Molecular and Structural characterisation of rare GPCR genetic variants in patients with impaired haemostasis

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Blood clotting requires recruitment of platelets (specialised blood cells) to the site of injury asone of the first (of many) events that prevents bleeding. Platelet G-protein-coupled receptors(GPCRs) are critical regulators of platelet function where these receptors can be blocked fortherapeutic intervention to treat and prevent abnormal blood clotting which can be associatedwith atherosclerosis and stroke. Platelet function disorders can cause a range of bleedingsymptoms and often associated with heterozygous mutations in GPCR platelet proteins andcan be co-inherited with other genetic disorders of haemostasis such as type 1 vonWillebrand's disease, thus the cause can be multifactorial in some patients and can beconsidered as a complex disease. Through the the Genotyping and Phenotyping of Platelets(GAPP) study patients have been recruited with abnormal bleeding and platelet dysfunction.These patients have been investigated through platelet phenotyping in combination with wholeexome sequencing and targeted gene sequencing and a number of mutations in GPCRs havebeen identified. To understand the molecular consequences of these mutations on G-proteincoupledreceptor-mediated signalling in this cohort of patients, genetic, structural andpharmacological approaches will be applied which may allow tailoring of drug therapies insuch patients.