Gene Summary

Gene:NLRP7; NLR family pyrin domain containing 7
Aliases: HYDM, PAN7, NALP7, NOD12, PYPAF3, CLR19.4
Summary:This gene encodes a member of the NACHT, leucine rich repeat, and PYD containing (NLRP) protein family. It has an N-terminal pyrin domain, followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region. NLRP proteins are implicated in the activation of proinflammatory caspases through multiprotein complexes called inflammasomes. This gene may act as a feedback regulator of caspase-1-dependent interleukin 1-beta secretion. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:NACHT, LRR and PYD domains-containing protein 7
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
NLRP7 is implicated in:
- ATP binding
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Abortion, Spontaneous
  • Diploidy
  • Missense Mutation
  • Oocytes
  • Pregnancy Outcome
  • Genotype
  • Genetic Association Studies
  • Genomic Imprinting
  • Mutation
  • Polymerase Chain Reaction
  • Epigenetics
  • Case-Control Studies
  • DNA Methylation
  • Single Nucleotide Polymorphism
  • DNA Mutational Analysis
  • HEK293 Cells
  • FISH
  • Neoplasm Recurrence, Local
  • Family
  • Immunohistochemistry
  • Pregnancy
  • Base Sequence
  • Pedigree
  • Molecular Sequence Data
  • Inheritance Patterns
  • Alleles
  • Homozygote
  • Beckwith-Wiedemann syndrome
  • TNF
  • Genetic Predisposition
  • Proteins
  • Exons
  • DNA Sequence Analysis
  • Silver-Russell Syndrome
  • Hydatidiform Mole
  • Signal Transducing Adaptor Proteins
  • Adolescents
  • Heterozygote
  • Abortion, Habitual
  • Chromosome 19
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NLRP7 (cancer-related)

Mu X, Yin R, Wang D, et al.
Hepatic toxicity following actinomycin D chemotherapy in treatment of familial gestational trophoblastic neoplasia: A case report.
Medicine (Baltimore). 2018; 97(38):e12424 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Familial hydatidiform mole is extremely rare while familial gestational trophoblastic neoplasia (GTN) has never been reported. Inspired by 2 biological sisters with postmolar GTN and liver toxicity, we reviewed susceptible maternal-effect genes and explored the role of possible drug transporter genes in the development of GTN.
PATIENT CONCERNS: We reported one Chinese family where the two sisters developed postmolar GTN while experiencing fast remission and significant hepatic toxicity from actinomycin D chemotherapy.
DIAGNOSES: The index pregnancy was diagnosed with curettage. The following GTN was confirmed when there was a rise in beta-hCG for three consecutive weekly measurements over at least a period of 2 weeks. Computed tomography was used to identify lung metastasis. The elder sister was diagnosed with gestational trophoblastic neoplasia (III: 2) while the younger sister was diagnosed as III: 3 according to WHO scoring system.
INTERVENTIONS: Patients were treated with actinomycin D of 10 μg/kg intravenously for 5 days every 2 weeks. When hepatic toxicity was indicated, polyene phosphatidyl choline and magnesium isoglycyrrhizinate were prescribed.
OUTCOMES: Both patients responded extremely well to the 5-day actinomycin D regimen. Beta-hCG remained less than 2 mIU/ml after 5 cycles while computed tomography scan showed downsized pulmonary nodules. Both experienced significant rise in ALT and AST levels that could be ameliorated with corresponding medication. Monthly followed-up showed negative beta-hCG levels and normal liver enzyme levels.
LESSONS: We speculated that the known or unknown NLRP7 and KHDC3L mutations might be correlated with drug disposition in liver while liver drug transporters such as P-glycoprotein family that are also expressed in trophoblasts might be correlated to GTN susceptibility. Future genomic profiles of large samples alike using next generation sequencing are needed to confirm our hypothesis and discover yet unknown genes.

Kalogiannidis I, Kalinderi K, Kalinderis M, et al.
Recurrent complete hydatidiform mole: where we are, is there a safe gestational horizon? Opinion and mini-review.
J Assist Reprod Genet. 2018; 35(6):967-973 [PubMed] Free Access to Full Article Related Publications
Benign hydatidiform mole, complete or partial, is the most common type of gestational trophoblastic disease (GTD) characterised by excessive trophoblastic proliferation and abnormal embryonic development. Although most complete hydatidiform moles (CHMs) are diploid androgenetic, a few cases of CHMs are biparental, characterised by recurrence and familial clustering. In these rare cases, mutations in NLRP7 or KHDC3L genes, associated with maternal imprinting defects, have been implicated. Current data regarding future pregnancy options in hydatidiform moles are discussed and our opinion is presented based on an incidence that took place in our hospital with a woman with consecutive molar pregnancies. In recurrent hydatidiform moles, DNA testing should be performed and when NLRP7 or KHDC3L mutation are detected, oocyte donation should be proposed as an option to maximise woman's chances of having a normal pregnancy.

Qian J, Nguyen NMP, Rezaei M, et al.
Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles.
Eur J Hum Genet. 2018; 26(7):1007-1013 [PubMed] Free Access to Full Article Related Publications
Recurrent hydatidiform moles (RHM) are aberrant human pregnancies characterized by absence of, or abnormal, embryonic development, hydropic degeneration of chorionic villi, and hyperproliferation of the trophoblast. Biallelic mutations in two maternal-effect genes, NLRP7 and KHDC3L, underlie the causation of RHM in 60% of patients. We performed exome sequencing on a patient with six pregnancy losses, two miscarriages and four HM, and found no variants that affect the functions of the known genes. We found biallelic missense variants that affect conserved amino acids in PADI6 and segregate with the disease phenotype in the family. PADI6 is another maternal-effect gene and a member of the subcortical maternal complex that has been shown to have recessive variants that affect the gene function in four unrelated women with infertility who also experienced early embryonic arrest during preimplantation development after IVF. We demonstrated that PADI6 co-localizes with NLRP7 in human oocytes and preimplantation embryos and reviewed the morphology and genotypes of four products of conception from our patient. Our data expand the involvement of PADI6 to other forms of reproductive loss and highlight the commonality between infertility, miscarriages, and molar pregnancies, in some cases.

Nguyen NMP, Khawajkie Y, Mechtouf N, et al.
The genetics of recurrent hydatidiform moles: new insights and lessons from a comprehensive analysis of 113 patients.
Mod Pathol. 2018; 31(7):1116-1130 [PubMed] Related Publications
Hydatidiform mole is an aberrant human pregnancy characterized by early embryonic arrest and excessive trophoblastic proliferation. Recurrent hydatidiform moles are defined by the occurrence of at least two hydatidiform moles in the same patient. Fifty to eighty percent of patients with recurrent hydatidiform moles have biallelic pathogenic variants in NLRP7 or KHDC3L. However, in the remaining patients, the genotypic types of the moles are unknown. We characterized 80 new hydatidiform mole tissues, 57 of which were from patients with no mutations in the known genes, and we reviewed the genotypes of a total of 123 molar tissues. We also reviewed mutation analysis in 113 patients with recurrent hydatidiform moles. While all hydatidiform moles from patients with biallelic NLRP7 or KHDC3L mutations are diploid biparental, we demonstrate that those from patients without mutations are highly heterogeneous and only a small minority of them are diploid biparental (8%). The other mechanisms that were found to recur in patients without mutations are diploid androgenetic monospermic (24%) and triploid dispermic (32%); the remaining hydatidiform moles were misdiagnosed as moles due to errors in the analyses and/or their unusual mechanisms. We compared three parameters of genetic susceptibility in patients with and without mutations and show that patients without mutations are mostly from non-familial cases, have fewer reproductive losses, and more live births. Our data demonstrate that patients with recurrent hydatidiform moles and no mutations in the known genes are, in general, different from those with mutations; they have a milder genetic susceptibility and/or a multifactorial etiology underlying their recurrent hydatidiform moles. Categorizing these patients according to the genotypic types of their recurrent hydatidiform moles may facilitate the identification of novel genes for this entity.

Moein-Vaziri N, Fallahi J, Namavar-Jahromi B, et al.
Clinical and genetic-epignetic aspects of recurrent hydatidiform mole: A review of literature.
Taiwan J Obstet Gynecol. 2018; 57(1):1-6 [PubMed] Related Publications
Hydatidiform Mole (HM) is the most common form of Gestational Trophoblastic Disease (GTD), defined by hyper-proliferation of trophoblastic cells. HM is typified as abnormal proliferation of extraembryonic trophoblastic (placental) tissues and failure of embryonic tissues development and is the only GTD with Mendelian inheritance, which can reoccur in different pregnancies. Moles are categorized into Complete Hydatidiform Moles (CHM) or Partial Hydatidiform Moles (PHM) and a rare familial trait, which forms a CHM and despite having androgenetic pattern, shows normal biparental inheritance, conceived from one sperm and egg. Recessive maternal-effect mutations in NLRP7 (NACHT, leucine rich repeat and PYD containing 7) and KHDC3L (KH Domain Containing 3-Like) genes have been shown to be responsible for Recurrent Hydatidiform Moles (HYDM1 MIM# 231090 when is caused by mutation in the NLRP7 gene and HYDM2 MIM#614293 when is caused by mutation in the KHDC3L gene). Methylation aberration in multiple maternally imprinted genes is introduced as the cause of Recurrent HYDM pathology. The current article reviews the histopathology, risk factors, and genetic and epigenetic characteristics of Recurrent HYDMs.

Monk D, Sanchez-Delgado M, Fisher R
NLRPs, the subcortical maternal complex and genomic imprinting.
Reproduction. 2017; 154(6):R161-R170 [PubMed] Related Publications
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

Hui P, Buza N, Murphy KM, Ronnett BM
Hydatidiform Moles: Genetic Basis and Precision Diagnosis.
Annu Rev Pathol. 2017; 12:449-485 [PubMed] Related Publications
Hydatidiform moles are intriguing pathologic entities representing abnormal placental villous tissue with unique genetic profiles and a wide spectrum of morphologic features, which makes accurate diagnosis challenging. Overrepresentation of the paternal genome in sporadic hydatidiform moles (purely androgenetic in complete hydatidiform moles and diandric triploid in partial hydatidiform moles) is a fundamental genetic event leading to global alteration of imprinting gene expression in the molar trophoblast. Rare familial biparental hydatidiform moles (due to NLRP7 or KHDC3L mutations) share such global imprinting alterations, implying a common end point of pathogenesis. Despite being the cornerstone of diagnosis, routine morphologic assessment of hydatidiform moles continues to suffer from interobserver diagnostic variability, emphasizing the need for new diagnostic modalities. Analyses of p57 expression by immunohistochemistry and polymerase chain reaction-based DNA genotyping have emerged as powerful diagnostic methods for accurate classification of hydatidiform moles. Algorithmic approaches combining histology and these ancillary techniques provide the best diagnostic practice currently available.

Hemida R, van Doorn H, Fisher R
A Novel Genetic Mutation in a Patient With Recurrent Biparental Complete Hydatidiform Mole: A Brief Report.
Int J Gynecol Cancer. 2016; 26(7):1351-3 [PubMed] Related Publications
Recurrent hydatidiform moles are defined by the occurrence of two or more molar pregnancies in the same patient. Familial recurrent hydatidiform moles (FRHM) is a rare autosomal recessive condition where women have an inherited predisposition to have molar pregnancies. Genotyping demonstrated that they are diploid and biparental. We report a case of FRHM from Egypt with a history of 6 recurrent complete moles. Sequencing of the NLPR7 gene revealed a deleterious homozygous base change in exon 2, c.197G>A, which would result in a truncated protein p.W66*. To the best of our knowledge, this mutation has not been described before.

Reddy R, Nguyen NM, Sarrabay G, et al.
The genomic architecture of NLRP7 is Alu rich and predisposes to disease-associated large deletions.
Eur J Hum Genet. 2016; 24(10):1445-52 [PubMed] Free Access to Full Article Related Publications
NLRP7 is a major gene responsible for recurrent hydatidiform moles. Here, we report 11 novel NLRP7 protein truncating variants, of which five deletions of more than 1-kb. We analyzed the transcriptional consequences of four variants. We demonstrate that one large homozygous deletion removes NLRP7 transcription start site and results in the complete absence of its transcripts in a patient in good health besides her reproductive problem. This observation strengthens existing data on the requirement of NLRP7 only for female reproduction. We show that two other variants affecting the splice acceptor of exon 6 lead to its in-frame skipping while another variant affecting the splice donor site of exon 9 leads to an in-frame insertion of 54 amino acids. Our characterization of the deletion breakpoints demonstrated that most of the breakpoints occurred within Alu repeats and the deletions were most likely mediated by microhomology events. Our data define a hotspot of Alu instability and deletions in intron 5 with six different breakpoints and rearrangements. Analysis of NLRP7 genomic sequences for repetitive elements demonstrated that Alu repeats represent 48% of its intronic sequences and these repeats seem to have been inserted into the common NLRP2/7 primate ancestor before its duplication into two genes.

Ito Y, Maehara K, Kaneki E, et al.
Novel Nonsense Mutation in the NLRP7 Gene Associated with Recurrent Hydatidiform Mole.
Gynecol Obstet Invest. 2016; 81(4):353-8 [PubMed] Related Publications
AIM: This study aimed to clarify the genetic and epigenetic features of recurrent hydatidiform mole (RHM) in Japanese patients.
METHODS: Four Japanese isolated RHM cases were analyzed using whole-exome sequencing. Villi from RHMs were collected by laser microdissection for genotyping and DNA methylation assay of differentially methylated regions (DMRs). Single nucleotide polymorphisms of PEG3 and H19 DMRs were used to confirm the parental origin of the variants.
RESULTS: A novel homozygous nonsense mutation in NLRP7 (c.584G>A; p.W195X) was identified in 1 patient. Genotyping of one of her molar tissue revealed that it was biparental but not androgenetic in origin. Despite the fact that the RHM is biparental, maternally methylated DMRs of PEG3, SNRPN and PEG10 showed complete loss of DNA methylation. A paternally methylated DMR of H19 retained normal methylation.
CONCLUSIONS: This is the first Japanese case of RHM with a novel homozygous nonsense NLRP7 mutation and a specific loss of maternal DNA methylation of DMRs. Notably, the mutation was identified in an isolated case of an ethnic background that has not previously been studied in this context. Our data underscore the involvement of NLRP7 in RHM pathophysiology and confirm that DNA methylation of specific regions is critical.

Sunde L, Lund H, J Sebire N, et al.
Paternal Hemizygosity in 11p15 in Mole-like Conceptuses: Two Case Reports.
Medicine (Baltimore). 2015; 94(44):e1776 [PubMed] Free Access to Full Article Related Publications
Hydatidiform mole is an abnormal human pregnancy characterized by the fetus being absent or nonviable, and the chorionic villi being vesicular and with trophoblastic hyperplasia. Most often, the mole phenotype is seen in conceptuses with an excess of paternally inherited genome set(s) relative to maternally inherited genome set(s), suggesting that the phenotype is caused by an excess of genome with a paternal imprinting pattern. However, it is unknown if correct parental origin of every imprinted gene is crucial for normal early differentiation or if abnormal parental imprinting of only one, or some, gene(s) can cause the mole phenotype.Two conceptuses included in the Danish Mole Project stood out since they presented with vesicular chorionic villi and without signs of fetal differentiation, and had apparently biparental diploid genomes, and no mutations in NLRP7 or KHDC3L were detected in the mothers. These conceptuses were subjected to a centralized histopathological revision and their genetic complements were scrutinized using fluorescence in situ hybridization, and DNA-marker and array comparative genomic hybridization analyses. Both conceptuses showed dysmorphic chorionic villi with some similarities to hydatidiform moles; however, no definite florid trophoblast hyperplasia was observed. Both conceptuses showed paternal hemizygosity of 11pter-11p15.4, most likely in nonmosaic state.Our findings suggest that the product of one (or a few) maternally expressed gene(s) on the tip of chromosome 11 is necessary for normal early embryonic differentiation. However, since the present two cases did not exhibit all features of hydatidiform moles, it is likely that abnormal parental imprinting of genes in other regions contribute to the phenotype of a hydatidiform mole.

Sanchez-Delgado M, Martin-Trujillo A, Tayama C, et al.
Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting.
PLoS Genet. 2015; 11(11):e1005644 [PubMed] Free Access to Full Article Related Publications
Familial recurrent hydatidiform mole (RHM) is a maternal-effect autosomal recessive disorder usually associated with mutations of the NLRP7 gene. It is characterized by HM with excessive trophoblastic proliferation, which mimics the appearance of androgenetic molar conceptuses despite their diploid biparental constitution. It has been proposed that the phenotypes of both types of mole are associated with aberrant genomic imprinting. However no systematic analyses for imprinting defects have been reported. Here, we present the genome-wide methylation profiles of both spontaneous androgenetic and biparental NLRP7 defective molar tissues. We observe total paternalization of all ubiquitous and placenta-specific differentially methylated regions (DMRs) in four androgenetic moles; namely gain of methylation at paternally methylated loci and absence of methylation at maternally methylated regions. The methylation defects observed in five RHM biopsies from NLRP7 defective patients are restricted to lack-of-methylation at maternal DMRs. Surprisingly RHMs from two sisters with the same missense mutations, as well as consecutive RHMs from one affected female show subtle allelic methylation differences, suggesting inter-RHM variation. These epigenotypes are consistent with NLRP7 being a maternal-effect gene and involved in imprint acquisition in the oocyte. In addition, bioinformatic screening of the resulting methylation datasets identified over sixty loci with methylation profiles consistent with imprinting in the placenta, of which we confirm 22 as novel maternally methylated loci. These observations strongly suggest that the molar phenotypes are due to defective placenta-specific imprinting and over-expression of paternally expressed transcripts, highlighting that maternal-effect mutations of NLRP7 are associated with the most severe form of multi-locus imprinting defects in humans.

Docherty LE, Rezwan FI, Poole RL, et al.
Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans.
Nat Commun. 2015; 6:8086 [PubMed] Free Access to Full Article Related Publications
Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.

Singer H, Biswas A, Nuesgen N, et al.
NLRP7, Involved in Hydatidiform Molar Pregnancy (HYDM1), Interacts with the Transcriptional Repressor ZBTB16.
PLoS One. 2015; 10(6):e0130416 [PubMed] Free Access to Full Article Related Publications
Mutations in the maternal effect gene NLRP7 cause biparental hydatidiform mole (HYDM1). HYDM1 is characterized by abnormal growth of placenta and lack of proper embryonic development. The molar tissues are characterized by abnormal methylation patterns at differentially methylated regions (DMRs) of imprinted genes. It is not known whether this occurs before or after fertilization, but the high specificity of this defect to the maternal allele indicates a possible maternal germ line-specific effect. To better understand the unknown molecular mechanism leading to HYDM1, we performed a yeast two-hybrid screen against an ovarian library using NLRP7 as bait. We identified the transcriptional repressor ZBTB16 as an interacting protein of NLRP7 and verified this interaction in mammalian cells by immunoprecipitation and confocal microscopy. Native protein analysis detected NLRP7 and ZBTB16 in a 480kD protein complex and both proteins co-localize in the cytoplasm in juxtanuclear aggregates. HYDM1-causing mutations in NLRP7 did not show altered patterns of interaction with ZBTB16. Hence, the biological significance of the NLRP7-ZBTB16 interaction remains to be revealed. However, a clear effect of harvesting ZBTB16 to the cytoplasm when the NLRP7 protein is overexpressed may be linked to the pathology of the molar pregnancy disease.

Akoury E, Gupta N, Bagga R, et al.
Live births in women with recurrent hydatidiform mole and two NLRP7 mutations.
Reprod Biomed Online. 2015; 31(1):120-4 [PubMed] Related Publications
Hydatidiform mole (HM) is an aberrant human pregnancy with abnormal embryonic development and excessive proliferation of the trophoblast. Recessive mutations in NLRP7 are responsible for recurrent HM (RHM). Women with recessive NLRP7 mutations fail to have normal pregnancies from spontaneous conceptions with the exception of three out of 131 reported patients. Because there is no treatment for RHM and maternal-effect genes are needed in the oocytes to sustain normal embryonic development until the activation of the embryonic genome, one patient with recessive NLRP7 mutations tried ovum donation and achieved a successful pregnancy. This study reports three additional live births from donated ova to two patients with recessive NLRP7 mutations. The occurrence of two live births from spontaneous conceptions to two other patients is also reported. The reproductive outcomes and mutations of all reported patients were reviewed and it was found that live births are associated with some missense mutations expected to have mild functional consequences on the protein. The data support a previous observation that ovum donation appears the best management option for these patients to achieve normal pregnancies and provide an explanation for the rare occurrence of live births from natural spontaneous conceptions in patients with two NLRP7 mutations.

Nguyen NM, Zhang L, Reddy R, et al.
Comprehensive genotype-phenotype correlations between NLRP7 mutations and the balance between embryonic tissue differentiation and trophoblastic proliferation.
J Med Genet. 2014; 51(9):623-34 [PubMed] Related Publications
BACKGROUND: Hydatidiform mole (HM) is a human pregnancy with excessive trophoblastic proliferation and abnormal embryonic development that may be sporadic or recurrent. In the sporadic form, the HM phenotype is driven by an abnormal ratio of paternal to maternal genomes, whereas in the recurrent form, the HM phenotype is caused by maternal-recessive mutations, mostly in NLRP7, despite the diploid biparental origin of the HM tissues. In this study, we characterised the expression of the imprinted, maternally expressed gene, CDKN1C (p57(KIP2)), the genotype, and the histopathology of 36 products of conception (POC) from patients with two defective alleles in NLRP7 and looked for potential correlations between the nature of the mutations in the patients and the various HM features.
METHODS/RESULTS: We found that all the 36 POCs are diploid biparental and have the same parental contribution to their genomes. However, some of them expressed variable levels of p57(KIP2) and this expression was strongly associated with the presence of embryonic tissues of inner cell mass origin and mild trophoblastic proliferation, which are features of triploid partial HMs, and were associated with missense mutations. Negative p57(KIP2) expression was associated with the absence of embryonic tissues and excessive trophoblastic proliferation, which are features of androgenetic complete HMs and were associated with protein-truncating mutations.
CONCLUSIONS: Our data suggest that NLRP7, depending on the severity of its mutations, regulates the imprinted expression of p57(KIP2) and consequently the balance between tissue differentiation and proliferation during early human development. This role is novel and could not have been revealed by any other approach on somatic cells.

Zhao W, Muhetaer A, Luo T, et al.
Absence of KHDC3L mutations in Chinese patients with recurrent and sporadic hydatidiform moles.
Cancer Genet. 2013 Sep-Oct; 206(9-10):327-9 [PubMed] Related Publications
To date, two maternal-effect genes have been shown to play causal roles in recurrent hydatidiform moles (RHMs). NLRP7, a major gene for this condition, codes for a nucleotide-binding oligomerization domain-like receptor and is mutated in 48 to 60% of patients with RHMs. KHDC3L is a recently identified gene that is mutated in 14% of NLRP7-negative patients. We screened KHDC3L for mutations in a total of 101 Chinese patients, 15 with at least two hydatidiform moles, 16 with at least two reproductive losses including one hydatidiform mole, and 70 with one hydatidiform mole and no other form of reproductive loss, but did not find any mutation. Our data favor the causal role of KHDC3L in a minority of RHM cases, demonstrate its noninvolvement in other forms of reproductive loss, and indicate the presence of other unidentified genes that cause or increase patients' susceptibility to RHMs in the Chinese population.

Mahadevan S, Wen S, Balasa A, et al.
No evidence for mutations in NLRP7 and KHDC3L in women with androgenetic hydatidiform moles.
Prenat Diagn. 2013; 33(13):1242-7 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The objective of this study was to evaluate the mutational spectrum of NLRP7 and KHDC3L (C6orf221) in women with sporadic and recurrent androgenetic complete hydatidiform moles (AnCHM) and biparental hydatidiform moles (BiHM) to address the hypothesis that autosomal recessive mutations in these genes are only or primarily associated with BiHM.
METHOD: We recruited 16 women with suspected recurrent and sporadic AnCHM and five women with suspected BiHM in addition to their reproductive partners into our study. We then sequenced the coding exons of NLRP7 and KHDC3L from DNA isolated from either blood or saliva from the study subjects.
RESULTS: Sequence analysis of NLRP7 and KHDC3L revealed previously described single nucleotide polymorphisms in patients with AnCHM. However, in patients with BiHM, we identified a novel homozygous mutation and a previously described intragenic duplication of exons 2 to 5 in NLRP7, both of which are likely to be disease causing. We did not identify mutations in KHDC3L in patients with either form of hydatidiform moles.
CONCLUSIONS: The absence of mutations in women with AnCHM supports a role for NLRP7 or KHDC3L in BiHM only. The absence of mutations in KHDC3L in women with BiHM is consistent with its minor role in this disease compared with NLRP7, the major BiHM gene.

Fonseca-Sanchéz MA, Pérez-Plasencia C, Fernández-Retana J, et al.
microRNA-18b is upregulated in breast cancer and modulates genes involved in cell migration.
Oncol Rep. 2013; 30(5):2399-410 [PubMed] Related Publications
microRNAs are small non-coding RNAs of ~22 nucleotides that function at post-transcriptional level as negative regulators of gene expression. Aberrant expression of microRNAs could promote uncontrolled proliferation, migration and invasion of human cancer cells. In this study, we analyzed the expression of microRNA-18b (miR-18b) in breast cancer cell lines and in a set of clinical specimens. Our results showed that miR-18b was upregulated in four out of five breast cancer cell lines and also in breast tumors. In order to identify potential gene targets, we carried out transcriptional profiling of MDA-MB-231 breast cancer cells that ectopically expressed miR-18b. Our results showed that 263 genes were significantly modulated in miR-18b-deficient cells (fold change >1.5; P≤0.05). We found that knock-down of miR-18b induced the upregulation of 55 olfactory receptor (OR) genes and nine genes (NLRP7, KLK3, OLFM3, POSTN, MAGED4B, KIR3DL3, CRX, SEMG1 and CEACAM5) with key roles in cell migration and metastasis. Consistently, we found that ectopic inhibition of miR-18b suppressed the migration of two breast cancer cell models in vitro. In conclusion, we have uncovered genes directly or indirectly modulated by miR-18b which may represent potential therapeutic targets in breast cancer. Our data also pointed out a role of miR-18b in migration of breast cancer cells.

Andreasen L, Christiansen OB, Niemann I, et al.
NLRP7 or KHDC3L genes and the etiology of molar pregnancies and recurrent miscarriage.
Mol Hum Reprod. 2013; 19(11):773-81 [PubMed] Related Publications
Women with mutation in both alleles of the NLRP7 or C6orf221/KHDC3L genes are predisposed to diploid biparental moles, but it has also been suggested that mutation in these genes can predispose to diploid androgenetic or triploid moles and to other kinds of reproductive wastage. We have investigated the association between molar pregnancy and recurrent miscarriages regarding changes in the NLRP7 and C6orf221/KHDC3L genes. Our study group can be divided into three sub-cohorts: (i) women having had at least one molar pregnancy and at least two non-mole miscarriages, (ii) women having had recurrent androgenetic hydatidiform moles and (iii) women having had one diploid androgenetic hydatidiform mole and a relative having had a hydatidiform mole (familial hydatidiform moles). We observed a statistically non-significant tendency of non-synonymous variants in NLRP7 to be more frequent in women with familial hydatidiform mole and in women with female family members with hydatidiform mole or non-mole miscarriage compared with women with no family history of mole or miscarriage. However, we did not find any unequivocal pathogenic mutations (the term 'unequivocal pathogenic mutations' refers to mutations that indubitably have a pathogenic effect on the affected woman) in NLRP7 or C6orf221/KHDC3L in any of the women in the study group. This indicates that recurrent miscarriages plus hydatidiform mole, recurrent androgenetic hydatidiform moles and familial androgenetic hydatidiform moles in general do not have the same monogenetic etiology as familiar diploid biparental moles.

Ulker V, Gurkan H, Tozkir H, et al.
Novel NLRP7 mutations in familial recurrent hydatidiform mole: are NLRP7 mutations a risk for recurrent reproductive wastage?
Eur J Obstet Gynecol Reprod Biol. 2013; 170(1):188-92 [PubMed] Related Publications
OBJECTIVE: Familial recurrent hydatidiform mole is an exceedingly rare clinical condition. Affected women are predisposed to molar pregnancies of diploid, biparental origin rather than androgenetic origin. At present, NLRP7 and KHDC3L (C6orf221) are the only genes known to be associated with familial recurrent hydatidiform mole. This study investigated the genetic dispositions in two large Turkish families with recurring molar conceptuses.
STUDY DESIGN: Copy number variation analysis was performed followed by NLRP7 gene sequencing. The finding of a mono-allelic condition in one family led to investigation of the adjacent NLRP2 gene and recently associated KHDC3L gene. Sampled molar tissues were genotyped using microsatellite markers.
RESULTS: In one family, a homozygous single nucleotide insertion that caused a frameshift leading to an early stop codon, c.2940_2941insC (p.Glu981ArgfsX13), was identified in the affected sisters. In the other family, a heterozygous 60-kb deletion eliminating substantial portions of the NLRP2 and NLRP7 genes on one allele was found. Screening of NLRP2 and KHDC3L genes revealed no alterations that were considered to be pathological. Genotyping of six independent molar conceptions revealed that five were of diploid, biparental origin and one was of diandric, triploid origin.
CONCLUSIONS: Two novel protein-truncating mutations in the NLRP7 gene were found to be associated with familial recurrent hydatidiform mole. Mutations in the NLRP7 gene causing recurrent biparental hydatidiform mole may also be associated with other forms of recurrent reproductive wastage.

Dias RP, Maher ER
Genes, assisted reproductive technology and trans-illumination.
Epigenomics. 2013; 5(3):331-40 [PubMed] Related Publications
Genomic imprinting is a parent-of-origin allele-specific epigenetic process that is critical for normal development and health. The establishment and maintenance of normal imprinting is dependent on both cis-acting imprinting control centers, which are marked by differentially (parental allele specific) methylated marks, and trans mechanisms, which regulate the establishment and/or maintenance of the correct methylation epigenotype at the imprinting control centers. Studies of rare human imprinting disorders such as familial hydatidiform mole, Beckwith-Wiedemann syndrome and familial transient neonatal diabetes mellitus have enabled the identification of genetic (e.g., mutations in KHDC3L [C6ORF221], NLRP2 [NALP2], NLRP7 [NALP7] and ZFP57) and environmental (assisted reproductive technologies) factors that can disturb the normal trans mechanisms for imprinting establishment and/or maintenance. Here we review the clinical and molecular aspects of these imprinting disorders in order to demonstrate how the study of rare inherited disorders can illuminate the molecular characteristics of fundamental epigenetic processes, such as genomic imprinting.

Brown L, Mount S, Reddy R, et al.
Recurrent pregnancy loss in a woman with NLRP7 mutation: not all molar pregnancies can be easily classified as either "partial" or "complete" hydatidiform moles.
Int J Gynecol Pathol. 2013; 32(4):399-405 [PubMed] Related Publications
Recurrent hydatidiform moles is an uncommon occurrence. Over the past decade, genetic studies of women with multiple recurrent molar pregnancies have revealed that maternal mutations in two different genes, NLRP7 and C6orf221, result in recurrent moles. We report a 23 year old woman, born of unrelated parents, who has experienced three molar pregnancies in succession. Whilst the first pregnancy was classified as a complete hydatidiform mole, the second and third moles defied classification as complete or partial mole using conventional histology, p57 nuclear staining pattern and ploidy studies. Molecular and cytogenetic studies proved that all three molar pregnancies were diploid and biparental in origin. Gene sequencing analysis showed that the patient is homozygous for a previously described mutation in NLRP7. A SNP microarray ruled out the presence of deletion of the NLRP7 locus. This case draws attention to the fact that recurrent molar pregnancies may be the result of specific, identifiable gene mutations, even in patients from non-consanguineous backgrounds. When pathologists encounter patients with molar pregnancies that are diploid and p57 negative and yet have fetal elements such as nucleated red blood cells or immature fetal tissues, it should heighten their suspicion of a possible genetic basis and appropriate molecular genetic workup performed with counseling offered.

Manokhina I, Hanna CW, Stephenson MD, et al.
Maternal NLRP7 and C6orf221 variants are not a common risk factor for androgenetic moles, triploidy and recurrent miscarriage.
Mol Hum Reprod. 2013; 19(8):539-44 [PubMed] Related Publications
Maternal effect genes control early events of embryogenesis. Maternal homozygous and compound mutations in two such genes, NLRP7 and c6orf221, have been detected in the majority of women experiencing recurrent biparental hydatidiform moles. It was suggested that other forms of reproductive wastage, including diploid androgenetic moles, partial moles, polyploidy, recurrent spontaneous abortions and stillbirths of uncertain etiology, may be caused by NLRP7 or c6orf221 mutations in the mother. To elucidate which subpopulations of women with adverse reproductive outcomes should be screened for NLRP7/C6orf221 variants, we sequenced coding sequence and exon/intron boundaries of NLRP7 and C6orf221 in a well-defined group of 17 women with recurrent miscarriage and additional triploidy or complete hydatidiform moles. The major findings for this group were non-synonymous variants of NLRP7, rather than clearly pathogenic mutations. To assess the role of these variants, we genotyped them in a larger group including women with primary recurrent miscarriage (n = 39), paternal triploid conceptions (n = 22) and women with proven fertility after age 37 and no prior history of miscarriage or pregnancy complications (n = 52). No associations between non-synonymous NLRP7 variants and primary recurrent miscarriage or partial hydatidiform molar pregnancies were detected. Our findings suggest that neither mutations nor variants in NLRP7 and C6orf221 are major factors contributing to the risk of these types of pregnancy complications. Further studies in larger groups of patients and controls are needed to specify the impact of NLRP7 rare non-synonymous variants on genetic susceptibility to recurrent reproductive wastage.

Estrada H, Buentello B, Zenteno JC, et al.
The p.L750V mutation in the NLRP7 gene is frequent in Mexican patients with recurrent molar pregnancies and is not associated with recurrent pregnancy loss.
Prenat Diagn. 2013; 33(3):205-8 [PubMed] Related Publications
OBJECTIVE: The aim of this study is to analyze NLRP7 mutation frequency in 20 Mexican patients with recurrent hydatidiform moles (RHMs).
PATIENTS: Twenty patients with RHMs, 50 couples with recurrent pregnancy loss (RPL), and 100 controls were included in the study. Molecular analysis of the NLRP7 coding region was performed in patients with RHMs. Restriction enzyme digestion analysis and direct sequencing of the identified mutations were performed in controls and patients with RPL.
RESULTS: Patients displayed between two and six moles, and 10 of them presented other forms of pregnancy loss. Twelve (60%) patients were homozygous for the missense mutation c.2248C > G (p.L750V), five (25%) patients were heterozygous for the p.L750V mutation and the c.1018 G > A (p.E340K) variant, and three (15%) patients were heterozygous for the c.1018 G > A (p.E340K) variant. Five (5%) control women and four women and one man (5%) with RPL were heterozygous for the p.L750V mutation and two (2%) patients with RPL were heterozygous for the p.E340K variant.
CONCLUSIONS: A total of 60% of our RHM patients presented homozygous p.L750V mutations, 25% were compound heterozygotes for p.L750V mutation and the p.E340K variant, and 15% were heterozygous for p.E340K variant. Heterozygous p.L750V mutations were frequently observed in our population. Homozygous mutations were also present in patients with RHMs. Additional studies are needed to understand the role of the p.E340K variant in RHMs and RPL.

Reddy R, Akoury E, Phuong Nguyen NM, et al.
Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7.
Eur J Hum Genet. 2013; 21(9):957-64 [PubMed] Free Access to Full Article Related Publications
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.

Fallahian M, Sebire NJ, Savage PM, et al.
Mutations in NLRP7 and KHDC3L confer a complete hydatidiform mole phenotype on digynic triploid conceptions.
Hum Mutat. 2013; 34(2):301-8 [PubMed] Related Publications
Digynic triploidy is classically associated with a severely growth restricted fetus and a small nonmolar placenta. However, in genotyping hydatidiform moles as part of clinical practice, we identified two digynic triploid conceptions presenting with histopathological features of classical complete hydatidiform mole (CHM). Both cases occurred in women with a history of previous molar pregnancies and no normal pregnancies. Pathological review and genotyping of other molar pregnancies in these cases showed them to be typical CHM with negative p57(KIP2) immunostaining of the cytotrophoblast cells and villous stroma and to be diploid but biparental, confirming a diagnosis of familial recurrent hydatidiform mole (FRHM). Mutation screening of NLRP7 had identified a homozygous duplication, leading to a truncated protein, in case 1 whereas mutation screening of KHDC3L (C6orf221) in case 2 showed both the proband and her sister to be compound heterozygotes for mutations in KHDC3L. The observation of a single digynic, triploid conception presenting as a CHM in women with FRHM, where other pregnancies are diploid and biparental, supports the hypothesis that the role of both NLRP7 and KHDC3L in pregnancy is in setting and/or maintaining the maternal imprint. Clinically, a diagnosis of FRHM should be considered in women with genetically unusual conceptions that are phenotypically CHM.

Andreasen L, Bolund L, Niemann I, et al.
Mosaic moles and non-familial biparental moles are not caused by mutations in NLRP7, NLRP2 or C6orf221.
Mol Hum Reprod. 2012; 18(12):593-8 [PubMed] Related Publications
Hydatidiform moles (HMs) most often occur sporadically and are either diploid androgenetic or triploid. The very rare familial recurrent HMs (FRHMs) have been related to NLRP7 and C6orf221 mutations in the mother. FRHMs are most often diploid with both maternal and paternal origin of the molar genome. We have screened a cohort of 11 women with diploid HMs with biparental contributions to the molar genome with regard to mutations in NLRP7, NLRP2, the NLRP gene most homologous to NLRP7, and C6orf221. This was done in order to reveal if mutations in the mentioned genes play a major role in development of non-recurrent biparental moles. Recently, we have shown that eight of these diploid moles consist of two different cell lines. Only one woman had a mutation in the coding DNA sequence of NLRP7, which most likely contributed to HM development. This woman had non-mosaic repeated moles, and she was the only woman in our cohort with FRHM. We found no unequivocal pathogenic mutations in NLRP2 or C6orf221. Our observations suggest that although NLRP7 and C6orf221 mutations are related to diploid biparental FRHMs, neither of these genes, nor NLRP2, are related to diploid HMs with biparental contributions to the molar genome, in general.

Abdalla EM, Hayward BE, Shamseddin A, Nawar MM
Recurrent hydatidiform mole: detection of two novel mutations in the NLRP7 gene in two Egyptian families.
Eur J Obstet Gynecol Reprod Biol. 2012; 164(2):211-5 [PubMed] Related Publications
OBJECTIVES: Hydatidiform mole is an aberrant pregnancy with hyperproliferative vesicular trophoblast and defective fetal development. In 2006, mutations in NLRP7 were found to be responsible for recurrent hydatidiform moles (RHM), but genetic heterogeneity has been demonstrated and mutations of C6orf221 were later reported in several families. Here we report a new Egyptian family in which two sisters had eleven and four molar pregnancies, respectively. The objective was to present the results of the mutation analysis of NLRP7 and C6orf221 genes in Egyptian women with RHM.
STUDY DESIGN: Three women from two unrelated Egyptian families; two sisters and a previously described sporadic case, all presenting with RHM, were enrolled. The cases were subjected to detailed history taking, karyotyping and screening for mutations in NLRP7 and C6orf221.
RESULTS: Two NLRP7 mutations have been detected, one in each family. In the first family, sequencing identified a homozygous 2 bp deletion in the seventh coding exon of NLRP7, while a homozygous G-to-A substitution in the third coding exon of NLRP7 was detected in the second family. Both of them result in a truncated protein. The two mutations have not been previously described in the literature. No mutations in C6orf221 were found in any of the samples.
CONCLUSION: The detection of an NLRP7 mutation in both the familial and the apparently isolated case of RHM provides further evidence for the previously established role of NLRP7 mutations in the pathophysiology of RHM and increases the diversity of mutations described in the Egyptian population. Our results also expand further the spectrum of reproductive wastage associated with NLRP7 mutations to patients with recurrent spontaneous abortion.

Landolsi H, Rittore C, Philibert L, et al.
NLRP7 mutation analysis in sporadic hydatidiform moles in Tunisian patients: NLRP7 and sporadic mole.
Arch Pathol Lab Med. 2012; 136(6):646-51 [PubMed] Related Publications
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.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. NLRP7, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 30 August, 2019     Cancer Genetics Web, Established 1999