Researchers have identified specific genetic variants in the SLC39A10 gene, which encodes the zinc importer ZIP10, that are significantly enriched in populations of African ancestry and functionally impair cellular zinc handling. Published in the journal Genes & Nutrition, this study integrates population genomic analyses with molecular and functional characterization to demonstrate that these ancestry-linked missense variants act as hypomorphic alleles, reducing the transporter’s capacity to regulate the cytosolic labile zinc pool. The findings provide mechanistic insight into how population-specific genetic variation can modulate a fundamental micronutrient transport process, potentially explaining interindividual and interpopulation differences in zinc utilization and susceptibility to deficiency.
Zinc is the second most abundant trace element in the human body after iron and serves as a structural or catalytic cofactor for more than 3,000 proteins, including numerous enzymes and transcription factors. The adult human body contains approximately 2 to 3 grams of zinc, most of which is localized intracellularly, requiring tightly regulated homeostatic mechanisms to maintain a sufficient supply while preventing cytotoxic accumulation. Despite its essential role, zinc deficiency remains a major global public health problem, affecting nearly one-fifth of the global population and contributing to impaired growth, increased susceptibility to infection, and adverse pregnancy outcomes. The burden is particularly severe in low- and middle-income regions, including sub-Saharan Africa, where dietary zinc bioavailability from cereal-based staples is limited.
While inadequate dietary intake is a primary determinant of zinc status, it does not fully explain the substantial interindividual variability in zinc status or responsiveness to supplementation observed across populations. Increasing evidence suggests that genetic variation in genes regulating zinc transport and cellular utilization contributes to these differences. At the cellular level, zinc homeostasis is governed primarily by two transporter families: members of the SLC39A (ZIP) family mediate zinc influx into the cytosol, whereas SLC30A (ZnT) transporters facilitate zinc efflux or sequestration into intracellular compartments. Within the ZIP family, SLC39A10 has emerged as a critical regulator of cytosolic zinc availability, particularly under zinc-restricted conditions, making it a key candidate for investigating genetic determinants of zinc handling.
To identify potentially functional genetic variation, the study team analyzed sequencing data from the Genome Aggregation Database, a large resource integrating exome and genome datasets from diverse population studies. They prioritized missense variants with an allele frequency greater than 0.5% in at least one ancestry group and identified three variants that met these criteria: rs13419724 (T87S), rs114992984 (H194Q), and rs76182486 (H609Y). All three variants showed pronounced enrichment among individuals of African or African American ancestry and were rare or absent in other ancestry groups represented in the database. This ancestry-restricted distribution is consistent with population-specific mutational history, genetic drift, or local selective pressures, suggesting that these variants may contribute to interpopulation differences in ZIP10-mediated zinc handling.
Structural and computational analyses provided a rationale for experimental evaluation of these substitutions. The T87S variant represents a conservative change between polar uncharged residues, whereas H194Q and H609Y involve the replacement of histidine residues with neutral polar amino acids. Because histidine side chains frequently participate in zinc coordination through their imidazole nitrogen, such substitutions may influence metal binding or transporter regulation, particularly within histidine-rich regions characteristic of ZIP family proteins. Multiple sequence alignment demonstrated strong evolutionary conservation of H194 and H609 across vertebrate orthologs, whereas T87 showed limited conservation. Topology modeling positioned H194 adjacent to an extracellular histidine-rich motif and H609 within a cytosolic loop proximal to a second histidine-rich region implicated in transporter regulation.
To assess the functional consequences of these substitutions, the researchers generated site-directed mutants and transiently expressed them in HEK293T cells. Quantitative PCR and immunoblot analyses confirmed comparable ZIP10 mRNA and protein abundance across all constructs, indicating that these substitutions did not substantially affect steady-state expression. Under basal zinc conditions, the induction of metallothionein transcripts was similar across all constructs. However, when cells were exposed to a zinc pulse of 150 micromolar zinc chloride for one hour to enhance measurable flux, MT1X and MT2A transcript levels were significantly lower in cells expressing the H194Q and H609Y variants compared to the common-allele transporter. These differential responses are consistent with reduced transporter-dependent zinc acquisition associated with the histidine substitutions.
Direct measurement of cytosolic labile zinc using the fluorescent indicator FluoZin-3AM further supported these findings. Overexpression of the common-allele ZIP10 increased probe-detectable intracellular zinc signals to approximately 1.6-fold above vector control, consistent with enhanced transporter-mediated zinc entry. In contrast, cells expressing the H194Q or H609Y variants displayed significantly lower labile zinc signals, whereas signals in T87S-expressing cells remained comparable to the common allele. Live-cell fluorescence imaging following transient zinc exposure confirmed significant reductions in mean fluorescence intensity for both histidine-replacing variants. Immunofluorescence microscopy revealed that the reduced probe-detectable zinc signals were not due to altered protein trafficking, as all constructs were predominantly localized to the plasma membrane with comparable intracellular distributions.
To explore potential physiological relevance, the study team conducted genotype-phenotype association analyses using the African ancestry subset of the VA Million Veteran Program, which comprises more than 100,000 participants and approximately 2,000 clinical traits. Although no associations met phenome-wide significance thresholds, several nominal associations suggested biologically plausible relationships between the SLC39A10 variants and hematologic, renal, and metabolic phenotypes. The minor allele of the H194Q variant was nominally associated with risk of aplastic anemia, pancytopenia, and anemia secondary to neoplastic disease. The H609Y variant showed nominal associations with leukopenia and anemia among individuals with chronic kidney disease. Both variants also demonstrated suggestive associations with renal phenotypes, including chronic kidney disease and elevated serum creatinine.
In the metabolic domain, both variants were nominally associated with increased risk of type 2 diabetes and related complications, including neuropathy and retinopathy. The H194Q variant additionally showed a suggestive association with keloid formation, a fibrotic skin condition disproportionately prevalent among individuals of African ancestry. These variant-trait patterns are broadly consistent with the tissue expression profile of ZIP10, which is enriched in the kidney, immune cells, and skin. Together with the functional data, these findings support the possibility that partial loss-of-function SLC39A10 alleles may influence tissue-specific zinc handling and contribute to interindividual variability in disease susceptibility.
From an evolutionary standpoint, the enrichment of these alleles in African ancestry populations may reflect local selective pressures, such as host-pathogen competition for zinc, a process often termed nutritional immunity. During infection, hosts actively redistribute trace metals to restrict microbial proliferation, and in malaria, which remains endemic in many regions of sub-Saharan Africa, membrane transporters have been implicated in regulating metal availability within infected erythrocytes. Reduced ZIP10-mediated zinc uptake could theoretically limit zinc accessibility to intracellular pathogens. However, genetic variants that may have conferred adaptive advantages in pathogen-rich environments could have different consequences in contemporary settings, potentially predisposing carriers to marginal zinc insufficiency when dietary intake is limited or inflammatory conditions alter systemic zinc distribution.
Current biomarkers such as plasma zinc concentration have limited sensitivity and are influenced by inflammation, infection, and circadian variation, making them insufficient for detecting mild deficiency or identifying genetic determinants of micronutrient utilization. The present findings support the concept that incorporating genetic variation into nutritional risk assessment may improve the identification of individuals who could benefit from targeted zinc interventions, particularly among physiologically vulnerable groups such as pregnant women and young children. By identifying functionally sensitive residues required for efficient ZIP10-mediated zinc transport, this study illustrates how population-specific genetic variation can modulate a fundamental micronutrient transport process.
These findings identify SLC39A10 as a locus of nutrigenetic diversity and demonstrate ancestry-linked variation in cellular zinc handling. The characterization of African-enriched hypomorphic ZIP10 variants provides mechanistic insight into genetic influences on micronutrient homeostasis. Although future in vivo studies will be required to determine how SLC39A10 genotype shapes systemic zinc homeostasis and physiological zinc requirements, the current results highlight the importance of considering genetic determinants in trace element metabolism. As precision nutrition frameworks continue to develop, defining these genetic determinants will be critical for advancing equitable, genotype-informed nutritional strategies aimed at reducing population-specific vulnerability to zinc deficiency and improving global health outcomes.
Subject of Research: Functional characterization of African-enriched SLC39A10 missense variants and their impact on cellular zinc homeostasis and health-related traits.
Article Title: African-enriched SLC39A10 (ZIP10) missense variants differentially affect cellular zinc homeostasis and associate with health-related traits
Article References: Song, J.-O., Cho, S., Kim, J., Ye, K., & Ryu, M.-S. (2026). African-enriched SLC39A10 (ZIP10) missense variants differentially affect cellular zinc homeostasis and associate with health-related traits. Genes & Nutrition, 21(1), Article 9. https://doi.org/10.1186/s12263-026-00801-3
Image Credits: AI Generated
DOI: 10.1186/s12263-026-00801-3
Keywords: SLC39A10, ZIP10, zinc homeostasis, genetic variation, African ancestry, micronutrient transport, nutrigenetics, cellular biology, zinc deficiency, phenome-wide association, African-enriched, missense
News Source: Drew Townsend. (November 7, 2026). African-enriched ZIP10 variants reduce cellular zinc uptake. Scienmag.
