Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice

Steven Hutchens, Chunyi Liu, Thomas Jursa, William Shawlot, Beth K. Chaffee, Weiling Yin, Andrea C. Gore, Michael Aschner, Donald R. Smith, Somshuvra Mukhopadhyay

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Abstract

Manganese is an essential metal that becomes toxic at elevated levels. Loss-of-function mutations in SLC30A10, a cellsurface- 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, knockouts 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 ∼6-8 weeks of age). At 6 weeks, manganese levels in the brain, blood, and liver of the knock-outs were ∼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 knockouts had markedly reduced thyroxine levels (∼50-80%) and profoundly increased thyroid-stimulating hormone levels (∼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.

Original languageEnglish (US)
Pages (from-to)9760-9773
Number of pages14
JournalJournal of Biological Chemistry
Volume292
Issue number23
DOIs
Publication statusPublished - 2017

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Hutchens, S., Liu, C., Jursa, T., Shawlot, W., Chaffee, B. K., Yin, W., ... Mukhopadhyay, S. (2017). Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice. Journal of Biological Chemistry, 292(23), 9760-9773. https://doi.org/10.1074/jbc.M117.783605