| First Author | Hutchens S | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 23 | Pages | 9760-9773 |
| PubMed ID | 28461334 | Mgi Jnum | J:243657 |
| Mgi Id | MGI:5909356 | Doi | 10.1074/jbc.M117.783605 |
| Citation | Hutchens S, et al. (2017) Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice. J Biol Chem 292(23):9760-9773 |
| abstractText | Manganese is an essential metal that becomes toxic at elevated levels. Loss-of-function mutations in SLC30A10, a cell-surface-localized manganese efflux transporter, cause a heritable manganese metabolism disorder resulting in elevated manganese 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 knock-out mice. During early development, knock-outs were indistinguishable from controls. Surprisingly, however, after weaning and compared with controls, knock-out mice failed to gain weight, were smaller, and died prematurely (by approximately 6-8 weeks of age). At 6 weeks, manganese levels in the brain, blood, and liver of the knock-outs were approximately 20-60-fold higher than controls. Unexpectedly, histological analyses revealed that the brain and liver of the knock-outs were largely unaffected, but their thyroid exhibited extensive alterations. Because 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 knock-outs had markedly reduced thyroxine levels ( approximately 50-80%) and profoundly increased thyroid-stimulating hormone levels ( approximately 800-1000-fold), indicating that Slc30a10 knock-out mice develop hypothyroidism. Importantly, a low-manganese diet produced lower tissue manganese levels in the knock-outs and rescued the phenotype, suggesting that manganese toxicity was the underlying cause. Our unanticipated discovery highlights the importance of determining the role of thyroid dysfunction in the onset and progression of manganese-induced disease and identifies Slc30a10 knock-out mice as a new model for studying thyroid biology. |
