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

凝血需要将血小板(特殊血细胞)重新聚集到损伤部位，作为防止出血的第一个(许多)事件之一。血小板G蛋白偶联受体(GPCRs)是血小板功能的重要调节因子，可以阻断这些受体进行治疗干预，以治疗和预防与动脉粥样硬化和卒中相关的异常凝血。血小板功能障碍可引起一系列出血症状，通常与GPCR血小板蛋白杂合突变相关，并可与其他遗传性止血疾病如1型血管性血友病共同遗传，因此在某些患者中，病因可能是多因素的，可被认为是一种复杂的疾病。通过血小板基因分型和表型分析(GAPP)研究，招募了有异常出血和血小板功能障碍的患者，通过血小板表型结合全外显子组测序和靶向基因测序对这些患者进行了调查，发现了一些GPCRs突变。为了了解这些突变对这组患者中G蛋白偶联受体介导的信号转导的分子后果，将应用遗传、结构和药理学方法，可能允许对此类患者进行量身定制的药物治疗。

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.