Molecular and Clinical Biology of VWD

描述（由申请人提供）： 美国VWD项目旨在从分子和临床角度了解这种疾病。目前对VWF低下或异常的遗传原因以及病理生理学和生物学中涉及的分子机制缺乏了解。虽然有大量的人有低或异常的VWF异常出血症状，这是不科学的，如果这是一种“疾病”或VWF是一个持续的出血危险因素。执业医生对这组疾病的一般理解并不是最佳的，如何评价和治疗这些患者往往不清楚。该PPG将主要关注1型VWD，但将包括一些2型VWD患者相关的临床和实验室异常。我们将确定出血和低VWF是否与VWF基因位点遗传相关;如果不是，其他修饰基因对临床或实验室表型的影响程度如何。项目1将确定一个大型VWD患者队列的临床和实验室表型，特别强调1型和3型VWD携带者。将研究选定的2型变异体，以对比其表型突变率、临床突变率，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，以表征这些患者及其家族内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女性亚组的实验室特征、出血症状和评分，以获得出血评分，实验室VWF表型分型项目2将定义项目1、3和4中确定的临床和实验室表型/基因型背后的机制。项目3将确定影响异常VWF水平、生存、功能和临床表现的修饰基因。该项目将利用大型的、特征明确的VWD家族（在项目1/核心A中鉴定）来鉴定与人类基因组区域而不是12号染色体上的VWF基因座的关联。项目4将探讨在一个扩展的启动子区域，剪接突变，和特定的VWF单倍型异常的原因异常或低VWF。它将利用通过核心A收集的样本，其中未识别VWF基因的编码区突变。该项目还将进一步研究非连锁VWD的VWF基因座以外的其他原因。这4个项目将由核心A（行政支持和患者采集）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.