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Nat Commun. 2016 Mar 29;7:11097. doi: 10.1038/ncomms11097.

Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg(2+) homeostasis and cytoskeletal architecture.

Author information

1
Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.
2
Rudolf Virchow Centre, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.
3
Institut Hospitalo-Universitaire LIRYC, Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan, Avenue du Haut Lévêque, 33604 Pessac, France.
4
Assistance Publique-Hôpitaux de Paris, Haematological Laboratory, Armand Trousseau Children Hospital, 26 Avenue du Docteur Arnold-Netter, 75012 Paris, France.
5
Inserm U1170, Gustave Roussy, University Paris Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France.
6
Inra, UMR_INRA 1260, 27 Boulevard Jean Moulin, 13385 Marseille, France.
7
Aix Marseille Université, 58 Boulevard Charles Livon, 13284 Marseille, France.
8
Inserm UMR_S 1062, 27 Boulevard Jean Moulin, 13385 Marseille, France.
9
Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestraße 33, 80336 Munich, Germany.
10
Division of Haematology, Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA.
11
Department of Paediatrics, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA.
12
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Francis Crick Ave, Cambridge CB2 0S, UK.
13
NHS Blood and Transplant, Cambridge Biomedical Campus, Francis Crick Ave, Cambridge CB2 0S, UK.
14
Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Robinson Way, Cambridge CB2 0SR, UK.
15
NIHR BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Hills Rd, Cambridge CB2 0QQ, UK.
16
Endocrinology and Diabetes Unit, Department of Internal Medicine I, University Hospital of Würzburg, Oberdürrbacher Strasse 6, 97080 Würzburg, Germany.
17
Department of Molecular &Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Okinawa 903-0215, Japan.
18
Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, Du Cane Road, London SW7 2AZ, UK.
19
Imperial College Healthcare NHS Trust, Du Cane Road, London SW7 2AZ, UK.
20
Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, Max-Lebsche-Platz 31, 81377 Munich, Germany.
21
DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Lazarettstraße 36, 80636 Munich, Germany.

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.

PMID:
27020697
PMCID:
PMC4820538
DOI:
10.1038/ncomms11097
[Indexed for MEDLINE]
Free PMC Article

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