A missense variant in
| Autor: | Toru, Nakata, Elizabeth A, Creasey, Motohiko, Kadoki, Helen, Lin, Martin K, Selig, Junmei, Yao, Ariel, Lefkovith, Mark J, Daly, Daniel B, Graham, Ramnik J, Xavier |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance SLC39A8 A391T exhibits remarkable pleiotropic effects on multiple conditions, including cardiovascular diseases, Parkinson’s disease, and Crohn’s disease. However, how this single coding variant impacts such a wide range of pathologies has not been investigated. We generated Slc39a8 A391T knockin mice and show that they exhibit severe Mn deficiency in the colon, and impaired intestinal barrier integrity due to glycoprotein barrier structure defects, leading to indolent inflammation that can prime further inflammation driven by epithelial injury. Thus, we highlight the importance of Mn in gut homeostasis, and mechanistically unravel how A391T impacts intestinal barrier integrity. Common genetic variants interact with environmental factors to impact risk of heritable diseases. A notable example of this is a single-nucleotide variant in the Solute Carrier Family 39 Member 8 (SLC39A8)geneencoding the missense variant A391T, which is associated with a variety of traits ranging from Parkinson’s disease and neuropsychiatric disease to cardiovascular and metabolic diseases and Crohn’s disease. The remarkable extent of pleiotropy exhibited by SLC39A8 A391T raises key questions regarding how a single coding variant can contribute to this diversity of clinical outcomes and what is the mechanistic basis for this pleiotropy. Here, we generate a murine model for the Slc39a8 A391T allele and demonstrate that these mice exhibit Mn deficiency in the colon associated with impaired intestinal barrier function and epithelial glycocalyx disruption. Consequently, Slc39a8 A391T mice exhibit increased sensitivity to epithelial injury and pathological inflammation in the colon. Taken together, our results link a genetic variant with a dietary trace element to shed light on a tissue-specific mechanism of disease risk based on impaired intestinal barrier integrity. |
| Databáze: | OpenAIRE |
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