MOLECULAR IMPACT OF VWF ON CLINICAL VWD

项目1将包括对von Willebrand病患者的多机构研究，并将执行 这些患者的临床评估和1)确定低或异常的VWF在家庭内的联系，2) 确定vwf基因中可能导致这些临床表现的基因突变，或3)确定 由位于vwf基因外的其他遗传位点引起的遗传性vwf异常的频率。侯选人 可能导致这种情况的基因将通过项目3和4来确定。当基因vwf突变是 确定，项目2将表达突变的vwf并定义潜在的病理生理机制(S)在 体外和体内。目的1确定vwf基因突变在临床患者中的频率。 VWD的诊断，并将这些与他们的实验室测试以及临床评分系统相关联 对欧盟VWD研究中使用的一种方法进行了修改。它将决定基因的光谱是否 导致3型VWD的突变(或其杂合子携带者与VWFlined中发现的突变不同 类型1 VWD。目标2将确定导致变异的突变，2型VWD并确定 临床出血症状的外显率与用于研究1型患者的评分系统。临床 将进行实验室表型鉴定，以对比受影响的有关联的家庭的异常程度 会员。目标3将确定由于血浆清除量增加而导致的VWD频率 通过比较血浆VWF前肽(VWFpp)和VWF的水平来检测，确定VWF的清除 由DDAVP发布，并将确定O型血和非O型血个体之间的差异。 由于VWD已被报道在月经过多的女性中很常见，Aim 4将研究 与年龄匹配的对照组相比，这些女性的VWF低或异常。在那些减少或异常的人中 VWF，我们将确定突变的频率和分布是否与在类型1中发现的相似 VWD。项目1将导致对临床VWD的范围和影响及其能力的更好的理解 在临床和研究实验室被检测到。

Project 1 will consist of a multi-institutional study of patients with von Willebrand disease and will perform a clinical assessment of these patients and 1) determine the linkage of low or abnormal VWF within families, 2) determine genetic mutations in the VWF gene that could result in these clinical manifestations or 3) identify the frequency of inheritable abnormal VWF caused by other genetic loci residing outside the VWF gene. Candidate genes that might cause this will be identified through Projects 3 and 4. When genetic VWF mutations are identified, Project 2 will express the mutant VWF and define the underlying pathophysiologic mechanism(s) in vitro and in vivo. Aim 1 will identify the frequency of VWF gene mutations in patients with the clinical diagnosis of VWD and correlate these to their laboratory testing as well as a clinical scoring system that is a modification of the one used in the European Union Study of VWD. It will determine if the spectrum of genetic mutations causing type 3 VWD (or it's heterozygous carriers differs from those mutations identified in VWFlinked type 1 VWD. Aim 2 will identify the mutations causing variant, type 2 VWD and determine the penetrance of clinical bleeding symptoms with the scoring system used to study type 1 patients. Clinical laboratory phenotyping will be performed to contrast the degree of abnormality in affected, linked family members. Aim 3 will determine the frequency of VWD that is caused by increased plasma clearance that can be detected by comparing plasma levels of the VWF propeptide (VWFpp) to VWF, identifying clearance of VWF released by DDAVP, and will determine the differences between these in blood group O and non-O individuals. Since VWD has been reported to be common in women with menorrhagia, Aim 4 will study the prevalence of low or abnormal VWF in these women compared to age-matched controls. In those with reduced or abnormal VWF, we will determine if the mutation rate and distribution of mutations is similar to those identified in type 1 VWD. Project 1 will lead to a greater understanding of the scope and impact of clinical VWD and its ability to be detected in the clinical and research laboratory.