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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD045970-03
Application #
7149972
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Taymans, Susan
Project Start
2004-12-06
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
3
Fiscal Year
2007
Total Cost
$256,010
Indirect Cost
Name
Baylor College of Medicine
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Mahadevan, Sangeetha; Wen, Shu; Wan, Ying-Wooi et al. (2014) NLRP7 affects trophoblast lineage differentiation, binds to overexpressed YY1 and alters CpG methylation. Hum Mol Genet 23:706-16
Mahadevan, Sangeetha; Wen, Shu; Balasa, Alfred et al. (2013) No evidence for mutations in NLRP7 and KHDC3L in women with androgenetic hydatidiform moles. Prenat Diagn 33:1242-7
Kou, Y C; Shao, L; Peng, H H et al. (2008) A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles. Mol Hum Reprod 14:33-40
Van den Veyver, I B; Al-Hussaini, T K (2006) Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring. Hum Reprod Update 12:233-42
Panichkul, Prisana C; Al-Hussaini, Tarek K; Sierra, Rebecca et al. (2005) Recurrent biparental hydatidiform mole: additional evidence for a 1.1-Mb locus in 19q13.4 and candidate gene analysis. J Soc Gynecol Investig 12:376-83