Identification of Acer2 as a First Susceptibility Gene for Lithium-Induced Nephrogenic Diabetes Insipidus in Mice

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  • Theun de Groot, Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
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  • Lena K Ebert, Department II of Internal Medicine, Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
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  • Birgitte Mønster Christensen
  • Karolina Andralojc, Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
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  • Lydie Cheval, Physiology of Renal and Tubulopathies, CNRS (Centre National de la Recherche Scientifique) ERL 8228, Cordeliers Research Center, INSERM, Sorbonne University, Sorbonne Paris Cité University, Paris Descartes University, Paris Diderot University, Paris, France.
  • ,
  • Alain Doucet, Cordeliers Research Center, Sorbonne University, Pierre and Marie Curie University Paris 06, INSERM (Institut National de la Santé et de la Recherche Médicale), Paris Descartes University, Sorbonne Paris Cité, UMR_S (Unité Mixte de Recherche en Sciences) 1138, Paris, France.
  • ,
  • Cungui Mao, Stony Brook Cancer Center, Stony Brook, New York.
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  • Ruben Baumgarten, Reinier-Haga Medical Diagnostic Center, Delft, The Netherlands.
  • ,
  • Benjamin E Low, The Jackson Laboratory, Bar Harbor, Maine.
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  • Roger Sandhoff, Centre for Applied Sciences at Technical Universities (ZAFH)-Applied Biomedical Mass Spectrometry (ABIMAS), Mannheim, Germany.
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  • Michael V Wiles, The Jackson Laboratory, Bar Harbor, Maine.
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  • Peter M T Deen, Departments of Physiology,
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  • Ron Korstanje, The Jackson Laboratory, Bar Harbor, Maine;

BACKGROUND: Lithium, mainstay treatment for bipolar disorder, causes nephrogenic diabetes insipidus and hypercalcemia in about 20% and 10% of patients, respectively, and may lead to acidosis. These adverse effects develop in only a subset of patients treated with lithium, suggesting genetic factors play a role.

METHODS: To identify susceptibility genes for lithium-induced adverse effects, we performed a genome-wide association study in mice, which develop such effects faster than humans. On day 8 and 10 after assigning female mice from 29 different inbred strains to normal chow or lithium diet (40 mmol/kg), we housed the animals for 48 hours in metabolic cages for urine collection. We also collected blood samples.

RESULTS: In 17 strains, lithium treatment significantly elevated urine production, whereas the other 12 strains were not affected. Increased urine production strongly correlated with lower urine osmolality and elevated water intake. Lithium caused acidosis only in one mouse strain, whereas hypercalcemia was found in four strains. Lithium effects on blood pH or ionized calcium did not correlate with effects on urine production. Using genome-wide association analyses, we identified eight gene-containing loci, including a locus containing Acer2, which encodes a ceramidase and is specifically expressed in the collecting duct. Knockout of Acer2 led to increased susceptibility for lithium-induced diabetes insipidus development.

CONCLUSIONS: We demonstrate that genome-wide association studies in mice can be used successfully to identify susceptibility genes for development of lithium-induced adverse effects. We identified Acer2 as a first susceptibility gene for lithium-induced diabetes insipidus in mice.

Original languageEnglish
JournalJournal of the American Society of Nephrology : JASN
Pages (from-to)2322-2336
Number of pages15
Publication statusPublished - 2019

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