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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #224629
Title: A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles

Author
item KOU, Y - BAYLOR COLLEGE MED
item SHAO, L - BAYLOR COLLEGE MED
item PENG, H - BAYLOR COLLEGE MED
item ROSETTA, R - BAYLOR COLLEGE MED
item DEL GAUDIO, D - BAYLOR COLLEGE MED
item WAGNER, A - UNIV OKLAHOMA
item AL-HUSSAINI, T - ASSIUT UNIV
item Van Den Veyver, Ignatia

Submitted to: Molecular Human Reproduction
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/25/2007
Publication Date: 1/1/2008
Citation: Kou, Y.C., Shao, L., Peng, H.H., Rosetta, R., del Gaudio, D., Wagner, A.F., Al-Hussaini, T.K., Van den Veyver, I.B. 2008. A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles. Molecular Human Reproduction. 14(1):33-40.

Interpretive Summary: Imprinted genes are genes for which only either the maternally or paternally inherited copy is expressed. They are known to play an important role in placental function and balanced fetal nutrition. How the imprinting marks that indicate whether a gene is maternally or paternally inherited are established and maintained is still incompletely understood. With this work we try to further understand the mechanisms that are involved by studying a rare pregnancy abnormality, biparental hydatidiform moles. We found new mutations in a gene that causes women to have these abnormal pregnancies and show new data on how imprinting in their pregnancies is disturbed. This work contributes to the understanding of placental imprinting and may further our knowledge to its role in fetal nutrition.

Technical Abstract: A complete hydatidiform mole (CHM) is an abnormal pregnancy with hyperproliferative vesicular trophoblast and no fetal development. Most CHM are sporadic and androgenetic, but recurrent HM have biparental inheritance (BiHM) with disrupted DNA methylation at differentially methylated regions (DMRs) of imprinted loci. Some women with recurrent BiHM have mutations in the NLRP7 gene on chromosome 19q13.42. Using bisulfite genomic sequencing at eight imprinted DMRs on DNA from two BiHMs, we found a pattern of failure to acquire or maintain DNA methylation at DMRs (PEG3, SNRPN, KCNQ1OT1, GNAS exon 1A) that normally acquire CpG methylation during oogenesis, but not at H19, which acquires CpG methylation during spermatogenesis. Secondary imprints at the GNAS locus showed variable abnormal patterns with both gain and loss of CpG methylation. We found novel missense and splice-site mutations in NLRP7 in women with non-familial recurrent BiHM. We identified and characterized a homozygous intragenic tandem duplication including exons 2 through 5 of NLRP7 that results in a predicted truncated protein in affected women of three unrelated Egyptian kindreds, suggesting a founder effect. Our findings firmly establish that NLRP7 mutations are a major cause of BiHM and confirm presence of a complex pattern of imprinting abnormalities in BiHM tissues.