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Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg2+ homeostasis and cytoskeletal architecture

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Stritt, Simon | Nurden, Paquita | Favier, Remi | Favier, Marie | Ferioli, Silvia | Gotru, Sanjeev K. | van Eeuwijk, Judith M. M. | Schulze, Harald | Nurden, Alan T. | Lambert, Michele P. | Turro, Ernest | Burger-Stritt, Stephanie | Matsushita, Masayuki | Mittermeier, Lorenz | Ballerini, Paola | Zierler, Susanna | Laffan, Michael A. | Chubanov, Vladimir | Gudermann, Thomas | Nieswandt, Bernhard | Braun, Attila

Edité par CCSD ; Nature Publishing Group -

International audience. Mg2+ plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg2+](i) in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic alpha-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7(fl/fl-Pf4Cre)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7(fl/fl-Pf4Cre) MKs, which is rescued by Mg2+ supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.

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