Mol. Hum. Reprod. Advance Access originally published online on November 26, 2007
Molecular Human Reproduction 2008 14(1):33-40; 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, One Baylor Plaza, Room 721E, Mailstop BCM225, Houston, TX 77030, USA 2Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA 3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 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, Assiut 71111, Egypt
6 Correspondence address. Tel: +1-713-798-4914; Fax: +1-713-798-5997; 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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