Identification of the molecular genetic basis of the hepatic veno-occlusive disease with immunodeficiency syndrome

骨髓移植最严重的并发症之一是静脉闭塞病（VOD），也称为窦阻塞综合征（SOS）。这种情况发生在10%的移植患者中，其特征在于肝功能异常，肝脏增大，凝血异常，液体潴留，最终多器官衰竭，30-50%的病例死亡。VOD的原因是未知的，它的发生无法预测在个别患者。八个家庭已被描述，其中一些人死于一种临床和组织学上与VOD无法区分的疾病。受影响的个体也有一种形式的免疫缺陷（因此称为VODI），并且异常以常染色体隐性模式遗传。所有八个人都是黎巴嫩人，这表明一个单一的遗传祖先突变是所有家庭中这种疾病的原因，他们是远亲。我们已经获得了其中三个家庭的遗传物质，并正在确定致病的遗传异常。我们假设，了解这种异常将导致对骨髓移植后发生VOD的理解。我们已经使用了800个多态性遗传标记分散在整个基因组中，以确定遗传异常的位置，并已定位的缺陷，2号染色体的区域，其中包含约37个已知的和预测的基因。我们现在的目标是确定候选区域中的哪一个基因负责VODI，并计划检查移植后患有VOD的个体的DNA，以确定他们是否有相关的异常。发现VODI基因将有利于这些家庭通过提供载体检测，也可能导致了解骨髓移植后发生的静脉闭塞性疾病。

One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight families have been described in whom a number of individuals have succumbed to a condition which is clinically and histologically indistinguishable from VOD. Affected individuals also have a form of immunodeficiency (hence termed VODI), and the abnormalities are inherited in an autosomal recessive pattern. All eight are of Lebanese origin, suggesting that a single genetic ancestral mutation was responsible for the disorder in all families, who are distantly related. We have access to genetic material from three of these families, and are on the way to identifying the causative genetic abnormality. We hypothesise that understanding this abnormality will lead to an understanding of VOD which occurs after bone marrow transplantation. We have used 800 polymorphic genetic markers scattered throughout the genome to identify the location of the genetic abnormality, and have localised the defect to a region of chromosome 2 which contains approximately 37 known and predicted genes. We now aim to determine which of the gene(s) in the candidate region is responsible for VODI, and plan to examine DNA from individuals who have had VOD after transplantation to determine if they have a related abnormality. Finding the VODI gene will benefit these families through the availability of carrier detection and may also lead to an understanding of the veno-occlusive disease that occurs after bone marrow transplantation.