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 function at the organism level, we generated 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 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 knock-out mice as a new model for studying thyroid biology.

Bile acid composition regulates the manganese transporter Slc30a10 in intestine

“…But the intestine appears to play an important role in Mn homeostasis as well, especially when liver excretion has been saturated (60). While deletion of Slc30a10 only in hepatocytes is insufficient to cause hypermanganesemia, combined deletion in liver and gastrointestinal tract causes severe hypermanganesemia and neurotoxicity (39,41), mimicking the whole-body Slc30a10 knockout mice, though less severe (39,40). These findings support the notion that intestine and hepatobiliary excretion systems both participate in Mn homeostasis.…”

Generation and Validation of Tissue‐Specific Knockout Strains for Toxicology Research

“…Tissue specificity is established by the promoter controlling the expression of Cre recombinase. For example, the Sox2-Cre strain can be used to generate global knockouts, while the Nestin-and Albumin-Cre strains can be used to generate brain-and liver-specific knockouts, respectively (Hutchens et al, 2017;Liu et al, 2017;Taylor et al, 2019). In the Nestin-Cre strain, Cre expression is under the control of the Nestin promoter, which is expressed in neuronal and glial precursors (Tronche et al, 1999).…”

“…For example, to understand how loss of the manganese efflux transporter SLC30A10 induces neurological disease, we used the Cre‐ loxP system to generate full‐body and tissue‐specific Slc30a10 knockout mice. Full‐body Slc30a10 knockout mice exhibited extremely elevated manganese in the brain, blood, and liver (Hutchens et al., ; Liu et al., ; Taylor et al., ). These knockouts were also hypothyroid, highlighting a previously unappreciated relationship between manganese toxicity and thyroid function (Hutchens et al., ; Liu et al., ; Taylor et al., ).…”

“…Full‐body Slc30a10 knockout mice exhibited extremely elevated manganese in the brain, blood, and liver (Hutchens et al., ; Liu et al., ; Taylor et al., ). These knockouts were also hypothyroid, highlighting a previously unappreciated relationship between manganese toxicity and thyroid function (Hutchens et al., ; Liu et al., ; Taylor et al., ). Interestingly, brain‐specific Slc30a10 knockouts had no change in brain manganese levels under basal conditions, whereas liver‐ and digestive‐system‐specific knockouts showed moderate and extreme elevations in brain manganese, respectively (Taylor et al., ).…”

“…full-body and tissue-specific Slc30a10 knockout mice. Full-body Slc30a10 knockout mice exhibited extremely elevated manganese in the brain, blood, and liver (Hutchens et al, 2017;Liu et al, 2017;Taylor et al, 2019). These knockouts were also hypothyroid, highlighting a previously unappreciated relationship between manganese toxicity and thyroid function (Hutchens et al, 2017;Liu et al, 2017;Taylor et al, 2019).…”