Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region

Wang, Chiuhui Mary; Dixon, Peter H.; Decordova, S; Hodges, Matt; Sebire, Neil J.; Ozalp, S. Sinan; Fallahian, Masoumeh; Ashrafi, Fereshteh; Repiská,; Zhao, Jialiang; Xiang, Yang; Savage, Philip; Seckl, MJ; Fisher, Rosemary A.

doi:10.1136/jmg.2008.064196

Cited by 138 publications

(114 citation statements)

References 29 publications

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“…NLRP7 is mutated in 88% and 60% of analyzed familial and singleton cases of RHMs, respectively. [9][10][11][12][13][14] Recently, we demonstrated that ex vivo lipopolysaccharides (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) from patients with mutations and rare variants in NLRP7 have defective interleukin-1 beta (IL-1b) and tumor necrosis factor secretion but normal to higher intracellular levels of pro-and mature-IL-1b. 13,15 The requirement of NLRP7 for normal IL-1b secretion by macrophages was also confirmed in in vitro studies after NLRP7 silencing using small interfering RNA (siRNA).…”

Section: Introductionmentioning

confidence: 99%

Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7

et al. 2012

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To date, two maternal-effect genes have been shown to have causative roles in recurrent hydatidiform moles (RHMs); NLRP7 that is mutated in 48-60% of patients with RHMs and C6orf221 (HUGO-approved nomenclature is now KHDC3L), a recently identified gene, that is mutated in 14% of patients with RHMs who are negative for NLRP7 mutations. We sequenced KHDC3L in 97 patients with RHMs and reproductive loss who are mostly negative for NLRP7 mutations. We identified three unrelated patients, each homozygous for one of the two protein-truncating mutations, a novel 4-bp deletion resulting in a frameshift, c.299_302delTCAA, p.Ile100Argfs*2, and a previously described 4-bp deletion, c.322_325delGACT, p.Asp108Ilefs*30, transmitted on a shared haplotype to three patients from different populations. We show that five HM tissues from one of these patients are diploid and biparental similar to HMs from patients with two defective NLRP7 mutations. Using immunofluorescence, we show that KHDC3L protein displays a juxta perinuclear signal and colocalizes with NLRP7 in lymphoblastoid cell lines from normal subjects. Using cell lines from patients, we demonstrate that the KHDC3L mutations do not change the subcellular localization of the protein in hematopoietic cells. Our data highlight the similarities between the two causative genes for RHMs, KHDC3L and NLRP7, in their subcellular localization, the parental contribution to the HM tissues caused by them, and the presence of several founder mutations and variants in both of them indicating positive selection and adaptation.

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Section: Introductionmentioning

confidence: 99%

Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7

et al. 2012

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“…We also suggest a comparison of the status of DNA methylation on imprinted genes between cases of sporadic HM with heterozygous NLRP7 mutations and other cases with no mutation. Whereas it is now clear that homozygous NLRP7 mutations cause a recurrent HM or conception loss, 20,25,[27][28][29]31 our present findings suggest that the heterozygous state could be a risk factor for developing sporadic mole. Figure 2.…”

Section: Commentmentioning

confidence: 64%

“…Most NLRP7 mutations disrupted the leucine-rich repeat, an important functional domain of NLRP7 that may play a role in protein-protein interactions or pattern recognition. 25,27,39,41 In our study, only the p.Ala719Val mutation occurs in the leucine-rich repeat domain; the other mutations (p.Lys511Arg, p.Ala494Thr, and p.Val182Met) were found upstream of the leucinerich repeat region. As the new variant, 544G.A (p.Val182-Met), was also found in the heterozygous state in a Tunisian woman from the group of controls, it is probably a benign polymorphism.…”

Section: Commentmentioning

confidence: 90%

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NLRP7 Mutation Analysis in Sporadic Hydatidiform Moles in Tunisian Patients: NLRP7 and Sporadic Mole

Landolsi¹,

Rittore²,

Hmissa³

et al. 2012

Archives of Pathology &Amp; Laboratory Medicine

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Context.—Hydatidiform mole, an aberrant human pregnancy, is commonly a nonrecurrent disease. Recently, a rare autosomal recessive form of familial and/or recurrent molar pregnancies was associated with mutations in the NLRP7 gene. Objective.—To investigate whether NLRP7 mutations exist in Tunisian women with sporadic hydatidiform moles. Design.—Genomic DNA from 38 unrelated Tunisian patients with sporadic hydatidiform moles were screened by sequencing all NLRP7 exons. A high-resolution melting curve analysis was performed on 170 DNA controls to analyze new sequence variants. Results.—More than 13% of these patients were heterozygous for NLRP7 mutations. We found 2 novel missense mutations in the heterozygous state, c.544G>A (p.Val182Met) in 1 patient and c.1480G>A (p.Ala494Thr) in 2 patients, and 2 already reported mutations, c.1532A>G (p.Lys511Arg) and c.2156C>T (p.Ala719Val), in 2 patients. None of these mutations were identified in 170 controls except for 1 woman who was heterozygous for p.Val182Met. Conclusion.—As homozygous NLRP7 mutations are associated with recurrent hydatidiform mole or conception loss, the heterozygous state could represent a risk factor for nonrecurrent mole.

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“…Ten years following the initial reports of NLRP7 being responsible for recurrent BiHM, ~60 pathogenic variants have been reported in females homozygous or compound heterozygous for these defective alleles. These include missense mutations, nonsense mutations, splice site mutations and Alu-mediated deletions (Wang et al 2009, Dixon et al 2012, Reddy et al 2016.…”

Section: Biparental Hydatidiform Molesmentioning

confidence: 99%

NLRPs, the subcortical maternal complex and genomic imprinting

Monk¹,

Sánchez-Delgado²,

Fisher³

2017

Reproduction

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Before activation of the embryonic genome, the oocyte provides many of the RNAs and proteins required for the epigenetic reprogramming and the transition to a totipotent state. Targeted disruption of a subset of oocyte-derived transcripts in mice results in early embryonic lethality and cleavage-stage embryonic arrest as highlighted by the members of the subcortical maternal complex (SCMC). Maternal-effect recessive mutations of NLRP7, KHDC3L and NLRP5 in humans are associated with variable reproductive outcomes, biparental hydatidiform moles (BiHM) and widespread multi-locus imprinting disturbances. The precise mechanism of action of these genes is unknown, but the maternal-effect phenomenon suggests a function during early pre-implantation development, while biochemical and genetic studies implement them as SCMC members or interacting partners. In this review article, we discuss the role of the NLRP family members and the SCMC proteins in the establishment of genomic imprints and post-zygotic methylation maintenance, the recent advances made in the understanding of the biology involved in BiHM formation and the wider roles of the SCMC in mammalian reproduction.Reproduction (2017) 154 R161-R170

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Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region

Cited by 138 publications

References 29 publications

Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7

Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7

NLRP7 Mutation Analysis in Sporadic Hydatidiform Moles in Tunisian Patients: NLRP7 and Sporadic Mole

NLRPs, the subcortical maternal complex and genomic imprinting

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