Genetic Studies in Gestational Trophoblastic Disease

妊娠滋养细胞疾病的遗传学研究

基本信息

批准号：
7863954
负责人：
IGNATIA B VAN DEN VEYVER
金额：
$ 0.75万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7863954
关键词：
19q13.4 Affect Assisted Reproductive Technology Attention CDKN1C gene Candidate Disease Gene Chromosomes Complete Hydatidiform Moles DNA DNA Methylation Defect Development Diploidy Discipline of obstetrics Disease Embryo Embryonic Development Family Female Fetal Development Fetal Growth Fetus Functional disorder Genes Genetic Genome Genome Scan Genomic Imprinting Germ Cells Goals Haploidy Human Hydatidiform Mole Inherited Lead Link Maps Methylation Minority Mole the mammal Molecular Mus Mutate Mutation Mutation Analysis Parents Partial Hydatidiform Mole Paternal uniparental disomy Pathogenesis Pathology Patients Phenotype Placenta Play Pre-Eclampsia Pregnancy Recurrence Reporting Reproductive Biology Reproductive Health Resources Role Site Tissues Uniparental Disomy United States Woman Work follow-up genome wide association study genome-wide imprint insight loss of function maternal imprint next generation novel offspring trophoblast

项目摘要

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.

描述（由申请人提供）：完整的氢化痣（CHM）是一种异常妊娠，具有超增殖性滋养细胞和无胎儿。从遗传上讲，大多数CHM是二倍体雄激素（锚），仅包含父亲DNA。因此，这会导致所有染色体和锚固的单亲父亲疾病，因此可以将其视为全基因组的印迹障碍，具有烙印基因表达不平衡，这会导致滋养细胞的异常发展。有趣的是，罕见的家族性和非家族性复发型摩尔鼠具有正常的两种遗传（BICHM），但是在女配子中建立的烙印标记的全基因组缺陷。这些家庭中受影响的妇女在大多数情况下与19q13.4相关的常染色体隐性突变。该项目的假设是CHM作为一种疾病创造了研究生殖健康和疾病中基因组烙印的理想资源。通过将BICHM和Anchm的研究结合在一起，我们有机会在同时识别影响建立印迹痕迹及其目标的基因。在特定目的1和2中，我们建议研究来自家族性和非家族性复发性CHM的受影响妇女的DNA，以鉴定出突变后引起BICHM的基因，并具有全基因组印迹异常的发展。识别该基因将显着有助于理解在女配子中如何建立母体印迹或在早期胚胎中维持的。在特定的目标3和4中，我们将执行DNA甲基化筛选，以在锚固中找到印迹基因。这将导致发现新颖的基因，这些基因印在滋养细胞中。其中的子集将是负责CHM表型的BICHM基因的靶标。这些研究共同有利于我们对CHM发病机理的理解以及印迹基因在胎盘功能和胎儿发育中的作用。