Characterization and Prevention of Slc30a10 Deficiency Phenotypes in Young Mice

Conboy, Heather

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Overview

Year:: 2020
Contributor:: Conboy, Heather (creator); Gruppuso, Phil (Reader); Plavicki, Jessica (Reader); Bartnikas, Thomas (Advisor); Zhitkovich, Anatoly (Reader); Brown University. Department of Molecular Pharmacology, Physiology and Biotechnology (sponsor)
Genre:: theses
Subject:: Metabolism; Metals; Manganese; Rare diseases
Extent:: xix, 217 p.

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Abstract:: Manganese (Mn) is an essential dietary nutrient. However, Mn excess can cause irreversible neurological damages often referred to as manganism. While Mn excess is typically caused by environmental or other exposures, in 2012 the first case of inherited Mn excess was identified in a small group of patients carrying homozygous mutations in SLC30A10. Patients with SLC30A10 deficiency exhibit Mn excess, a Parkinson-like disorder, polycythemia, and liver cirrhosis. Originally thought to transport zinc, SLC30A10 is now known as a Mn efflux transporter, but how Mn is regulated by SLC30A10 still remains unclear. Therefore, we have generated several mouse models to further our understanding of Mn metabolism. First we use Slc30a10neo/neo and Slc30a10GFP/GFP mice to identify main sites of Slc30a10 expression. Using these mouse models we identified that Slc30a10 is localized on the membrane of hepatocytes in the liver and enterocytes in the small and large intestine. We then generated a global knockout mouse line (Slc30a10KO/KO) and established disease progression in Slc30a10 deficiency. Establishing disease progression is essential to identify critical time points for treatment since damages from Mn excess can be irreversible. We demonstrate that Slc30a10 is expressed in mice at P14. We also observed severe Mn excess, liver abnormalities, and Mn excretion defects in Slc30a10KO/KO mice by P21. Using a dietary approach we then establish that younger mice are more susceptible to Mn toxicity but not excess when compared to older mice. Lastly, we used tissue-specific Slc30a10-deficient mice to determine the function of Slc30a10 in main sites identified in Slc30a10GFP/GFP and Slc30a10neo/neo mice. Using genetic and surgical approaches, we demonstrate that Slc30a10 is essential for Mn loading into the bile for hepatobiliary excretion and for Mn efflux from enterocytes into the intestinal lumen for fecal excretion. Overall, these studies suggest younger individuals are more susceptible to Mn toxicity than older individuals and that Slc30a10 contributes to Mn metabolism through intestinal and hepatobiliary excretion.
Notes:: Thesis (Ph. D.)--Brown University, 2020

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Citation

Conboy, Heather, "Characterization and Prevention of Slc30a10 Deficiency Phenotypes in Young Mice" (2020). Molecular Pharmacology, Physiology, and Biotechnology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:yykgx8fm/

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Molecular Pharmacology, Physiology, and Biotechnology Theses and Dissertations

Theses and Dissertations for the Molecular Pharmacology, Physiology, and Biotechnology department.
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