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Rima Slim - One of the best experts on this subject based on the ideXlab platform.
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Women heterozygous for NALP7/NLRP7 mutations are at risk for reproductive wastage: report of two novel mutations.
Human Mutation, 2020Co-Authors: Jinhua Qian, Catherine Deveault, Rashmi Bagga, Rima SlimAbstract:Familial recurrent hydatidiform moles are a rare recessive condition in which molar tissues have biparental contribution to their genome. One maternal locus responsible for this condition has been mapped to 19q13.4 and the causative gene, NALP7, identified (HUGO-approved nomenclature is now NLRP7). Here we report a first stop codon, c.295G>T (p.Glu99X) and a missense mutation, c.1970A>T (p.Asp657Val) in NLRP7 in two sisters with RHMs. We found these two mutations and a previously reported one, c.2078G>C (p.Arg693Pro) in a homozygous state, in males with normal reproductive outcomes. This suggests that NLRP7 is not required for normal spermatogenesis. The mother of the patients is heterozygous for Glu99X and had one stillbirth and three normal pregnancies. Our data on this new family and on heterozygous women from previously reported families indicate that women heterozygous for NLRP7 mutations are at risk for reproductive wastage without the manifestation of molar phenotype. © 2007 Wiley-Liss, Inc.
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pathogenic variant in NLRP7 19q13 42 associated with recurrent gestational trophoblastic disease data from early embryo development observed during in vitro fertilization
Clinical and Experimental Reproductive Medicine, 2017Co-Authors: Scott E Sills, Alexandra J Obregontito, Thomas K Mcwilliams, Anthony T Gordon, Catharine A Adams, Rima SlimAbstract:OBJECTIVE: To describe in vitro development of human embryos derived from an individual with a homozygous pathogenic variant in NLRP7 (19q13.42) and recurrent hydatidiform mole (HM), an autosomal recessive condition thought to occur secondary to an oocyte defect. METHODS: A patient with five consecutive HM pregnancies was genomically evaluated via next generation sequencing followed by controlled ovarian hyperstimulation, in vitro fertilization (IVF) with intracytoplasmic sperm injection, embryo culture, and preimplantation genetic screening. Findings in NLRP7 were recorded and embryo culture and biopsy data were tabulated as a function of parental origin for any identified ploidy error. RESULTS: The patient was found to have a pathogenic variant in NLRP7 (c.2810+2T>G) in a homozygous state. Fifteen oocytes were retrieved and 10 embryos were available after fertilization via intracytoplasmic sperm injection. Developmental arrest was noted for all 10 embryos after 144 hours in culture, thus no transfer was possible. These non-viable embryos were evaluated by karyomapping and all were diploid biparental; two were euploid and eight had various aneuploidies all of maternal origin. CONCLUSION: This is the first report of early human embryo development from a patient with any NLRP7 mutation. The pathogenic variant identified here resulted in global developmental arrest at or before blastocyst stage. Standard IVF should therefore be discouraged for such patients, who instead need to consider oocyte (or embryo) donation with IVF as preferred clinical methods to treat infertility.
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eLS - Genetics and Epigenetics of Hydatidiform Moles
eLS, 2017Co-Authors: Rima Slim, Yassemine Khawajkie, Kurosh Rahimi, Philippe SauthierAbstract:A hydatidiform mole (HM) is an abnormal human pregnancy characterised by absence of, or abnormal, embryonic development, excessive trophoblastic proliferation and hydropic degeneration of placental villi. The common types of moles are sporadic, not recurrent, and affect 1 in 1000 pregnancies in western countries. HM may recur in the same patient, which is referred to as recurrent HM (RHM), and indicates that the patient is genetically susceptible to HM. Through the examination of rare familial cases of RHM, two maternal-effect genes, NLRP7 and KHDC3L, responsible for this condition have been identified. Pathogenic variants in these genes appear to impair imprinting establishment during oogenesis. Herein, we review current knowledge on the genetics and epigenetics of RHM, and highlight the benefits of testing patients for pathogenic variants in the known genes. Key Concepts RHM from patients with recessive pathogenic variants in NLRP7 or KHDC3L are diploid biparental and originate from a different mechanism than sporadic androgenetic or triploid HM. At the epigenetic level, RHM from patients with recessive pathogenic variants in NLRP7 or KHDC3L lack maternal methylation marks on differentially methylated regions (DMR) and mimic diploid androgenetic CHM, which lack a maternal genome. RHM from patients with recessive pathogenic variants in NLRP7 have defective oocytes and benefit from ovum donation. Diploid biparental HM from patients with pathogenic variants in NLRP7 have an imbalance between embryonic tissue differentiation and trophoblastic proliferation. The same imbalance is also observed in sporadic androgenetic and triploid HM. NLRP7 is part of the innate immune system and its pathogenic variants downregulate inflammation. Keywords: hydatidiform mole; recurrent hydatidiform mole; NLRP7; KHDC3L; reproductive loss; imprinting; epigenetics; oocyte; trophoblastic proliferation; androgenetic monospermic HM; triploid dispermic HM; ovum donation
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Two novel mutations in the KHDC3L gene in Asian patients with recurrent hydatidiform mole.
Human genome variation, 2016Co-Authors: Maryam Rezaei, Rima Slim, Ngoc Minh Phuong Nguyen, Leila Foroughinia, Pratima Dash, Fatemeh Ahmadpour, Ishwar C. Verma, Majid FardaeiAbstract:Recurrent hydatidiform mole (RHM) is defined by the occurrence of repeated molar pregnancies in affected women. Two genes, NLRP7 and KHDC3L, play a causal role in RHM and are responsible for 48–80% and 5% of cases, respectively. Here, we report the results of screening these two genes for mutations in one Iranian and one Indian patient with RHM. No mutations in NLRP7 were identified in the two patients. KHDC3L sequencing identified two novel protein-truncating mutations in a homozygous state, a 4-bp deletion, c.17_20delGGTT (p.Arg6Leufs*7), in the Iranian patient and a splice mutation, c.349+1G>A, that affects the invariant donor site at the junction of exon 2 and intron 2 in the Indian patient. To date, only four mutations in KHDC3L have been reported. The identification of two additional mutations provides further evidence for the important role of KHDC3L in the pathophysiology of RHM and increases the diversity of mutations described in Asian populations. Two new mutations have been identified in a gene associated with recurrent hydatidiform moles (RHMs). A RHM is a form of non-viable pregnancy in which the placenta develops into a mass of cysts. This condition occurs in higher frequencies in the Middle and Far East. Majid Fardaei of Shiraz University of Medical Science in Iran and colleagues screened Iranian and Indian women for mutations in two genes, NLRP7 and KHDC3L. These genes have been implicated as having a role in 48—80% and 5% of RHMs, respectively. In two patients, no mutations were found in NLRP7, but two new mutations were identified in KHDC3L that were not found in controls or two large gene databases. The findings confirm a causal role for KHDC3L in RHMs, which should be screened for when mutations are not detected in NLRP7.
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live births in women with recurrent hydatidiform mole and two NLRP7 mutations
Reproductive Biomedicine Online, 2015Co-Authors: Elie Akoury, Christine Dery, Neerja Gupta, Rashmi Bagga, Stephen Brown, Madhulika Kabra, Radhika Srinivasan, Rima SlimAbstract:Hydatidiform mole (HM) is an aberrant human pregnancy with abnormal embryonic development and excessive prolifera- tion of the trophoblast. Recessive mutations in NLRP7 are responsible for recurrent HM (RHM). Women with recessive NLRP7 muta- tions 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 success- ful 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 ex- pected 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. © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
Wafaa Chebaro - One of the best experts on this subject based on the ideXlab platform.
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NLRP7 and the genetics of post molar choriocarcinomas in senegal
Molecular Human Reproduction, 2012Co-Authors: Rima Slim, Philippe Coullin, Angelucien Diatta, Wafaa Chebaro, David Courtin, Sonia Abdelhak, Andre GarciaAbstract:Gestational choriocarcinomas are malignant tumors of trophoblastic cells that affect 5-25% of women with sporadic hyda- tidiform moles (HMs) depending on countries and studies. Nucleotide binding and oligomerization domain-like receptor protein 7 (NLRP7 )i s a major gene responsible for recurrent HMs and recently mutations in this gene have also been shown in 13% of women with sporadic, non- recurrent moles. To investigate the role of NLRP7 in the genetic susceptibility for the malignant degeneration of moles, we sequenced its 11 exons in 43 Senegalese patients with post-molar choriocarcinomas. We report the presence of three novel NLRP7 variants that were found only in patients but not in 100 controls from the Senegalese general population, 100 controls from the Tunisian general population, and 100 controls from the Canadian population. In addition, this analysis revealed significant differences in the frequencies of four non-synonymous NLRP7 variants between European and Senegalese controls with the biggest difference being for variant G487E present at a minor allele frequency of 3.5% in Europeans, 18.1% in Tunisians and 45.6% in Senegalese. Comparing human NLRP7 and its paralog, NLRP2, with their mammalian counterparts revealed that allele E at position 487 is most likely the ancestral allele that was acquired in Africa but driven to low frequencies in Europeans and Asians due to migration, population bottlenecks and selective pressures. This study is the first attempt to investigate the role of NLRP7 in choriocarcinomas and highlights the higher frequencies of NLRP7 variants in the general Sene- galese and Tunisian populations both known to have higher frequencies of moles and choriocarcinomas.
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the genetics of recurrent hydatidiform moles in china correlations between NLRP7 mutations molar genotypes and reproductive outcomes
Molecular Human Reproduction, 2011Co-Authors: Wafaa Chebaro, Qi Cheng, Jianhua Qian, Sharlene Murdoch, Chengming Xu, Xiaofei Zhang, Rima SlimAbstract:Hydatidiform mole (HM) is a human pregnancy with abnormal embryonic development. NLRP7 is a major autosomal reces- sive gene responsible for recurrent molar pregnancies and associated reproductive wastage in patients from several populations. Here, we report NLRP7 mutation analysis in 35 unrelated Chinese patients with recurrent reproductive wastage, including at least one HM. We describe three new protein-truncating mutations in NLRP7 and show the presence of three founder mutations in China and Asian popu- lations. We determined the parental contribution to six molar tissues and show the occurrence of three diploid androgenetic moles in patients with one defective allele, while three diploid biparental moles occurred in patients with two defective alleles. We document the failure of pregnancies after assisted reproductive technologies (ARTs) in three patients with two defective alleles each and a successful preg- nancy in one of two patients with one defective allele. Our data suggest that patients with a single defective allele have better reproductive outcomes than patients with two defective alleles, and some of them may benefit from ART.
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NLRP7 in the spectrum of reproductive wastage rare non synonymous variants confer genetic susceptibility to recurrent reproductive wastage
Journal of Medical Genetics, 2011Co-Authors: Christiane Messaed, Wafaa Chebaro, Cecile Rittore, Raphael B Di Roberto, Annie Cheung, Jocelyne Arseneau, Ariel Schneider, Moy Fong Chen, Kurt Bernishke, Urvashi SurtiAbstract:Background NLRP7 mutations are responsible for recurrent molar pregnancies and associated reproductive wastage. To investigate the role of NLRP7 in sporadic moles and other forms of reproductive wastage, the authors sequenced this gene in a cohort of 135 patients with at least one hydatidiform mole or three spontaneous abortions; 115 of these were new patients. Methods/Results All mutations were reviewed and their number, nature and locations correlated with the reproductive outcomes of the patients and histopathology of their products of conception. The presence of NLRP7 mutations was demonstrated in two patients with recurrent spontaneous abortions, and some rare non-synonymous variants (NSVs), present in the general population, were found to be associated with recurrent reproductive wastage. These rare NSVs were shown to be associated with lower secretion of interleukin 1b and tumour necrosis factor and therefore to have functional consequences similar to those seen in cells from patients with NLRP7 mutations. The authors also attempted to elucidate the cause of stillbirths observed in 13% of the patients with NLRP7 mutations by examining available placentas of the stillborn babies and live births from patients with mutations or rare NSVs. A number of severe to mild placental abnormalities were found, all of which are known risk factors for perinatal morbidity. Conclusions The authors recommend close follow-up of patients with NLRP7 mutations and rare NSVs to prevent the death of the rare or reduced number of babies that reach term.
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recurrent triploid and dispermic conceptions in patients with NLRP7 mutations
Placenta, 2011Co-Authors: Rima Slim, Wafaa Chebaro, Asangla Ao, Annie Cheung, Jocelyne Arseneau, Urvashi Surti, Lori Hoffner, Li Zhang, Anita WischmeijerAbstract:To understand the mechanisms leading to hydatidiform mole formation in patients with NLRP7 mutations, we used a combination of various approaches to characterize five products of conception, from two patients, shown by flow cytometry to contain non-diploid cells. We demonstrate that four of these conceptions are triploid and two of them originated from fertilization with more than one sperm. We show that three of these triploid conceptions fulfill the histopathological criteria of partial hydatidiform mole and one fulfills the histopathological criteria of spontaneous abortion. Our data demonstrate that some oocytes from one patient with NLRP7 mutations are not able to prevent polyspermic fertilization and highlight the importance of using several approaches to characterize the genetic complexity of molar tissues and reproductive wastage. Altogether, our previous and current data show the association of NLRP7 mutations with several types of hydatidiform moles and with triploid spontaneous abortions.
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NLRP7 mutations in women with diploid androgenetic and triploid moles a proposed mechanism for mole formation
Human Molecular Genetics, 2009Co-Authors: Catherine Deveault, Philippe Coullin, Wafaa Chebaro, Jianhua Qian, Lucy Gilbert, Asangla Ao, Anita Wischmeijer, Amira Mehio, Rabia Khan, Rima SlimAbstract:Hydatidiform mole is an aberrant pregnancy with abnormal embryonic development and hydropic placental villi. Common moles are sporadic, not recurrent and affect one in every 1500 pregnancies in Western societies. Approximately, half of common moles are complete and mostly diploid androgenetic, whereas the remaining are partial and mostly triploid diandric. NLRP7 has been found to be responsible for a recurrent form of molar pregnancies. Recently, we showed that patients with NLRP7 mutations have an impaired inflammatory response to various stimuli. To date, molar tissues analyzed from patients with NLRP7 mutations have been found to be diploid and biparental. In this study, we report 10 new non-synonymous variants and one stop codon found in patients and not in controls. We demonstrate the presence of different types of moles, diploid biparental, diploid androgenetic, triploid and tetraploid conceptions, in patients with NLRP7 variants. We document in vitro and in vivo early embryo cleavage abnormalities in three patients. We propose a two-hit mechanism at the origin of androgenetic moles. This mechanism consists of variable degrees of early embryo cleavage abnormalities leading to chaotic mosaic aneuploidies, with haploid, diploid, triploid and tetraploid blastomeres. Surviving embryonic cells that reach implantation are then subject to the maternal immune response. Because of the patients’ impaired inflammatory response, androgenetic cells, which are complete allograft, are able to grow and proliferate. In women with normal immune system, chaotic mosaic aneuploidies may also occur during early cleavage, however, androgenetic cells would die after implantation or stay undetected, confined to a small portion of the placenta.
Sangeetha Mahadevan - One of the best experts on this subject based on the ideXlab platform.
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no evidence for mutations in NLRP7 nlrp2 or khdc3l in women with unexplained recurrent pregnancy loss or infertility
Human Reproduction, 2015Co-Authors: Lusine Aghajanova, Sangeetha Mahadevan, Peter H Dixon, N J Sebire, Robert A. Fisher, Signe Altmae, Anneli Stavreusevers, L Regan, I B Van Den VeyverAbstract:STUDY QUESTION: Are mutations in NLRP2/7 (NACHT, LRR and PYD domains-containing protein 2/7) or KHDC3L (KH Domain Containing 3 Like) associated with recurrent pregnancy loss (RPL) or infertility?SU ...
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NLRP7 affects trophoblast lineage differentiation binds to overexpressed yy1 and alters cpg methylation
Human Molecular Genetics, 2014Co-Authors: Sangeetha Mahadevan, Hsiu Huei Peng, Subhendu Otta, Michelina Iacovino, Elisabeth Mahen, Michael Kyba, Bekim Sadikovic, Ignatia B Van Den VeyverAbstract:Maternal-effect mutations in NLRP7 cause rare biparentally inherited hydatidiform moles (BiHMs), abnormal pregnancies containing hypertrophic vesicular trophoblast but no embryo. BiHM trophoblasts display abnormal DNA methylation patterns affecting maternally methylated germline differentially methylated regions (gDMRs), suggesting that NLRP7 plays an important role in reprogramming imprinted gDMRs. How NLRP7—a component of the CATERPILLAR family of proteins involved in innate immunity and apoptosis—causes these specific DNA methylation and trophoblast defects is unknown. Because rodents lack NLRP7, we used human embryonic stem cells to study its function and demonstrate that NLRP7 interacts with YY1, an important chromatin-binding factor. Reduced NLRP7 levels alter DNA methylation and accelerate trophoblast lineage differentiation. NLRP7 thus appears to function in chromatin reprogramming and DNA methylation in the germline or early embryonic development, functions not previously associated with members of the NLRP family.
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no evidence for mutations in NLRP7 and khdc3l in women with androgenetic hydatidiform moles
Prenatal Diagnosis, 2013Co-Authors: Sangeetha Mahadevan, Alfred Balasa, Gary Fruhman, Julio Mateus, Andrew Wagner, Tarek K Alhussaini, Ignatia B Van Den VeyverAbstract: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. © 2013 John Wiley & Sons, Ltd.
Urvashi Surti - One of the best experts on this subject based on the ideXlab platform.
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A novel NLRP7 protein-truncating mutation associated with discordant and divergent p57 immunostaining in diploid biparental and triploid digynic moles
Virchows Archiv, 2020Co-Authors: Fabienne Allias, Touria Hajri, Nawel Mechtouf, Lucie Gaillot-durand, Lori Hoffner, Mojgan Devouassoux-shisheboran, Jérôme Massardier, François Golfier, Pierre-adrien Bolze, Urvashi SurtiAbstract:NLRP7 is a maternal-effect gene that has a primary role in the oocyte. Its biallelic mutations are a major cause for recurrent diploid biparental hydatidiform moles (HMs). Here, we describe the full characterization of four HMs from a patient with a novel homozygous protein-truncating mutation in NLRP7 . We found that some HMs have features of both complete and partial moles. Two HMs expressed p57 in the cytotrophoblast and stromal cells and exhibited divergent and discordant immunostaining. Microsatellite DNA-genotyping demonstrated that two HMs are diploid biparental and one is triploid digynic due to the failure of meiosis II. FISH analysis demonstrated triploidy in the cytotrophoblast and stromal cells in all villi. Our data highlight the atypical features of HM from patients with recessive NLRP7 mutations and the important relationship between NLRP7 defects in the oocyte and p57 expression that appear to be the main contributor to the molar phenotype regardless of the zygote genotype.
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NLRP7 in the spectrum of reproductive wastage rare non synonymous variants confer genetic susceptibility to recurrent reproductive wastage
Journal of Medical Genetics, 2011Co-Authors: Christiane Messaed, Wafaa Chebaro, Cecile Rittore, Raphael B Di Roberto, Annie Cheung, Jocelyne Arseneau, Ariel Schneider, Moy Fong Chen, Kurt Bernishke, Urvashi SurtiAbstract:Background NLRP7 mutations are responsible for recurrent molar pregnancies and associated reproductive wastage. To investigate the role of NLRP7 in sporadic moles and other forms of reproductive wastage, the authors sequenced this gene in a cohort of 135 patients with at least one hydatidiform mole or three spontaneous abortions; 115 of these were new patients. Methods/Results All mutations were reviewed and their number, nature and locations correlated with the reproductive outcomes of the patients and histopathology of their products of conception. The presence of NLRP7 mutations was demonstrated in two patients with recurrent spontaneous abortions, and some rare non-synonymous variants (NSVs), present in the general population, were found to be associated with recurrent reproductive wastage. These rare NSVs were shown to be associated with lower secretion of interleukin 1b and tumour necrosis factor and therefore to have functional consequences similar to those seen in cells from patients with NLRP7 mutations. The authors also attempted to elucidate the cause of stillbirths observed in 13% of the patients with NLRP7 mutations by examining available placentas of the stillborn babies and live births from patients with mutations or rare NSVs. A number of severe to mild placental abnormalities were found, all of which are known risk factors for perinatal morbidity. Conclusions The authors recommend close follow-up of patients with NLRP7 mutations and rare NSVs to prevent the death of the rare or reduced number of babies that reach term.
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recurrent triploid and dispermic conceptions in patients with NLRP7 mutations
Placenta, 2011Co-Authors: Rima Slim, Wafaa Chebaro, Asangla Ao, Annie Cheung, Jocelyne Arseneau, Urvashi Surti, Lori Hoffner, Li Zhang, Anita WischmeijerAbstract:To understand the mechanisms leading to hydatidiform mole formation in patients with NLRP7 mutations, we used a combination of various approaches to characterize five products of conception, from two patients, shown by flow cytometry to contain non-diploid cells. We demonstrate that four of these conceptions are triploid and two of them originated from fertilization with more than one sperm. We show that three of these triploid conceptions fulfill the histopathological criteria of partial hydatidiform mole and one fulfills the histopathological criteria of spontaneous abortion. Our data demonstrate that some oocytes from one patient with NLRP7 mutations are not able to prevent polyspermic fertilization and highlight the importance of using several approaches to characterize the genetic complexity of molar tissues and reproductive wastage. Altogether, our previous and current data show the association of NLRP7 mutations with several types of hydatidiform moles and with triploid spontaneous abortions.
Lone Sunde - One of the best experts on this subject based on the ideXlab platform.
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Recurrent diploid biparental mole
Ugeskrift for Læger, 2019Co-Authors: Sedrah Arif Butt, Lone Sunde, Louise Kelstrup, Marianne Lidang, Mette Bertelsen, Karen Ejrnæs, Trine Lunde PerinAbstract:This review summarises the knowledge of recurrent diploid biparental hydatidiform mole, which is a rare genetic condition. Pathogenic variants in both alleles of NLRP7 or KHDC3L are associated with maternal imprinting defects and can cause the condition. Women with biallelic inactivation of NLRP7 can achieve a normal pregnancy by oocyte donation, and it is highly likely, that this applies to women with biallelic inactivation of KHDCL3 as well. Identifying the cause of the recurrent moles can prevent that couples waist time and possibly reduce medical expenses related to fertility treatment.
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The pivotal roles of the NOD-like receptors with a PYD domain, NLRPs, in oocytes and early embryo development†.
Biology of Reproduction, 2019Co-Authors: Mahboobeh Amoushahi, Lone Sunde, Karin Lykke-hartmannAbstract:Nucleotide-binding oligomerization domain (NOD)-like receptors with a pyrin domain (PYD), NLRPs, are pattern recognition receptors, well recognized for their important roles in innate immunity and apoptosis. However, several NLRPs have received attention for their new, specialized roles as maternally contributed genes important in reproduction and embryo development. Several NLRPs have been shown to be specifically expressed in oocytes and preimplantation embryos. Interestingly, and in line with divergent functions, NLRP genes reveal a complex evolutionary divergence. The most pronounced difference is the human-specific NLRP7 gene, not identified in rodents. However, mouse models have been extensively used to study maternally contributed NLRPs. The NLRP2 and NLRP5 proteins are components of the subcortical maternal complex (SCMC), which was recently identified as essential for mouse preimplantation development. The SCMC integrates multiple proteins, including KHDC3L, NLRP5, TLE6, OOEP, NLRP2, and PADI6. The NLRP5 (also known as MATER) has been extensively studied. In humans, inactivating variants in specific NLRP genes in the mother are associated with distinct phenotypes in the offspring, such as biparental hydatidiform moles (BiHMs) and preterm birth. Maternal-effect recessive mutations in KHDC3L and NLRP5 (and NLRP7) are associated with reduced reproductive outcomes, BiHM, and broad multilocus imprinting perturbations. The precise mechanisms of NLRPs are unknown, but research strongly indicates their pivotal roles in the establishment of genomic imprints and post-zygotic methylation maintenance, among other processes. Challenges for the future include translations of findings from the mouse model into human contexts and implementation in therapies and clinical fertility management.
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NLRP7 or khdc3l genes and the etiology of molar pregnancies and recurrent miscarriage
Molecular Human Reproduction, 2013Co-Authors: L Andreasen, Lone Sunde, Lars Bolund, Isa Niemann, Ole Bjarne ChristiansenAbstract: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 andro- genetic 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 patho- genic effect on the affected woman) in NLRP7 or C6orf221/KHDC3L in any of the women in the study group. This indicates that recurrent mis- carriages 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.
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mosaic moles and non familial biparental moles are not caused by mutations in NLRP7 nlrp2 or c6orf221
Molecular Human Reproduction, 2012Co-Authors: Lone Sunde, Lotte Andreasen, Lars Bolund, Isa Niemann, Estrid S HansenAbstract:Hydatidiform moles (HMs) most often occur sporadically and are either diploid androgenetic or triploid. The very rare fa- milial 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 ,a ndC6orf221. 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.