ResearchIn-Press PreviewGeneticsHepatology Open Access | 10.1172/jci.insight.169738
1Department of Pathology and Laboratory Medicine, Brown University, Providence, United States of America
2Department of Pathology and Laboratory Medicine, Brown University, United States of America
3Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, United States of America
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1Department of Pathology and Laboratory Medicine, Brown University, Providence, United States of America
2Department of Pathology and Laboratory Medicine, Brown University, United States of America
3Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, United States of America
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1Department of Pathology and Laboratory Medicine, Brown University, Providence, United States of America
2Department of Pathology and Laboratory Medicine, Brown University, United States of America
3Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, United States of America
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1Department of Pathology and Laboratory Medicine, Brown University, Providence, United States of America
2Department of Pathology and Laboratory Medicine, Brown University, United States of America
3Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, United States of America
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1Department of Pathology and Laboratory Medicine, Brown University, Providence, United States of America
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3Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, United States of America
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1Department of Pathology and Laboratory Medicine, Brown University, Providence, United States of America
2Department of Pathology and Laboratory Medicine, Brown University, United States of America
3Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, United States of America
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1Department of Pathology and Laboratory Medicine, Brown University, Providence, United States of America
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3Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, United States of America
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1Department of Pathology and Laboratory Medicine, Brown University, Providence, United States of America
2Department of Pathology and Laboratory Medicine, Brown University, United States of America
3Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, United States of America
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1Department of Pathology and Laboratory Medicine, Brown University, Providence, United States of America
2Department of Pathology and Laboratory Medicine, Brown University, United States of America
3Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, United States of America
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1Department of Pathology and Laboratory Medicine, Brown University, Providence, United States of America
2Department of Pathology and Laboratory Medicine, Brown University, United States of America
3Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, United States of America
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1Department of Pathology and Laboratory Medicine, Brown University, Providence, United States of America
2Department of Pathology and Laboratory Medicine, Brown University, United States of America
3Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, United States of America
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Published April 23, 2024 - More info
Manganese is an essential yet potentially toxic metal. Initially reported in 2012, mutations in SLC30A10 are the first known inherited cause of manganese excess. SLC30A10 is an apical membrane protein that exports manganese from hepatocytes into bile and from enterocytes into the lumen of the gastrointestinal tract. SLC30A10 deficiency results in impaired gastrointestinal manganese excretion, leading to manganese excess, neurologic deficits, liver cirrhosis, polycythemia, and erythropoietin excess. Neurologic and liver disease are attributed to manganese toxicity. Polycythemia is attributed to erythropoietin excess. The goal of this study was to determine the basis of erythropoietin excess in SLC30A10 deficiency. Here we demonstrate that transcription factors hypoxia-inducible factor 1a (Hif1a) and 2a (Hif2a), key mediators of the cellular response to hypoxia, are both upregulated in livers of Slc30a10-deficient mice. Hepatic Hif2a deficiency corrected erythropoietin expression and polycythemia and attenuated aberrant hepatic gene expression in Slc30a10-deficient mice, while hepatic Hif1a deficiency had no discernible impact. Hepatic Hif2a deficiency also attenuated manganese excess, although the underlying cause of this is not clear at this time. Overall, our results indicate that hepatic HIF2 is a key determinant of pathophysiology in SLC30A10 deficiency and expand our understanding of the contribution of HIFs to human disease.