Trial reportThe Journal of biological chemistry2012
A dominant negative heterozygous G87R mutation in the zinc transporter, ZnT-2 (SLC30A2), results in transient neonatal zinc deficiency.
Trial report in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
46 citing papers in PubMed, 91 citations in OpenAlex.
- Zinc Transporter Gene Variants (SLC30A and SLC39A) in Human Disease: From Metal Homeostasis Disruption to Convergent Signaling Pathways.Human mutation · 2026Review
- Zinc deficiency-associated dermatitis in a prematurely born infant.Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG · 2025Article
- Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants.American journal of human genetics · 2024Article
- Structural insights into the calcium-coupled zinc export of human ZnT1.Science advances · 2024Article
- The impact of solute carrier proteins on disrupting substance regulation in metabolic disorders: insights and clinical applications.Frontiers in pharmacology · 2024Review
- Back in time to the Gly-rich prototype of the phosphate binding elementary function.Current research in structural biology · 2024Review
- NovelPediatric investigation · 2023Article
- Review
- Loss-of-function Mutations K11E or E271K Lead to Novel Tumor Suppression, Implicate Nucleolar Helicase DDX24 Oncogenicity.International journal of medical sciences · 2022Article
- Zinc Signaling in the Mammary Gland: For Better and for Worse.Biomedicines · 2021Review
- Metal transport mechanism of the cation diffusion facilitator (CDF) protein family - a structural perspective on human CDF (ZnT)-related diseases.RSC chemical biology · 2021Review
- Zinc homeostasis and signaling in the roundworm C. elegans.Biochimica et biophysica acta. Molecular cell research · 2021Review
- Review
- Review
- Milk-derived miRNA profiles elucidate molecular pathways that underlie breast dysfunction in women with common genetic variants in SLC30A2.Scientific reports · 2019Article
- Manganese influx and expression of ZIP8 is essential in primary myoblasts and contributes to activation of SOD2.Metallomics : integrated biometal science · 2019Article
- Crosstalk between zinc and free fatty acids in plasma.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2019Review
- ZnT2 is an electroneutral proton-coupled vesicular antiporter displaying an apparent stoichiometry of two protons per zinc ion.PLoS computational biology · 2019Article
- High proportion of transient neonatal zinc deficiency causing alleles in the general population.Journal of cellular and molecular medicine · 2019Article
- Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer.Cell death discovery · 2019Article
Corrections and comments
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Authors and funding
14 authors at 9 institutions in 3 countries.
Funding
Abstract
Zinc is an essential mineral, and infants are particularly vulnerable to zinc deficiency as they require large amounts of zinc for their normal growth and development. We have recently described the first loss-of-function mutation (H54R) in the zinc transporter ZnT-2 (SLC30A2) in mothers with infants harboring transient neonatal zinc deficiency (TNZD). Here we identified and characterized a novel heterozygous G87R ZnT-2 mutation in two unrelated Ashkenazi Jewish mothers with infants displaying TNZD. Transient transfection of G87R ZnT-2 resulted in endoplasmic reticulum-Golgi retention, whereas the WT transporter properly localized to intracellular secretory vesicles in HC11 and MCF-7 cells. Consequently, G87R ZnT-2 showed decreased stability compared with WT ZnT-2 as revealed by Western blot analysis. Three-dimensional homology modeling based on the crystal structure of YiiP, a close zinc transporter homologue from Escherichia coli, revealed that the basic arginine residue of the mutant G87R points toward the membrane lipid core, suggesting misfolding and possible loss-of-function. Indeed, functional assays including vesicular zinc accumulation, zinc secretion, and cytoplasmic zinc pool assessment revealed markedly impaired zinc transport in G87R ZnT-2 transfectants. Moreover, co-transfection experiments with both mutant and WT transporters revealed a dominant negative effect of G87R ZnT-2 over the WT ZnT-2; this was associated with mislocalization, decreased stability, and loss of zinc transport activity of the WT ZnT-2 due to homodimerization observed upon immunoprecipitation experiments. These findings establish that inactivating ZnT-2 mutations are an underlying basis of TNZD and provide the first evidence for the dominant inheritance of heterozygous ZnT-2 mutations via negative dominance due to homodimer formation.
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