A gain of function variant in RGS18 candidate for a familial mild bleeding syndrome

Area of Science:

• Hematology
• Genetics
• Molecular Biology

Background:

• Inherited platelet diseases are bleeding disorders with diverse genetic causes, often affecting platelet count or function.
• Platelet function defects are heterogeneous, with many patients lacking precise genetic diagnoses despite advancements.
• Understanding the genetic basis of rare bleeding disorders is crucial for diagnosis and treatment.

Purpose of the Study:

• To identify the genetic cause of a novel mild bleeding syndrome in a family.
• To investigate a selective defect in platelet aggregation within the affected family.

Main Methods:

• Studied 6 family members across 3 generations with impaired platelet aggregation.
• Assessed platelet aggregation response to various agonists (ADP, PAR-1, AA, epinephrine) but not collagen.
• Performed whole exome sequencing to identify causative gene variants.

Main Results:

• Identified a heterozygous RGS18 variant (c.643C>T, p.Arg215∗) in affected family members.
• RGS18 (Regulator of G protein signaling 18) is a negative regulator of G protein-coupled receptor signaling in platelets.
• The identified variant cosegregated with the bleeding phenotype in all affected individuals.

Conclusions:

• The RGS18 p.Arg215∗ variant truncates the protein, removing key phosphorylation sites and impairing its regulatory function.
• Loss of RGS18 function leads to excessive platelet inhibition, causing the observed mild bleeding disorder.
• This finding highlights RGS18's critical role in platelet signaling and provides a genetic explanation for this family's bleeding syndrome.