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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #231443
Title: An intragenic genomic duplication resulting in loss of function and other novel mutations in NLRP7 in women with recurrent biparental hydatidiform moles

Author
item KOU, Y - BAYLOR COLLEGE MED
item SHAO, L - BAYLOR COLLEGE MED
item ROSETTA, R - BAYLOR COLLEGE MED
item DEL GAUDIO, D - BAYLOR COLLEGE MED
item PENG, H - BAYLOR COLLEGE MED
item AL-HUSSAINI, T - ASSIUT UNIV
item 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.