Mol. Hum. Reprod. Advance Access published online on November 26, 2007
Molecular Human Reproduction, doi:10.1093/molehr/gam079
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A Recurrent Intragenic Genomic Duplication, other Novel Mutations in NLRP7 and imprinting defects in Recurrent Biparental Hydatidiform Moles
1Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, 77030, USA 2Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030, USA 3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA 4Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA 5Department of Obstetrics and Gynecology, Assiut University, Said, 71111, Egypt
Address correspondence to: Ignatia B. Van den Veyver, M.D. Department of Obstetrics and Gynecology, One Baylor Plaza, Room 721E, Mailstop BCM225, Houston, Texas, 77030, Phone: 713 798 4914; Fax: 713 798 5997; e-mail: iveyver{at}bcm.edu
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.
Key Words: biparental/hydatidiform mole/imprinting/mutation/NLRP7
* These two authors contributed equally to this work
Submitted on September 8, 2007; resubmitted on October 22, 2007; accepted on October 25, 2007.
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