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A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene
Vladimir T Manchev1, Morgane Hilpert1, Eliane Berrou2
1Institut 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;
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.
Insights
Inherited thrombocytopenias, specifically macrothrombocytopenias, can cause bleeding. A PRKACG gene mutation impairs platelet formation, leading to giant platelets and bleeding disorders.
Area of Science:
- Hematology
- Genetics
- Molecular Biology
Background:
- Macrothrombocytopenias are a heterogeneous group of inherited thrombocytopenias.
- Affected genes regulate diverse cellular functions, including signaling, cytoskeleton organization, and gene expression.
Purpose of the Study:
- To investigate the genetic basis of a severe autosomal recessive macrothrombocytopenia with thrombocytopathy in a consanguineous family.
- To identify the specific gene and mutation responsible for the observed bleeding disorder.
Main Methods:
- Clinical and hematological evaluation of affected family members.
- Exome sequencing to identify causative mutations.
- In vitro studies of megakaryocyte (MK) function, including proplatelet formation and filamin A levels.
- Rescue experiments using lentiviral vectors to overexpress wild-type PRKACG.
Main Results:
- A novel missense mutation (p.74Ile>Met) in the PRKACG gene was identified in homozygous patients.
- This mutation cosegregated with the macrothrombocytopenia and bleeding tendency.
- Homozygous patients exhibited impaired platelet activation, cytoskeleton reorganization, and markedly defective proplatelet formation.
- Reduced filamin A levels were observed in patient MKs.
- In vitro overexpression of wild-type PRKACG rescued the proplatelet formation defect.
Conclusions:
- PRKACG is a newly identified gene involved in inherited thrombocytopenia with giant platelets.
- The p.74Ile>Met PRKACG mutation disrupts platelet biogenesis, leading to macrothrombocytopenia and associated bleeding.
- PRKACG plays a critical role in megakaryocyte proplatelet formation and platelet production.
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