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

Abstract

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 ∼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 knock-outs 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.

• Authors: Steven Hutchens, Chunyi Liu, Thomas Jursa, William Shawlot, Beth K Chaffee, Weiling Yin, Andrea C Gore, Michael Aschner, Donald R Smith, Somshuvra Mukhopadhyay
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 23 Pg. 9760-9773 (06 09 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28461334 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Cation Transport Proteins
• Manganese

Topics

• Animals
• Cation Transport Proteins (deficiency)
• Disease Models, Animal
• Hypothyroidism (genetics, metabolism, pathology)
• Manganese (metabolism)
• Mice
• Mice, Knockout
• Thyroid Gland (metabolism, pathology)