A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene

Blood. 2014 Oct 16;124(16):2554-63. doi: 10.1182/blood-2014-01-551820.

Vladimir T Manchev ¹, Morgane Hilpert ¹, Eliane Berrou ², Ziane Elaib ², Achille Aouba ³, Siham Boukour ⁴, Sylvie Souquere ⁵, Gerard Pierron ⁵, Philippe Rameau ⁶, Robert Andrews ⁷, François Lanza ⁸, Regis Bobe ², William Vainchenker ⁹, Jean-Philippe Rosa ², Marijke Bryckaert ², Najet Debili ⁹, Remi Favier ¹⁰, Hana Raslova ⁹

Affiliations

1 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;
2 Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 770, Université Paris-Sud 11, Le Kremlin Bicêtre, France;
3 Assistance Publique-Hôpitaux de Paris, Médecine Interne-Immunologie Clinique, Antoine Beclere Hospital, Clamart, France;
4 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;
5 Gustave Roussy, Villejuif, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8122, Université Paris-Sud 11, Villejuif, France;
6 Gustave Roussy, Villejuif, France; Plate Forme Imagerie et Cytomètrie de Flux, Integrated Research Cancer Institute in Villejuif, Villejuif, France;
7 Australian Centre for Blood Diseases, Monash University, Melbourne, Australia;
8 Institut National de la Santé et de la Recherche Médicale, UMR S949, Université de Strasbourg, Etablissement Français du Sang Alsace, Strasbourg Cedex, France; and.
9 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;
10 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.

PMID: 25061177 DOI: 10.1182/blood-2014-01-551820

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.

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