title: Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg(2+) homeostasis and cytoskeletal architecture.
abstract: Mg(2+) plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg(2+)]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 α-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 Mg(2+) 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.
authors.affiliation: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.|Rudolf Virchow Centre, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.
authors.forename: Simon
authors.identifier: http://orcid.org/0000-0002-4299-4934
authors.initials: S
authors.lastname: Stritt
authors.affiliation: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.|Institut Hospitalo-Universitaire LIRYC, Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan, Avenue du Haut Lévêque, 33604 Pessac, France.
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Haematological Laboratory, Armand Trousseau Children Hospital, 26 Avenue du Docteur Arnold-Netter, 75012 Paris, France.|Inserm U1170, Gustave Roussy, University Paris Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Remi
authors.initials: R
authors.lastname: Favier
authors.affiliation: Inserm U1170, Gustave Roussy, University Paris Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France.|Inra, UMR_INRA 1260, 27 Boulevard Jean Moulin, 13385 Marseille, France.|Aix Marseille Université, 58 Boulevard Charles Livon, 13284 Marseille, France.|Inserm UMR_S 1062, 27 Boulevard Jean Moulin, 13385 Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Favier
authors.affiliation: Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestraße 33, 80336 Munich, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ferioli
authors.affiliation: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.|Rudolf Virchow Centre, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Gotru
authors.affiliation: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.|Rudolf Virchow Centre, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.
authors.forename: Judith M M
authors.initials: JM
authors.lastname: van Eeuwijk
authors.affiliation: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Schulze
authors.affiliation: Institut Hospitalo-Universitaire LIRYC, Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan, Avenue du Haut Lévêque, 33604 Pessac, France.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Nurden
authors.affiliation: Division of Haematology, Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA.|Department of Paediatrics, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michele P
authors.initials: MP
authors.lastname: Lambert
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Francis Crick Ave, Cambridge CB2 0S, UK.|NHS Blood and Transplant, Cambridge Biomedical Campus, Francis Crick Ave, Cambridge CB2 0S, UK.|Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Robinson Way, Cambridge CB2 0SR, UK.|NIHR BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Hills Rd, Cambridge CB2 0QQ, UK.
authors.forename: Ernest
authors.identifier: http://orcid.org/0000-0002-1820-6563
authors.initials: E
authors.lastname: Turro
authors.affiliation: Endocrinology and Diabetes Unit, Department of Internal Medicine I, University Hospital of Würzburg, Oberdürrbacher Strasse 6, 97080 Würzburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Burger-Stritt
authors.affiliation: Department of Molecular &Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Okinawa 903-0215, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestraße 33, 80336 Munich, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Mittermeier
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Haematological Laboratory, Armand Trousseau Children Hospital, 26 Avenue du Docteur Arnold-Netter, 75012 Paris, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Ballerini
authors.affiliation: Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestraße 33, 80336 Munich, Germany.
authors.forename: Susanna
authors.identifier: http://orcid.org/0000-0002-4684-0385
authors.initials: S
authors.lastname: Zierler
authors.affiliation: Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, Du Cane Road, London SW7 2AZ, UK.|Imperial College Healthcare NHS Trust, Du Cane Road, London SW7 2AZ, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laffan
authors.affiliation: Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestraße 33, 80336 Munich, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Chubanov
authors.affiliation: Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestraße 33, 80336 Munich, Germany.|Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, Max-Lebsche-Platz 31, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Lazarettstraße 36, 80636 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.affiliation: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.|Rudolf Virchow Centre, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.affiliation: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.|Rudolf Virchow Centre, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.
authors.forename: Attila
authors.initials: A
authors.lastname: Braun
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008274:Magnesium / Q000378:metabolism*; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000172:deficiency / Q000378:metabolism*; D013921:Thrombocytopenia / Q000378:metabolism / Q000473:pathology; D034061:Thrombopoiesis
chemical_list: D050505:Mutant Proteins; D050053:TRPM Cation Channels; C421903:Trpm7 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D024507:Nonmuscle Myosin Type IIA; D008274:Magnesium