Genetic Studies in Gestational Trophoblastic Disease

描述（由申请人提供）：完全性葡萄胎（CHM）是一种滋养层过度增殖且无胎儿的异常妊娠。从遗传学上来说，大多数 CHM 是二倍体雄激素遗传 (AnCHM)，仅包含父本 DNA。这导致所有染色体的单亲父本二体性，因此 AnCHM 可以被认为是一种全基因组印记疾病，印记基因表达不平衡，导致滋养层发育异常。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），但具有在雌配子中建立的全基因组印记标记缺陷。这些家庭中受影响的女性患有常染色体隐性突变，大多数情况下与 19q13.4 相关。 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 BiCHM 和 AnCHM 的研究，我们有机会同时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，以确定突变时导致出现具有全基因组印记异常的 BiCHM 的基因。识别该基因将极大地有助于了解母体印记标记如何在雌配子中建立或在早期胚胎中维持。在具体目标 3 和 4 中，我们将进行 DNA 甲基化筛选，以寻找 AnCHM 中的印记基因。这将导致印记在滋养层中的新基因的发现。其中的一个子集是 BiCHM 基因的靶标，这些靶标负责 CHM 表型。这些研究将有助于我们了解 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.