Fiche publication
Date publication
août 2016
Journal
Haematologica
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GACHET Christian
Tous les auteurs :
Léon C, Dupuis A, Gachet C, Lanza F
Lien Pubmed
Résumé
Constitutional thrombocytopenias result from platelet production abnormalities of hereditary origin. Long misdiagnosed and poorly studied, knowledge about these rare diseases has increased considerably over the last twenty years due to improved technology for the identification of mutations, as well as an improvement in obtaining megakaryocyte culture from patient hematopoietic stem cells. Simultaneously, the manipulation of mouse genes (transgenesis, total or conditional inactivation, introduction of point mutations, random chemical mutagenesis) have helped to generate disease models that have contributed greatly to deciphering patient clinical and laboratory features. Most of the thrombocytopenias for which the mutated genes have been identified now have a murine model counterpart. This review focuses on the contribution that these mouse models have brought to the understanding of hereditary thrombocytopenias with respect to what was known in humans. Animal models have either i) provided novel information on the molecular and cellular pathways that were missing from the patient studies; ii) improved our understanding of the mechanisms of thrombocytopoiesis; iii) been instrumental in structure-function studies of the mutated gene products; and iv) been an invaluable tool as preclinical models to test new drugs or develop gene therapies. At present, the genetic determinants of thrombocytopenia remain unknown in almost half of all cases. Currently available high-speed sequencing techniques will identify new candidate genes, which will in turn allow the generation of murine models to confirm and further study the abnormal phenotype. In a complementary manner, programs of random mutagenesis in mice should also identify new candidate genes involved in thrombocytopenia.
Mots clés
Animals, Autoantigens, metabolism, Bernard-Soulier Syndrome, etiology, Blood Platelets, metabolism, Cell Differentiation, genetics, Cytoskeleton, metabolism, Disease Models, Animal, Gene Expression Regulation, Humans, Iodide Peroxidase, metabolism, Iron-Binding Proteins, metabolism, Megakaryocytes, cytology, Mice, Receptors, Thrombopoietin, metabolism, Signal Transduction, Thrombocytopenia, diagnosis, Thrombopoiesis, Transcription Factors, metabolism, Wiskott-Aldrich Syndrome, etiology
Référence
Haematologica. 2016 08;101(8):896-908
