Manganese (Mn) is an essential metal that becomes toxic at elevated levels. Loss-of-function mutations in SLC30A10, a cell surface-localized Mn efflux transporter, cause a heritable Mn metabolism disorder resulting in elevated Mn levels and parkinsonian-like movement deficits. The underlying disease mechanisms are unclear; therefore, treatment is challenging. To understand the consequences of loss of SLC30A10 function at the organism level, we generated Slc30a10 knockout mice. During early development, knockouts were indistinguishable from controls. Surprisingly, however, after weaning and compared with controls, knockout mice failed to gain weight, were smaller, and died prematurely (by ~6-8 weeks of age). At 6 weeks, Mn levels in the brain, blood, and liver of the knockouts were ~20-60-fold higher than controls. Unexpectedly, histological analyses revealed that the brain and liver of the knockouts were largely unaffected, but that their thyroid exhibited extensive alterations. As hypothyroidism leads to growth defects and premature death in mice, we assayed for changes in thyroid and pituitary hormones. At 6 weeks and compared with controls, the knockouts had markedly reduced thyroxine levels (~50-80%) and profoundly increased thyroid stimulating hormone levels (~800-1000-fold), indicating that Slc30a10 knockout mice develop hypothyroidism. Importantly, a low Mn diet produced lower tissue Mn levels in the knockouts and rescued the phenotype, suggesting that Mn toxicity was the underlying cause. Our unanticipated discovery highlights the importance of determining the role of thyroid dysfunction in the onset and progression of Mn-induced disease and identifies Slc30a10 knockout mice as a new model for studying thyroid biology.
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