| [PMID]: | 28461334 |
| [Au] Autor: | Hutchens S; Liu C; Jursa T; Shawlot W; Chaffee BK; Yin W; Gore AC; Aschner M; Smith DR; Mukhopadhyay S |
| [Ad] Endereço: | From the Division of Pharmacology & Toxicology, College of Pharmacy, Institute for Cellular & Molecular Biology, and Institute for Neuroscience and. |
| [Ti] Título: | Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice. |
| [So] Source: | J Biol Chem;292(23):9760-9773, 2017 06 09. |
| [Is] ISSN: | 1083-351X |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | 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. |
| [Mh] Termos MeSH primário: |
Proteínas de Transporte de Cátions/deficiência
Hipotireoidismo/genética
Hipotireoidismo/metabolismo
Manganês/metabolismo
Glândula Tireoide/metabolismo
|
| [Mh] Termos MeSH secundário: |
Animais
Modelos Animais de Doenças
Hipotireoidismo/patologia
Camundongos
Camundongos Knockout
Glândula Tireoide/patologia
|
| [Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL |
[Nm] Nome de substância:
| 0 (Cation Transport Proteins); 42Z2K6ZL8P (Manganese) |
| [Em] Mês de entrada: | 1706 |
| [Cu] Atualização por classe: | 171228 |
[Lr] Data última revisão:
| 171228 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 170503 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1074/jbc.M117.783605 |
| |
|
