Department of Hematology, Christian Medical College, Vellore, Tamil Nadu, India.
Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
Haemophilia. 2018 Nov;24(6):930-940. doi: 10.1111/hae.13542. Epub 2018 Jul 8.
Type 3 von Willebrand disease (VWD) is the rare and most severe form of VWD which results from a near-complete deficiency of the von Willebrand factor (VWF). This study evaluates in detail the molecular pathology of type-3 VWD in India. One hundred and two patients from 90 families were evaluated.
Phenotypic data, including bleeding scores (BS), were documented using structured questionnaires. Diagnosis of type 3 VWD was based on undetectable VWF antigen levels in the plasma. Genomic DNA from these patients was screened for mutations in VWF gene. Structural modeling and expression studies were carried out for missense mutations.
Out of 102 patients, mutations could be identified in 91% (n = 93). Fifty-five different gene variants were identified. Thirty-four (61.8%) were novel. Mutations could be identified in both the alleles in 90 patients, while no causative mutation could be identified in 9 patients; twenty-four (23.5%) patients had mutations clustered in the propeptide region of VWF. Interestingly, five mutations accounted for the defects in 37/93 (39.8%) patients. Structural analysis and in vitro studies on missense mutations imply impaired processes associated with secretion of VWF.
This study is one of the largest series to define the molecular basis of type-3 VWD.
3 型血管性血友病（VWD）是 VWD 中罕见且最严重的形式，其原因是血管性血友病因子（VWF）几乎完全缺乏。本研究详细评估了印度 3 型 VWD 的分子病理学。评估了来自 90 个家庭的 102 名患者。
使用结构化问卷记录表型数据，包括出血评分（BS）。3 型 VWD 的诊断基于血浆中无法检测到 VWF 抗原水平。从这些患者的基因组 DNA 中筛选 VWF 基因的突变。对错义突变进行结构建模和表达研究。
在 102 名患者中，91%（n=93）可识别出突变。鉴定出 55 种不同的基因变异。其中 34 种（61.8%）是新的。90 名患者的两个等位基因中均可识别出突变，而 9 名患者中无法识别出致病突变；24 名（23.5%）患者的 VWF 前肽区域存在突变簇。有趣的是，有 5 种突变导致 37/93（39.8%）名患者的缺陷。对错义突变的结构分析和体外研究表明，VWF 分泌相关过程受损。
本研究是定义 3 型 VWD 分子基础的最大系列之一。
