boundaries. All of the cases analyzed have typical features of HHD suggesting several possible causes of this discrepancy. First, we cannot detect large deletions spanning the entire coding region of ATP2C1 with our detection system. Second, we cannot detect intronic mutations, mutations in the promoter regions, or mutations in the 3¢-untranslated region. The fact that Hu et al (2000) detected only 21 mutations out of a possible 61 HHD cases using the same primer sets supports our ®ndings.Among the ®ve families in which we could determine mutations, those with missense mutations (cases 2 and 3) and the one with a nonsense mutation in exon 25 (case 4) were predicted to produce abnormal ATP2C1 protein. These three cases showed early clinical symptoms (before the age of 40) compared with those with nonsense mutations in the 5¢ proximal exons (cases 1 and 5). In cases 1 and 5, severely reduced amounts of ATP2C1 protein are expected to be found because of ``nonsense-mediated mRNA decay'' (Frischmeyer and Dietz, 1999; Hentze and Kulozik, 1999). mRNA that has a nonsense mutation at the 5¢ proximal region would result in breakage because of the mechanism that is called ``nonsense-mediated mRNA decay'', and no abnormal truncated protein would be translated. On the other hand, mRNA that has a missense mutation or a nonsense mutation close to the end of the gene could be translated, and abnormal protein could interfere the action of normal ATP2C1 protein. Although HHD has been considered to be the result of haploinsuf®ciency of the ATP2C1 gene, the dominant negative effects of abnormal ATP2C1 protein might also contribute to the disease phenotype. Our data provide a signi®cant addition to the HHD mutation database and will contribute further to the understanding of HHD genotype/phenotype correlations and to the pathogenesis of this disease.

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.

Human growth hormone (GH) causes a variety of physiological and metabolic effects in humans and plays a pivotal role in postnatal growth. In somatotroph cells of the anterior pituitary, GH is stored in concentrated forms in secretory granules to be rapidly released upon GH-releasing hormone stimulation. During the process of secretory granule biogenesis, self-association of GH occurs in the compartments of the early secretory pathway (endoplasmic reticulum and Golgi complex). Since this process is greatly facilitated by the presence of zinc ions, it is of importance to understand the potential role of zinc transporters that participate in the fine-tuning of zinc homeostasis and dynamics, particularly in the early secretory pathway. Thus, the role of zinc transporters in supplying the secretory pathway with the sufficient amount of zinc required for the biogenesis of GH-containing secretory granules is essential for normal secretion. This report, illustrated by a clinical case report on transient neonatal zinc deficiency, focuses on the role of zinc in GH storage in the secretory granules and highlights the role of specific zinc transporters in the early secretory pathway.

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