Author
KOU, Y - BAYLOR COLLEGE MED | |
SHAO, L - BAYLOR COLLEGE MED | |
ROSETTA, R - BAYLOR COLLEGE MED | |
DEL GAUDIO, D - BAYLOR COLLEGE MED | |
PENG, H - BAYLOR COLLEGE MED | |
AL-HUSSAINI, T - ASSIUT UNIV | |
Van Den Veyver, Ignatia |
Submitted to: American Society of Human Genetics
Publication Type: Abstract Only Publication Acceptance Date: 10/23/2007 Publication Date: 10/23/2007 Citation: Kou, Y., Shao, L., Rosetta, R., Del Gaudio, D., Peng, H., Al-Hussaini, T., Van Den Veyver, I.B. 2007. An intragenic genomic duplication resulting in loss of function and other novel mutations in NLRP7 in women with recurrent biparental hydatidiform moles [abstract]. In: 57th Annual Meeting of The American Society of Human Genetics, October 23-27, 2007, San Diego, California. p. 47. Interpretive Summary: Technical Abstract: Hydatidiform mole (HM) is an abnormal development of the placenta with hyperproliferative trophoblast. Biparentally inherited HM (BiHM) have normal diploid biparental inheritance and are not androgenetic. Linkage using consanguineous pedigrees of women with BiHM refined a major locus to chromosome 19q13.42. Recently, mutations in the NACHT, leucine rich repeat (LRR) and PYD containing 7 (NLRP7) gene were identified in DNA of women with recurrent BiHM whose mutation maps to this region. We studied kindreds with several affected women and isolated cases of recurrent BiHM of confirmed biparental inheritance and first performed bisulfite genome sequencing of regulatory DMRs at several imprinted loci (NESP55, KCNQ1OT1, PEG3, H19, SNRPN) on DNA from BiHM tissue. We found failure to acquire or maintain DNA methylation that is established at imprinted DMRs during oogenesis. We sequenced coding exons of NLRP7 using DNA of women with recurrent BiHM and found new missense and splice-site mutations in isolated cases. We identified a homozygous missense mutation c.2234C>G (p.L745V) affecting a conserved leucine in the 2nd LRR of NLRP7, a compound heterozygous c.2234C>G, an exon 9 splice donor mutation (c.2796+2T>G) and a previously described c.2457+1G>A mutation. Southern analysis and quantitative RT-PCR (qPCR) revealed a 4Kb tandem intragenic duplication spanning exons 2-5 of NLRP7 in 5 patients from 3 unrelated Egyptian families but not in unaffected controls, suggesting the presence a founder effect in this population. The resulting mutant mRNA is predicted to translate into a truncated protein containing a frameshift of six amino acids and a stop codon after Thr710 and lacking all LRRs. This is second report confirms that NLRP7 deficiency is a major cause of BiHM. |