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Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function.

ABSTRACT: Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common single-nucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes an Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped 2 SLC30A10 non-coding SNPs (rs2275707 and rs12064812) by TaqMan PCR in cohorts from Bangladesh (N?=?406), the Argentinean Andes (N?=?198), and Italy (N?=?238). We also measured SLC30A10 expression in whole blood by TaqMan PCR in a sub-group (N?=?101) from the Andean cohort, and neurological parameters (sway velocity and finger-tapping speed) in the Italian cohort. The rs2275707 variant allele was associated with increased Mn concentrations in the Andes (8%, P?=?.027) and Italy (10.6%, P?=?.012), but not as clear in Bangladesh (3.4%, P?=?.21; linear regression analysis adjusted for age, gender, and plasma ferritin). This allele was also associated with increased sway velocity (15%, P?=?.033; adjusted for age and sex) and reduced SLC30A10 expression (-24.6%, P?=?.029). In contrast, the rs12064812 variant homozygous genotype was associated with reduced Mn concentrations, particularly in the Italian cohort (-18.4%, P?=?.04), and increased finger-tapping speed (8.7%, P?=?.025). We show that common SNPs in SLC30A10 are associated with blood Mn concentrations in 3 unrelated cohorts and that their influence may be mediated by altered SLC30A10 expression. Moreover, the SNPs appeared to influence neurological functions independent of blood Mn concentrations, suggesting that SLC30A10 could regulate brain Mn levels.

SUBMITTER: Wahlberg K

PROVIDER: S-EPMC4725612 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function.

Wahlberg Karin K Kippler Maria M Alhamdow Ayman A Rahman Syed Moshfiqur SM Smith Donald R DR Vahter Marie M Lucchini Roberto G RG Broberg Karin K

Toxicological sciences : an official journal of the Society of Toxicology 20151201 2

Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common single-nucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes an Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped 2 SLC30A10 non-coding SNPs (r ...[more]

PMID: 26628504

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Project description:The activity of the manganese (Mn) efflux transporter SLC30A10 in the liver and intestines is critical for Mn excretion and preventing Mn toxicity. Homozygous loss-of-function mutations in SLC30A10 are a well-established cause of hereditary Mn toxicity. But, the relationship between more common SLC30A10 polymorphisms, Mn homeostasis, and disease is only recently emerging. In 2021, the first coding SNP in SLC30A10 (T95I) was associated with liver disease raising the hypothesis that the T95I substitution may induce disease by inhibiting the Mn efflux function of SLC30A10. Here, we test this hypothesis using structural, viability, and metal quantification approaches. Analyses of a predicted structure of SLC30A10 revealed that the side chain of T95 pointed away from the putative Mn-binding cavity, raising doubts about the impact of the T95I substitution on SLC30A10 function. In HeLa or HepG2 cells, overexpression of SLC30A10-WT or T95I resulted in comparable reductions of intracellular Mn levels and protection against Mn-induced cell death. Furthermore, ΔSLC30A10 HepG2 cells, generated using CRISPR/Cas9, exhibited elevated Mn levels and heightened sensitivity to Mn-induced cell death, and these phenotypic changes were similarly rescued by expression of SLC30A10-WT or T95I. Finally, turnover rates of SLC30A10-WT or T95I were also comparable. In summary, our results indicate that the Mn transport activity of SLC30A10-T95I is essentially comparable to the WT protein. Our findings imply that SLC30A10-T95I either has a complex association with liver injury that extends beyond the simple reduction in SLC30A10 activity or alternatively the T95I mutation lacks a causal role in liver disease.NEW & NOTEWORTHY This study demonstrates that the T95I polymorphism in the manganese transporter SLC30A10, which has been associated with liver disease in human GWAS studies, does not impact transporter function in cell culture. These findings raise doubts about the causal relationship of the T95I polymorphism with human disease and highlight the importance of validating GWAS findings using mechanistic approaches.

Dataset Information

Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function.

Publications

Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function.

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