title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
abstract: Macrothrombocytopenias are the most important subgroup of inherited thrombocytopenias. This subgroup is particularly heterogeneous because the affected genes are involved in various functions such as cell signaling, cytoskeleton organization, and gene expression. Herein we describe the clinical and hematological features of a consanguineous family with a severe autosomal recessive macrothrombocytopenia associated with a thrombocytopathy inducing a bleeding tendency in the homozygous mutated patients. Platelet activation and cytoskeleton reorganization were impaired in these homozygous patients. Exome sequencing identified a c.222C>G mutation (missense p.74Ile>Met) in PRKACG, a gene encoding the γ-catalytic subunit of the cyclic adenosine monophosphate-dependent protein kinase, the mutated allele cosegregating with the macrothrombocytopenia. We demonstrate that the p.74Ile>Met PRKACG mutation is associated with a marked defect in proplatelet formation and a low level in filamin A in megakaryocytes (MKs). The defect in proplatelet formation was rescued in vitro by lentiviral vector-mediated overexpression of wild-type PRKACG in patient MKs. We thus conclude that PRKACG is a new central actor in platelet biogenesis and a new gene involved in inherited thrombocytopenia with giant platelets associated with a thrombocytopathy.
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1009, Université Paris-Sud 11, Equipe Labellisée Ligue Contre le Cancer, Villejuif, France; University Paris Diderot, Paris, France; Gustave Roussy, Villejuif, France;
authors: Vladimir T
authors: VT
authors: Manchev
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1009, Université Paris-Sud 11, Equipe Labellisée Ligue Contre le Cancer, Villejuif, France; University Paris Diderot, Paris, France; Gustave Roussy, Villejuif, France;
authors: Morgane
authors: M
authors: Hilpert
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 770, Université Paris-Sud 11, Le Kremlin Bicêtre, France;
authors: Eliane
authors: E
authors: Berrou
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 770, Université Paris-Sud 11, Le Kremlin Bicêtre, France;
authors: Ziane
authors: Z
authors: Elaib
authors: Assistance Publique-Hôpitaux de Paris, Médecine Interne-Immunologie Clinique, Antoine Beclere Hospital, Clamart, France;
authors: Achille
authors: A
authors: Aouba
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1009, Université Paris-Sud 11, Equipe Labellisée Ligue Contre le Cancer, Villejuif, France; Gustave Roussy, Villejuif, France; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 770, Université Paris-Sud 11, Le Kremlin Bicêtre, France;
authors: Siham
authors: S
authors: Boukour
authors: Gustave Roussy, Villejuif, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8122, Université Paris-Sud 11, Villejuif, France;
authors: Sylvie
authors: S
authors: Souquere
authors: Gustave Roussy, Villejuif, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8122, Université Paris-Sud 11, Villejuif, France;
authors: Gerard
authors: G
authors: Pierron
authors: Gustave Roussy, Villejuif, France; Plate Forme Imagerie et Cytomètrie de Flux, Integrated Research Cancer Institute in Villejuif, Villejuif, France;
authors: Philippe
authors: P
authors: Rameau
authors: Australian Centre for Blood Diseases, Monash University, Melbourne, Australia;
authors: Robert
authors: R
authors: Andrews
authors: Institut National de la Santé et de la Recherche Médicale, UMR S949, Université de Strasbourg, Etablissement Français du Sang Alsace, Strasbourg Cedex, France; and.
authors: François
authors: F
authors: Lanza
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 770, Université Paris-Sud 11, Le Kremlin Bicêtre, France;
authors: Regis
authors: R
authors: Bobe
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1009, Université Paris-Sud 11, Equipe Labellisée Ligue Contre le Cancer, Villejuif, France; Gustave Roussy, Villejuif, France;
authors: William
authors: W
authors: Vainchenker
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 770, Université Paris-Sud 11, Le Kremlin Bicêtre, France;
authors: Jean-Philippe
authors: JP
authors: Rosa
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 770, Université Paris-Sud 11, Le Kremlin Bicêtre, France;
authors: Marijke
authors: M
authors: Bryckaert
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1009, Université Paris-Sud 11, Equipe Labellisée Ligue Contre le Cancer, Villejuif, France; Gustave Roussy, Villejuif, France;
authors: Najet
authors: N
authors: Debili
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1009, Université Paris-Sud 11, Equipe Labellisée Ligue Contre le Cancer, Villejuif, France; Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, French Reference Center for Platelet Disorders, Haematological Laboratory, Paris, France.
authors: Remi
authors: R
authors: Favier
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1009, Université Paris-Sud 11, Equipe Labellisée Ligue Contre le Cancer, Villejuif, France; Gustave Roussy, Villejuif, France;
authors: Hana
authors: H
authors: Raslova
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology*; D002675:Child, Preschool; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics*; D003599:Cytoskeleton / Q000235:genetics / Q000473:pathology; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology*; D010375:Pedigree; D010976:Platelet Count; D013921:Thrombocytopenia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517763:PRKACG protein, human