Genetic Studies in Gestational Trophoblastic Disease

描述（申请人提供）：完全性葡萄胎（CHM）是一种异常妊娠，滋养层细胞过度增殖，无胎儿。在遗传学上，大多数CHM是二倍体雄核发育（AnCHM），只含有父本DNA。这导致所有染色体的单亲父系二体性，因此AnCHM可以被认为是一种全基因组印迹疾病，具有印迹基因的不平衡表达，这导致异常滋养层发育。有趣的是，罕见的家族性和非家族性复发性葡萄胎具有正常的双亲遗传（BiCHM），但在女性配子中建立的印记标记存在全基因组缺陷。在这些家庭中受影响的妇女有一个常染色体隐性突变，在大多数情况下与19q13.4。 该项目的假设是，CHM作为一种疾病，为研究生殖健康和疾病中的基因组印记创造了理想的资源。通过结合对BiCHM和AnCHM的研究，我们有机会平行鉴定影响印记标记建立的基因及其靶标。在具体目标1和2中，我们建议研究来自患有家族性和非家族性复发性CHM的受影响女性的DNA，以确定突变时导致BiCHM发展的基因，该基因具有全基因组印迹异常。识别该基因将大大有助于理解母体印记标记如何在雌性配子中建立或维持在早期胚胎中。在具体目标3和4中，我们将进行DNA甲基化筛选，以发现AnCHM中的印迹基因。这将导致发现新的基因，是在滋养层的印记。其子集将是负责CHM表型的BiCHM基因的那些靶标。这些研究将有助于我们理解CHM的发病机制以及印记基因在胎盘功能和胎儿发育中的作用。

DESCRIPTION (provided by applicant): A complete hydatidiform mole (CHM) is an abnormal pregnancy with hyperproliferative trophoblast and no fetus. Genetically, most CHM are diploid androgenetic (AnCHM), containing only paternal DNA. This results in uniparental paternal disomy of all chromosomes and AnCHM can therefore be considered a genome-wide imprinting disorder with unbalanced expression of imprinted genes, which results in abnormal trophoblast development. Interestingly, rare familial and non-familial recurrent hydatidiform moles have normal biparental inheritance (BiCHM), but have genome-wide defects of imprinting marks that are established in the female gamete. Affected women in these families have an autosomal recessive mutation linked in most cases to 19q13.4. The hypothesis for this project is that CHM as a disorder creates an ideal resource to study genomic imprinting in reproductive health and disease. By combining studies on BiCHM and AnCHM, we have an opportunity to identify in parallel a gene that affects establishment of imprinting marks as well as its targets. In specific aims 1 and 2 we propose to study DNA from affected women with familial and non-familial recurrent CHM to identify the gene that, when mutated, causes the development of BiCHM with genome-wide imprinting abnormalities. Identifying this gene will significantly contribute to the understanding of how maternal imprinting marks are established in the female gamete or maintained in the early embryo. In specific aims 3 and 4 we will perform DNA methylation screens to find imprinted genes in AnCHM. This will lead to the discovery of novel genes that are imprinted in trophoblast. A subset of which will be those targets of the BiCHM gene that are responsible for the CHM phenotype. Together these studies will benefit our understanding of the pathogenesis of CHM and the role of imprinted genes in placental function and fetal development.