Molecular and Clinical Biology of VWD

描述(由申请人提供)： 这个美国的VWD项目是针对这种疾病的分子和临床理解。目前对“低或异常VWF”的遗传原因以及涉及其病理生理和生物学的分子机制尚缺乏了解。虽然许多人有低VWF或异常的VWF，并有异常的出血症状，但科学上尚不清楚这是一种“疾病”，还是VWF是出血的持续危险因素。执业医生对这类疾病的一般理解并不是最理想的，应该如何评估和治疗这些患者往往不清楚。这项PPG将主要关注1型VWD，但将包括一些与临床和实验室异常相关的2型VWD患者。我们将确定出血和低VWF是否与VWF基因座有遗传联系；如果不是，临床或实验室表型上的其他修饰基因的大小。项目1将确定一大批VWD患者的临床和实验室表型，特别强调1型VWD患者和3型VWD携带者。将对选定的2型变异进行研究，以对比它们的表型外显率、临床外显率，并作为出血评分的相对验证。将进行完整的实验室表型和全长DNA VWF基因测序，以确定这些患者的特征以及他们家族内的等位基因遗传对出血和实验室表型的影响。将研究以月经过多为主要症状的妇女的实验室特征、出血症状和评分，以获得出血评分，实验室VWF表型项目2将确定项目1、3和4中确定的临床和实验室表型/基因背后的机制。项目3将确定影响异常VWF水平、存活率、功能和临床表现的修饰基因。这个项目将利用大的、特征良好的VWD家系(在项目1/核心A中确定)来确定与人类基因组中除12号染色体上的VWF基因座之外的其他区域的关联。项目4将探索延伸启动子区域的异常、剪接-连接突变和特定的VWF单倍型作为异常或低VWF的原因。它将利用通过核心A收集的样本，在这些样本中，没有发现VWF基因的编码区突变。该项目还将进一步研究VWF基因以外的其他原因引起的非连锁VWD。这4个项目将由用于行政支持和患者获取的核心A和核心B临床实验室和测序核心提供支持。

DESCRIPTION (provided by applicant): This Program Project on VWD in the US is directed at the molecular and clinical understanding of this disorder. There is a lack in understanding the genetic causes of "low or abnormal VWF" and the molecular mechanisms involved in the pathophysiology and biology. While a large number of individuals have low or abnormal VWF with abnormal bleeding symptoms, it is not scientifically clear if this is a "disease" or that VWF is a continuous risk-factor for bleeding. The general understanding by practicing physicians about this group of disorders is not optimal and how these patients should be evaluated and treated has been often unclear.. This PPG will primarily focus on type 1 VWD, but will include some type 2 VWD patients correlate clinical and laboratory abnormalities. We will determine if bleeding and low VWF are genetically linked to the VWF gene locus; and if not, what is the magnitude of other modifying genes on either the clinical or the laboratory phenotype. Project 1 will determine the clinical and laboratory phenotype of a large cohort of VWD patients with particular emphasis on type 1 and carriers of type 3 VWD. Selected type 2 variants will be studied to contrast their phenotypic penetrance, clinical penetrance, and as a relative validation of the bleeding score. Full laboratory phenotyping and full-length DNA VWF gene sequencing will be undertaken to characterize these patients and the impact of allelic inheritance within their family on bleeding and laboratory phenotype. The laboratory features, bleeding symptoms and scoring of a subgroup containing women who exhibit menorrhagia as a major symptom will be studied for bleeding score and laboratory VWF phenotyping Project 2 will define the mechanisms behind the clinical and laboratory phenotypes/genotypes identified in Project 1, 3, and 4. Project 3 will identify modifying genes that affect the level, survival, function, and clinical manifestations of abnormal VWF. This project will utilize large, well characterized families with VWD (identified in Project 1/Core A) to identify associations with areas of the human genome other than the VWF locus on Chromosome 12. Project 4 will explore abnormalities in an extended promoter region, splice-junction mutations, and specific VWF-haplotypes as causes of abnormal or low VWF. It will make use of samples collected through Core A in which coding region mutations of the VWF gene are not identified. This project will also further study non-linked VWD for other causes outside the VWF locus. These 4 projects will be supported by Core A for administrative support and patient acquisition and Core B Clinical Laboratory and Sequencing Core.