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J Biol Chem. 2017 Oct 6;292(40):16605-16615. doi: 10.1074/jbc.M117.804989. Epub 2017 Aug 31.

Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production.

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From the Division of Pharmacology and Toxicology, College of Pharmacy, Institute for Cellular & Molecular Biology, and Institute for Neuroscience and.
the Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, California 95064.
Mouse Genetic Engineering Facility, University of Texas, Austin, Texas 78712.
the Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy.
the Department of Veterinary Sciences, Michale E. Keeling Center for Comparative Medicine and Research, M. D. Anderson Cancer Center, Bastrop, Texas 78602, and.
the Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
From the Division of Pharmacology and Toxicology, College of Pharmacy, Institute for Cellular & Molecular Biology, and Institute for Neuroscience and


SLC30A10 and SLC39A14 are manganese efflux and influx transporters, respectively. Loss-of-function mutations in genes encoding either transporter induce hereditary manganese toxicity. Patients have elevated manganese in the blood and brain and develop neurotoxicity. Liver manganese is increased in patients lacking SLC30A10 but not SLC39A14. These organ-specific changes in manganese were recently recapitulated in knockout mice. Surprisingly, Slc30a10 knockouts also had elevated thyroid manganese and developed hypothyroidism. To determine the mechanisms of manganese-induced hypothyroidism and understand how SLC30A10 and SLC39A14 cooperatively mediate manganese detoxification, here we produced Slc39a14 single and Slc30a10/Slc39a14 double knockout mice and compared their phenotypes with that of Slc30a10 single knockouts. Compared with wild-type controls, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had higher manganese levels in the blood and brain but not in the liver. In contrast, Slc30a10 single knockouts had elevated manganese levels in the liver as well as in the blood and brain. Furthermore, SLC30A10 and SLC39A14 localized to the canalicular and basolateral domains of polarized hepatic cells, respectively. Thus, transport activities of both SLC39A14 and SLC30A10 are required for hepatic manganese excretion. Compared with Slc30a10 single knockouts, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had lower thyroid manganese levels and normal thyroid function. Moreover, intrathyroid thyroxine levels of Slc30a10 single knockouts were lower than those of controls. Thus, the hypothyroidism phenotype of Slc30a10 single knockouts is induced by elevated thyroid manganese, which blocks thyroxine production. These findings provide new insights into the mechanisms of manganese detoxification and manganese-induced thyroid dysfunction.


SLC30; SLC39; cation diffusion facilitator; excretion; liver; manganese; metal homeostasis; parkinsonism; thyroid; transporter

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