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

凝血需要血小板（特化血细胞）聚集到损伤部位，这是防止出血的第一个（或许多）事件。血小板G蛋白偶联受体（GPCRs）是血小板功能的重要调节因子，阻断这些受体可用于治疗和预防与动脉粥样硬化和中风相关的异常凝血。血小板功能障碍可引起一系列出血症状，通常与GPCR血小板蛋白的杂合突变有关，并可与其他止血遗传性疾病（如1型冯维勒布兰德病）共同遗传，因此在某些患者中，病因可能是多因素的，可被视为一种复杂的疾病。通过血小板基因分型和表型（GAPP）研究，招募了异常出血和血小板功能障碍的患者，通过血小板表型分析结合全外显子组测序和靶向基因测序对这些患者进行了研究，并鉴定了一些GPCR突变.为了了解这些突变对G蛋白偶联受体介导的信号传导的分子后果，将应用遗传学、结构学和药理学方法，这可能允许对这些患者进行药物治疗。

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.