RASGRP2 gene variations associated with platelet dysfunction and bleeding

Abstract

This manuscript reviews pathogenic variants in RASGRP2, which are the cause of a relatively new autosomal recessive and nonsyndromic inherited platelet function disorder, referred to as platelet-type bleeding disorder-18 (BDPLT18)(OMIM:615888). To date, 18 unrelated BDPLT18 pedigrees have been reported, harboring 19 different homozygous or compound heterozygous RASGRP2 variants. Patients with this disease present with lifelong moderate to severe bleeding, with epistaxis as the most common and relevant bleeding symptom. Biologically, they exhibit normal platelet count and morphology, reduced aggregation responses to ADP, epinephrine and low-dose collagen, and impaired αIIbβ3 integrin activation (fibrinogen or PAC-1 binding) in response to most agonists except PMA. Diagnosis is confirmed by genetic analysis of RASGRP2.

Keywords:

• Bleeding
• CalDAG-GEFI
• inherited platelet dysfunction
• RASGRP2

Main Findings

• A relatively novel autosomal recessive and nonsyndromic inherited platelet function disorder (BDPLT18) due to molecular pathology in RASGRP2 is currently well characterized.

• Rare variants in RASGRP2 are deleterious for the expression or function of CalDAG-GEFI.

• RASGRP2 pathogenic variants cause defective RAP1 and integrin activation, and consistently reduced platelet aggregation with weak agonists such as ADP, epinephrine and low dose collagen.

• While having normal platelet count and morphology, affected patients suffer from lifelong moderate to severe bleeding tendency, often requiring medical intervention and treatment.

• There is no consistent apparent genotype-phenotype correlation in this disorder.

• Discrepant observations are reported regarding the deleterious effect of RASGRP2 variants in leukocyte function, but patients do not display overt infections or immune defects.

Disclosure Statement

The authors declare no conflict of interest.

Additional information

Funding

Research by the group of MLA and JR is supported by grants from Instituto de Salud Carlos III and Feder (ISCIII&Feder) (PI17/01311 and CB15/00055) and Fundación Séneca (19873/GERM/15). Research by the group of JMB is supported by grants from ISCIII&Feder (PI17/01966), Instituto de Investigación Biomédica de Salamanca (IBSAL, IBY17/00006) and Gerencia Regional de Salud (GRS 1647/A/17 and GRS 1650/A/17). VPB holds a CIBERER PhD grant. The authors research in Inherited Platelet Disorders is conducted according to the aims of the Project “Functional and Molecular Characterization of Patients with Inherited Platelet Disorders” supported by the Hemorrhagic Diathesis Working Group of the Spanish Society of Thrombosis and Haemostasis;Instituto de Investigación Biomédica de Salamanca (IBSAL) [IBY17/00006];Gerencia Regional de Salud [GRS 1647/A/17,GRS 1650/A/17];Instituto de Salud Carlos III and Feder [CB15/00055,PI17/01311,PI17/01966].