolactin,” American Journal of Physiology—Cell Physiology, vol. 288, no. 5, pp. C1042–C1047, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. V. Petkovic, M. C. Miletta, and P. E. Mullis, “From endoplasmic reticulum to secretory granules: role of zinc in the secretory pathway of growth hormone,” Endocrine Development, vol. 23, pp. 96–108, 2012. View at Google Scholar
  29. P. S. Dannies, “Mechanisms for storage of prolactin and growth hormone in secretory granules,” Molecular Genetics and Metabolism, vol. 76, no. 1, pp. 6–13, 2002. View at Publisher · View at Google Scholar · View at Scopus
  30. S. A. Tooze, G. J. M. Martens, and W. B. Huttner, “Secretory granule biogenesis: rafting to the SNARE,” Trends in Cell Biology, vol. 11, no. 3, pp. 116–122, 2001. View at Publisher · View at Google Scholar · View at Scopus
  31. R. S. MacDonald, “The role of zinc in growth and cell proliferation,” Journal of Nutrition, vol. 130, pp. 1500S–1508S, 2000. View at Google Scholar · View at Scopus
  32. P. J. Fraker, L. E. King, T. Laakko, and T. L. Vollmer, “The dynamic link between the integrity of the immune system and zinc status,” Journal of Nutrition, vol. 130, pp. 1399S–1406S, 2000. View at Google Scholar · View at Scopus
  33. J. Apgar, “Effect of zinc deficiency on parturition in the rat,” The American Journal of Physiology, vol. 215, no. 1, pp. 160–163, 1968. View at Google Scholar · View at Scopus
  34. L. S. Hurley and P. B. Mutch, “Prenatal and postnatal development after transitory gestational zinc deficiency in rats,” Journal of Nutrition, vol. 103, no. 5, pp. 649–656, 1973. View at Google Scholar · View at Scopus
  35. L. A. Lichten and R. J. Cousins, “Mammalian zinc transporters: nutritional and physiologic regulation,” Annual Review of Nutrition, vol. 29, pp. 153–176, 2009. View at Publisher · View at Google Scholar · View at Scopus
  36. I. Sekler, S. L. Sensi, M. Hershfinkel, and W. F. Silverman, “Mechanism and regulation of cellular zinc transport,” Molecular Medicine, vol. 13, no. 7-8, pp. 337–343, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. O. Thorlacius-Ussing, “Zinc in the anterior pituitary of rat: a histochemical and analytical work,” Neuroendocrinology, vol. 45, no. 3, pp. 233–242, 1987. View at Google Scholar · View at Scopus
  38. P. S. Dannies, “Prolactin and growth hormone aggregates in secretory granules: the need to understand the structure of the aggregate,” Endocrine Reviews, vol. 33, pp. 254–270, 2012. View at Google Scholar
  39. M. M. Wu, M. Grabe, S. Adams, R. Y. Tsien, H. H. Moore, and T. E. Machen, “Mechanisms of pH regulation in the regulated secretory pathway,” The Journal of Biological Chemistry, vol. 276, no. 35, pp. 33027–33035, 2001. View at Publisher · View at Google Scholar · View at Scopus
  40. B. Sankoorikal, Y. L. Zhu, M. E. Hodsdon, E. Lolis, and P. S. Dannies, “Aggregation of human wild-type and H27A-prolactin in cells and in solution: roles of Zn2+, Cu2+, and pH,” Endocrinology, vol. 143, no. 4, pp. 1302–1309, 2002. View at Publisher · View at Google Scholar · View at Scopus
  41. B. C. Cunningham, M. G. Mulkerrin, and J. A. Wells, “Dimerization of human growth hormone by zinc,” Science, vol. 253, no. 5019, pp. 545–548, 1991. View at Google Scholar · View at Scopus
  42. D. I. Iliev, N. E. Wittekindt, M. B. Ranke, and G. Binder, “In vitro analysis of hGH secretion in the presence of mutations of amino acids involved in zinc binding,” Journal of Molecular Endocrinology, vol. 39, no. 1-2, pp. 163–167, 2007. View at Publisher · View at Google Scholar · View at Scopus
  43. Z. Sun, P. S. Li, P. S. Dannies, and J. C. Lee, “Properties of human prolactin (prl) and h27a-prl, a mutant that does not bind Zn++,” Molecular Endocrinology, vol. 10, no. 3, pp. 265–271, 1996. View at Google Scholar · View at Scopus
  44. T. Miura, K. Suzuki, N. Kohata, and H. Takeuchi, “Metal binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes,” Biochemistry, vol. 39, no. 23, pp. 7024–7031, 2000. View at Publisher · View at Google Scholar · View at Scopus
  45. S. S. Vembar and J. L. Brodsky, “One step at a time: endoplasmic reticulum-associated degradation,” Nature Reviews Molecular Cell Biology, vol. 9, no. 12, pp. 944–957, 2008. View at Publisher · View at Google Scholar · View at Scopus
  46. J. M. Berg and Y. Shi, “The galvanization of biology: a growing appreciation for the roles of zinc,” Science, vol. 271, no. 5252, pp. 1081–1085, 1996. View at Google Scholar · View at Scopus
  47. C. G. Neumann and G. G. Harrison, “Onset and evolution of stunting in infants and children. Examples from the Human Nutrition Collaborative Research Support Program. Kenya and Egypt studies,” European Journal of Clinical Nutrition, vol. 48, supplement 1, pp. S90–S102, 1994. View at Google Scholar · View at Scopus
  48. N. E. Krebs, C. Reidinger, J. Westcott, L. V. Miller, P. V. Fennessey, and K. M. Hambidge, “Whole body zinc metabolism in full-term breastfed and formula fed infants,” Advances in Experimental Medicine and Biology, vol. 352, pp. 223–226, 1994. View at Google Scholar · View at Scopus
  49. N. F. Krebs, C. J. Reidinger, A. D. Robertson, and K. M. Hambidge, “Growth and intakes of energy and zinc in infants fed human milk,” Journal of Pediatrics, vol. 124, no. 1, pp. 32–39, 1994. View at Google Scholar · View at Scopus