| NLR family pyrin domain containing 5 | OKDB#: 96 |
| Symbols: | NLRP5 | Species: | human | ||
| Synonyms: | MATER, NALP5, PAN11, PYPAF8, CLR19.8 | Locus: | 19q13.43 in Homo sapiens |
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| General Comment |
OP-1 is a just recently discovered 125 kDa protein located in the oocyte cytoplasm. It is not related to osteogenic protein-1 (OP-1=BMP-7). Tong and Nelson (1999) discovered a 3.75-kb ovarian transcript by screening a mouse ovarian complementary DNA expression library with autoimmune serum obtained from thymectomized mice. MATER (Maternal Antigen That Embryos Require) is an ooplasm-specific protein
first identified as an antigen (OP1) associated with ovarian autoimmunity in mice. Its primary structure has been deduced from full-length cDNA that
encodes a 125-kDa protein required for progression of the mouse embryo beyond
two cells. Expression of the gene encoding MATER is restricted to the oocyte,
which makes it one of a growing, but still limited, number of maternal-effect
genes in mammals. This is a maternal effect gene.//////////NOD-like receptors interfacing the immune and reproductive systems. Gorp HV 2014 et al.
NOD-like receptors (NLRs) are intracellular proteins that are chiefly known for their critical functions in inflammatory responses and host defense against microbial pathogens. Several NLRs have been demonstrated to assemble inflammasomes or to engage transcriptional signaling cascades that result in the production of pro-inflammatory cytokines and bactericidal factors. In recent years, NLRs have also emerged as key regulators of early mammalian embryogenesis and reproduction. A subset of phylogenetically-related NLRs represents a new class of maternal effect genes that are highly expressed in maturing oocytes and pre-implantation embryos. Mutations in several of these NLRs have been linked to hereditary reproductive defects and imprinting diseases. In this review, we will discuss the expression profiles, the emerging functions and molecular mode of action of these NLRs with newly recognized roles at the interfaces of the immune and reproductive systems. In addition, we provide an overview of coding mutations in NLRs that have been associated with human reproductive diseases, and outline crucial outstanding questions in this emerging research field. This article is protected by copyright. All rights reserved.
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NCBI Summary: The protein encoded by this gene belongs to the NALP protein family. Members of the NALP protein family typically contain a NACHT domain, a NACHT-associated domain (NAD), a C-terminal leucine-rich repeat (LRR) region, and an N-terminal pyrin domain (PYD). Expression of this gene is restricted to the oocyte. A mouse gene that encodes a maternal oocyte protein, similar to this encoded protein, is required for normal early embryogenesis. [provided by RefSeq, Jul 2008] |
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| General function |
Cell proliferation
, Epigenetic modifications |
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| Comment | Autoantibody response against NALP5/MATER in primary ovarian insufficiency and in autoimmune Addison's disease. Brozzetti A et al. (2015) NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) is an autoantigen in hypoparathyroidism associated with autoimmune polyendocrine syndrome type 1 (APS1) but is also expressed in the ovary. Mater is an autoantigen in experimental autoimmune oophoritis. The objectives of the study were to determine the frequency of NALP5/MATER autoantibodies (NALP5/MATER-Ab) in women with premature ovarian insufficiency (POI) and in patients with autoimmune Addison's disease (AAD) and to evaluate whether inhibin chains are a target for autoantibodies in POI. Autoantibodies against NALP5/MATER and inhibin chains-α and -βA were determined by radiobinding assays in 172 patients with AAD without clinical signs of gonadal insufficiency, 41 women with both AAD and autoimmune POI steroidogenic cell autoimmune POI (SCA-POI)], 119 women with idiopathic POI, 19 patients with APS1, and 211 healthy control subjects. NALP5/MATER-Ab were detected in 11 of 19 (58%) sera from APS1 patients, 12 of 172 (7%) AAD sera, 5 of 41 (12%) SCA-POI sera, 0 of 119 idiopathic POI sera and 1 of 211 healthy control sera (P < .001). None of 160 POI sera, including 41 sera from women with SCA-POI and 119 women with idiopathic POI, and none of 211 healthy control sera were positive for inhibin chain-α/βA autoantibodies. NALP5/MATER-Ab are associated with hypoparathyroidism in APS1 but are present also in patients with AAD and in women with SCA-POI without hypoparathyroidism. Inhibin chains do not appear to be likely candidate targets of autoantibodies in human POI.////////////////// [Tong ZB, et al 2000 reported that Mater encodes a maternal protein in mice with a leucine-rich repeat domain homologous to porcine ribonuclease inhibitor. Human MATER localization in specific cell domains of oocytes and follicular cells. Sena P et al. MATER (Maternal Antigen That Embryos Require) is an oocyte-specific protein dependent on the maternal genome and required for early embryonic development. The gene products expressed in oocytes play important roles in folliculogenesis, fertilization and pre-implantation development. The aim of this study was to characterize the localization and distribution pattern of the human MATER protein during follicular development and after ovulation, to determine its functional role. Immunocytochemistry experiments coupled with confocal and electron microscopy analysis were carried out to determine the ultrastructural localization of MATER in human ovarian tissue and in isolated oocytes, obtained during IVF procedures. Human cumulus cells were cultured, with or without cycloheximide, to confirm endogenous biosynthesis of the protein. Human MATER is detectable at the onset of the follicular maturation process, suggesting this protein has a role at earlier stages in the human compared with other mammalian species. The presence of MATER is specific to the oocyte and follicular cells that, during maturation, are spatially and functionally associated with the oocyte. The nuclear, nucleolar and mitochondrial localization hints at a possible role in RNA processing and the metabolic activity of the cell. | ||||
| Cellular localization | Nuclear, Mitochondrial | ||||
| Comment | NLRP5 Mediates Mitochondrial Function in Mouse Oocytes and Embryos. Fernandes R et al. Unravelling molecular pathways responsible for regulation of early embryonic development is crucial for our understanding of female infertility. Maternal determinants that control the transition from oocyte to embryo are crucial molecules that govern developmental competence of the newly conceived zygote. We describe a series of defects that are triggered by a disruption of maternal lethal effect gene, Nlrp5. Previous studies have shown that Nlrp5 hypomorph embryos fail to develop beyond the 2-cell stage. Despite its importance in pre-implantation development, the mechanism by which the embryo arrest occurs remains unclear. We confirmed that Nlrp5 mutant and wild-type females possess comparable ovarian germ pool, and follicular recruitment rates. However, ovulated oocytes lacking Nlrp5 have abnormal mitochondrial localization and increased activity in order to sustain physiological ATP content. This results in an accumulation of reactive oxygen species and increased cellular stress causing mitochondrial depletion. Compromised cellular state is also accompanied by increased expression of cell death inducer Bax and depletion of cytochrome C. However, neither genetic deletion (Bax/Nlrp5 double knockout) nor mimetic interference (BH4 domain or Bax inhibitory peptide) were sufficient to alleviate embryo demise caused by depletion of Nlrp5. We therefore conclude that lack of Nlrp5 in oocytes triggers premature activation of the mitochondrial pool, causing mitochondrial damage that cannot be rescued by inactivation of Bax. Tong ZB, et al show the expressional profile of Mater and its protein during oogenesis and embryogenesis as well as its subcellular localization in oocytes. Mater mRNA was detectable earliest in oocytes of type 2 follicles, whereas MATER protein appeared earliest in oocytes of type 3a primary follicles. Both mRNA and protein accumulated during oocyte growth. In situ hybridization showed that Mater mRNA appeared progressively less abundant in oocytes beyond type 5a primary follicles. By ribonuclease protection assay, Mater mRNA was abundant in germinal vesicle oocytes, but was undetectable in all stages of preimplantation embryos. In contrast, the protein persisted throughout preimplantation development. Immunogold electron microscopic analysis revealed that MATER was located in oocyte mitochondria and nucleoli, and close to nuclear pores. Taken together, our data indicate that Mater gene transcription and protein translation are active during oogenesis, but appear inactive during early embryogenesis. Thus, Mater and its protein are expressed in a manner typical of maternal effect genes. The presence of MATER protein in mitochondria and nucleoli suggests that it may participate in both cytoplasmic and nuclear events during early development. | ||||
| Ovarian function | Oocyte growth, Oocyte maturation, Early embryo development | ||||
| Comment | Differing molecular response of young and advanced maternal age human oocytes to IVM. Reyes JM et al. (2017) What effect does maternal age have on the human oocyte's molecular response to in vitro oocyte maturation? Although polyadenylated transcript abundance is similar between young and advanced maternal age (AMA) germinal vesicle (GV) oocytes, metaphase II (MII) oocytes exhibit a divergent transcriptome resulting from a differential response to in vitro oocyte maturation. Microarray studies considering maternal age or maturation stage have shown that either of these factors will affect oocyte polyadenylated transcript abundance in human oocytes. However, studies considering both human oocyte age and multiple stages simultaneously are limited to a single study that examined transcript levels for two genes by qPCR. Thus, polyadenylated RNA sequencing (RNA-Seq) could provide novel insight into age-associated aberrations in gene expression in GV and MII oocytes. The effect of maternal age (longitudinal analysis) on polyadenylated transcript abundance at different stages was analyzed by examining single GV and single in vitro matured MII oocytes derived from five young (YNG; < 30 years; average age 26.8; range 20-29) and five advanced maternal age (AMA; ≥40 years; average age 41.6 years; range 40-43 years) patients. Thus, a total of 10 YNG (5 GV and 5 MII) and 10 AMA (5 GV and 5 MII) oocytes were individually processed for RNA-Seq analysis. Patients undergoing infertility treatment at the Colorado Center for Reproductive Medicine (Lone Tree, CO, USA) underwent ovarian stimulation with FSH and received hCG for final follicular maturation prior to ultrasound guided oocyte retrieval. Unused GV oocytes obtained at retrieval were donated for transcriptome analysis. Single oocytes were stored (at -80°C in PicoPure RNA Extraction Buffer; Thermo Fisher Scientific, USA) immediately upon verification of immaturity or after undergoing in vitro oocyte maturation (24 h incubation), representing GV and MII samples, respectively. After isolating RNA and generating single oocyte RNA-Seq libraries (SMARTer Ultra Low Input RNA HV kit; Clontech, USA), Illumina sequencing (100 bp paired-end reads on HiSeq 2500) and bioinformatics analysis (CLC Genomics Workbench, DESeq2, weighted gene correlation network analysis (WGCNA), Ingenuity Pathway Analysis) were performed. A total of 12 770 genes were determined to be expressed in human oocytes (reads per kilobase per million mapped reads (RPKM) > 0.4 in at least three of five replicates for a minimum of one sample type). Differential gene expression analysis between YNG and AMA oocytes (within stage) identified 1 and 255 genes that significantly differed (adjusted P < 0.1 and log2 fold change >1) in polyadenylated transcript abundance for GV and MII oocytes, respectively. These genes included CDK1, NLRP5 and PRDX1, which have been reported to affect oocyte developmental potential. Despite the similarity in transcript abundance between GV oocytes irrespective of age, divergent expression patterns emerged during oocyte maturation. These age-specific differentially expressed genes were enriched (FDR < 0.05) for functions and pathways associated with mitochondria, cell cycle and cytoskeleton. Gene modules generated by WGCNA (based on gene expression) and patient traits related to oocyte quality (e.g. age and blastocyst development) were correlated (P < 0.05) and enriched (FDR < 0.05) for functions and pathways associated with oocyte maturation. Raw data from this study can be accessed through GSE95477. The human oocytes used in the current study were obtained from patients with varying causes of infertility (e.g. decreased oocyte quality and oocyte quality-independent factors), possibly affecting oocyte gene expression. Oocytes in this study were retrieved at the GV stage following hCG administration and the MII oocytes were derived by IVM of patient oocytes. Although the approach has the benefit of identifying intrinsic differences between samples, it may not be completely representative of in vivo matured oocytes. Transcriptome profiles of YNG and AMA oocytes, particularly at the MII stage, suggest that aberrant transcript abundance may contribute to the age-associated decline in fertility. J.M.R. was supported by an Austin Eugene Lyons Fellowship awarded by the University of California, Davis. The Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (awarded to P.J.R.; R01HD070044) and the Fertility Laboratories of Colorado partly supported the research presented in this manuscript.////////////////// The role of MATER in endoplasmic reticulum distribution and calcium homeostasis in mouse oocytes. Kim B 2014 et al. Ca(2+) oscillations are a hallmark of mammalian fertilization and play a central role in the activation of development. The calcium required for these oscillations is primarily derived from the endoplasmic reticulum (ER), which accumulates in clusters at the microvillar subcortex during oocyte maturation. The migration of the ER to the cortex during maturation is thought to play an important role in rendering the ER competent to generate the calcium transients, and the redistribution of ER is believed to be primarily mediated by microtubules and microfilaments. We have previously shown that the oocyte- and early embryo-restricted maternal effect gene Mater (Nlrp5) localizes to, and is required for, formation of the oocyte cytoplasmic lattices, a tubulin-containing structure that appears to play an important role in organelle positioning and distribution during oocyte maturation. Given these observations, we hypothesized that Mater may also be required for ER redistribution and Ca(2+) homeostasis in oocytes. To test this hypothesis, we first investigated ER localization in metaphase-II Mater(tm/tm) (hypomorph) oocytes and found ER clusters to be less abundant at the microvillar cortex when compared to wild type oocytes. To examine the potential mechanisms by which MATER mediates ER redistribution, we tested whether tubulin expression levels and localization were affected in the mutant oocytes and found that the Triton-insoluble fraction of tubulin was significantly decreased in Mater(tm/tm) oocytes. To identify potential functional defects associated with these ER abnormalities, we next set out to investigate if the pattern of Ca(2+) oscillations was altered in Mater(tm/tm) oocytes after fertilization in vitro. Intriguingly, Ca(2+) oscillations in Mater(tm/tm) oocytes exhibited a significantly lower first peak amplitude and a higher frequency when compared to wild type oocytes. We then found that the Ca(2+) oscillation defect in Mater(tm/tm) oocytes was likely caused by a reduced amount of Ca(2+) in the ER stores. Taken together, these observations support the hypothesis that MATER is required for ER distribution and Ca(2+) homeostasis in oocytes, likely due to defects in lattice-mediated ER positioning and/or redistribution. ///////////////////////// and quantification of maternal-effect gene transcripts in mouse second polar bodies: potential markers of embryo developmental competence. Jiao ZX et al. OBJECTIVE: To test the hypothesis that quantification of messenger RNAs originating from the second polar body (PB2) provides a noninvasive tool for assessing embryo quality. DESIGN: Prospective study. SETTING: Hospital-based academic research laboratory. ANIMAL(S): CD1 female mice. INTERVENTION(S): Metaphase II oocytes obtained from 7- to 8-week-old mice after pregnant mare's serum gonadotropin and hCG priming. After in?vitro fertilization, the PB2 was biopsied from zygote, followed by reverse transcription. Real-time polymerase chain reaction was performed to quantify gene expression levels in single PB2. The sibling zygotes were continuously cultured to blastocyst stage. MAIN OUTCOME MEASURE(S): Embryo developmental competence and six maternal-effect gene (Dnmt1, Mater, Nobox, Npm2, Tcl1, and Zar1) transcripts in the PB2. RESULT(S): Second polar body messenger RNA was detected in all candidate genes. Transcripts that were present in greater abundance in the zygote were more likely to be detected in quantitative polymerase chain reaction replicates from single PB2. Four candidate genes (Dnmt1, Nobox, Npm2, and Tcl1) expression levels in PB2 between two groups (two-cell embryo vs. blastocyts) approached statistical significance. CONCLUSION(S): Second polar bodies may contain a representative transcript profile to that of the zygote after fertilization. Differences in gene expression in PB2 may be potential biomarkers of embryo quality. In silico identification and structural features of six new genes similar to MATER specifically expressed in the oocyte Dade S, et al . In the present work, we have used the in silico subtraction methodology to identify six new mouse genes similar to NALP5/MATER, whose ESTs were represented almost exclusively in egg libraries. Five genes were selected for RT-PCR and/or in situ hybridization. These experiments confirmed their oocyte restricted expression. Five of these genes are localized on mouse chromosome 7, as is NALP5/MATER; among them, three are localized in a 300kb cluster. Potential Role for MATER in Cytoplasmic Lattice Formation in Murine Oocytes. Kim B et al. BACKGROUND: Mater and Padi6 are maternal effect genes that are first expressed during oocyte growth and are required for embryonic development beyond the two-cell stage in the mouse. We have recently found that PADI6 localizes to, and is required for the formation of, abundant fibrillar Triton X-100 (Triton) insoluble structures termed the oocyte cytoplasmic lattices (CPLs). Given their similar expression profiles and mutant mouse phenotypes, we have been testing the hypothesis that MATER also plays a role in CPL formation and/or function. METHODOLOGY/FINDINGS: Herein, we show that PADI6 and MATER co-localize throughout the oocyte cytoplasm following Triton extraction, suggesting that MATER co-localizes with PADI6 at the CPLs. Additionally, the solubility of PADI6 was dramatically increased in Mater(tm/tm) oocytes following Triton extraction, suggesting that MATER is involved in CPL nucleation. This prediction is supported by transmission electron microscopic analysis of Mater(+/+) and Mater(tm/tm) germinal vesicle stage oocytes which illustrated that volume fraction of CPLs was reduced by 90% in Mater(tm/tm) oocytes compared to Mater(+/+) oocytes. CONCLUSIONS: Taken together, these results suggest that, similar to PADI6, MATER is also required for CPL formation. Given that PADI6 and MATER are essential for female fertility, these results not only strengthen the hypothesis that the lattices play a critical role in mediating events during the oocyte-to-embryo transition but also increase our understanding of the molecular nature of the CPLs. | ||||
| Expression regulated by | |||||
| Comment | MATER PROTEIN AS SUBSTRATE OF PKC{epsilon} IN HUMAN CUMULUS CELLS. Maraldi T et al. High activity of the phosphoinositide (PI) 3-kinase/Akt pathway in cumulus cells plays an important role in FSH regulation of cell function and Protein Kinase C epsilon (PKCepsilon) collaborates with these signalling pathways to regulate cell proliferation. Relevant roles in follicular development are played by MATER (Maternal Antigen That Embryos Require) that is a cumulus cell- and oocyte-specific protein dependent on the maternal genome. We recently demonstrated that human MATER localizes at specific domains of oocytes and, for the first time, also in cumulus cells. MATER contains a carboxy-terminal leucine-rich repeat domain involved in protein-protein interactions regulating different cellular functions. Here we investigated the functional role of MATER. Thus, we performed coimmunoprecipitation experiments using HEK293T cells expressing human MATER; a similar approach was then followed in human cumulus/follicular cells. In Mater(+)HEK293T cells, we observed that this protein acts as a phosphorylation substrate of PKCepsilon. Western blot experiments indicate that, unlike oocytes, human cumulus cells express PKCepsilon. Immunoprecipitation and confocal analysis suggest for the first time that MATER protein interacts with this protein kinase, in cumulus cells under physiological conditions. Since PKCepsilon is known to collaborate with antiapoptotic signalling pathways this suggests a novel mechanism for the function of MATER in follicular maturation. | ||||
| Ovarian localization | Oocyte | ||||
| Comment | OP-1 expression is restricted to the oocyte Tong and Nelson (1999). . Bovine NALP5, NALP8, and NALP9 genes: assignment to a QTL region and the expression in adult tissues, oocytes, and preimplantation embryos. Ponsuksili S et al. A 3204-bp full-length cDNA of bovine NALP9 was cloned and its genomic organization was analyzed. The 2988-bp open reading frame covers 9 exons and encodes a deduced protein of 996 amino acids containing Pyrin, Nacht and leucine-rich repeat domains like the human NALP gene family members. Mapping with the WGRH5000 panel and fluorescence in situ hybridization assigned NALP9 in close vicinity to BM2078 (LOD score 25.71; distance 0.0 cR5000) on bovine chromosome 18, BTA18q25-q26, within a previously identified QTL region for reproductive traits flanked by the bovine marker BM2078 and TGLA227. BAC contig analysis revealed that NALP9, NALP8, and NALP5 map in this QTL region. Temporospatial expression of these members of the NALP gene family was monitored. Among the adult tissues examined, transcripts of NALP8 and NALP9 were detected exclusively in testis and ovary, whereas transcripts of the NALP5 gene are limited to the ovary. The transcripts of NALP9, NALP8, and NALP5 were detected in oocytes before and after in vitro maturation and with a gradual decline from 2-cell to 8-cell stage, suggesting no reactivation at the time of bovine maternal to embryonic transition. Assignment to a QTL region for reproductive traits and preferential expression of NALP9, NALP8, and NALP5 in oocyte, germinal lineage, and gonad cells may suggest their functional relevance to reproduction and possible contribution to phenotypic variation. | ||||
| Follicle stages | Primordial, Primary, Secondary | ||||
| Comment | Tong ZB, et al show the expressional profile of Mater and its protein during oogensis and embryogenesis as well as its subcellular localization in oocytes. Mater mRNA was detectable earliest in oocytes of type 2 follicles, while MATER protein appeared earliest in oocytes of type 3a primary follicles. Both mRNA and protein accumulated during oocyte growth. In situ hybridization showed that Mater mRNA appeared progressively less abundant in oocytes beyond type 5a primary follicles. By RNase protect assay, Mater mRNA was abundant in GV oocytes, but was undetectable in all stages of preimplantation embryos. In contrast, the protein persisted throughout preimplantation development. Immuno-gold electron microscopic analysis revealed that MATER was located in oocyte mitochondria, nucleoli, and close to nuclear pores. Taken together, our data indicate that Mater gene transcription and protein translation are active during oogenesis but appear inactive during early embryogenesis. Thus, Mater and its protein are expressed in a manner typical of maternal effect genes. The presence of MATER protein in mitochondria and nucleoli suggests that it may participate in both cytoplasmic and nuclear events during early development. MATER protein expression and intracellular localization throughout bovine folliculogenesis and preimplantation embryo development. Pennetier S et al. ABSTRACT: BACKGROUND: Mater (Maternal Antigen that Embryos Require), also known as Nalp5 (NACHT, leucine rich repeat and PYD containing 5), is an oocyte-specific maternal effect gene required for early embryonic development beyond the two-cell stage in mouse. We previously characterized the bovine orthologue MATER as an oocyte marker gene in cattle, and this gene was recently assigned to a QTL region for reproductive traits. RESULTS: Here we have analyzed gene expression during folliculogenesis and preimplantation embryo development. In situ hybridization and immunohistochemistry on bovine ovarian section revealed that both the transcript and protein are restricted to the oocyte from primary follicles onwards, and accumulate in the oocyte cytoplasm during follicle growth. In immature oocytes, cytoplasmic, and more precisely cytosolic localization of MATER was confirmed by immunohistochemistry coupled with confocal microscopy and immunogold electron microscopy. MATER protein persisted after fertilization up until the blastocyst stage, and was mostly degraded after hatching. A similar predominantly cytoplasmic localization was observed in blastomeres from embryos up to 8-cells, with an apparent concentration near the nuclear membrane. CONCLUSION: Altogether, these expression patterns are consistent with bovine MATER protein being an oocyte specific maternal effect factor as in mouse. | ||||
| Phenotypes | |||||
| Mutations |
8 mutations
Species: mouse
Species: mouse
Species: porcine
Species: other
Species: mouse
Species: human
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | Aug. 12, 1999, midnight | by: |
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| last update: | Oct. 21, 2020, 10:14 a.m. | by: | hsueh email: |
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