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NLR FAMILY, PYRIN DOMAIN-CONTAINING 7; NLRP7

NLR FAMILY, PYRIN DOMAIN-CONTAINING 7; NLRP7

Alternative titles; symbolsNACHT DOMAIN-, LEUCINE-RICH REPEAT-, AND PYD-CONTAINING PROTEIN 7; NALP7PYRIN DOMAIN-CONTAINING APAF1-LIKE PROTEIN 3; PYPAF3NOD12HGNC ...

Alternative titles; symbols

  • NACHT DOMAIN-, LEUCINE-RICH REPEAT-, AND PYD-CONTAINING PROTEIN 7; NALP7
  • PYRIN DOMAIN-CONTAINING APAF1-LIKE PROTEIN 3; PYPAF3
  • NOD12

HGNC Approved Gene Symbol: NLRP7

Cytogenetic location: 19q13.42 Genomic coordinates (GRCh38): 19:54,923,508-54,965,183 (from NCBI)

▼ Description
NALPs are cytoplasmic proteins that form a subfamily within the larger CATERPILLER protein family. Most short NALPs, such as NALP7, have an N-terminal pyrin (MEFV; 608107) domain (PYD), followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region. The long NALP, NALP1 (606636), also has a C-terminal extension containing a function to find domain (FIIND) and a caspase recruitment domain (CARD). NALPs are implicated in the activation of proinflammatory caspases (e.g., CASP1, 147678) via their involvement in multiprotein complexes called inflammasomes (Tschopp et al., 2003).

▼ Cloning and Expression
By microarray analysis of genes overexpressed in testicular germline tumors and semiquantitative RT-PCR analysis, Okada et al. (2004) identified NLRP7, which they termed NALP7. They obtained 3 NALP7 variants resulting from alternative splicing of exons 5, 9, and 10. Only NALP7 variant-1, which encodes a protein with PYD, NACHT, NAD, and LRR domains, was upregulated in seminomas. Northern blot analysis using a probe common to all 3 variants detected a 3.3-kb transcript in testis only. Immunoblot analysis showed expression in an embryonal carcinoma line. Immunohistochemistry demonstrated high expression in seminomas and weak expression in normal testicular germ cells.

Using RT-PCR analysis, Kinoshita et al. (2005) detected expression of NALP7 in all tissues tested except heart, brain, and skeletal muscle. NALP7 expression was also detected in most cell lines examined.

Mahadevan et al. (2014) stated that NLRP7 is highly expressed in oocytes and early human embryos and that it has no rodent ortholog. They found that transfection and overexpression of NLRP7 in HEK293T cells resulted in NLRP7 expression in both the nucleus and cytoplasm.

▼ Gene Structure
Okada et al. (2004) determined that the NLRP7 gene contains 11 exons. Alternative exons exist for exons 5 and 9.

▼ Mapping
By genomic sequence analysis, Okada et al. (2004) mapped the NLRP7 gene to chromosome 19q13.4, within a cluster of several other NLRP genes.

▼ Gene Function
Okada et al. (2004) found that knockdown of NALP7 by RNA interference reduced the growth of a carcinoma cell line. They concluded that NALP7 may play a crucial role in cell proliferation.

Using luciferase reporter analysis, Kinoshita et al. (2005) found that NALP2 (609364) inhibited NFKB (see 164011) activation induced by the combined expression of NALP3 (606416) and ASC (PYCARD; 606838), whereas NALP7 showed little such activity. In contrast, NALP7, but not NALP3, inhibited CASP1-dependent IL1B (147720) secretion by interacting with and inhibiting processing of pro-IL1B and pro-CASP1. Lipopolysaccharide stimulation of hemopoietic cell lines enhanced expression of NALP7, but not NALP2, and NALP7 inhibited endogenous production of IL1B in a monocyte cell line. Kinoshita et al. (2005) proposed that NALP7 is a feedback regulator of CASP1-dependent IL1B secretion.

Using protein pull-down and coimmunoprecipitation analyses of cotransfected HEK293T cells, Mahadevan et al. (2014) found that GST-tagged NLRP7 interacted with epitope-tagged YY1 (600013), a transcription factor that binds to imprinted differentially methylated regions (DMRs) in a methylation-dependent manner. Knockdown of NLRP7 via short hairpin RNA accelerated differentiation of human embryonic stem cells (hESCs) into trophoblasts and increased the secretion of chorionic gonadotropin (see 118850). Mahadevan et al. (2014) noted that increased cell proliferation and high chorionic gonadotropin production are characteristics of molar pregnancies. Knockdown of NLRP7 altered methylation patterns at multiple loci, predominantly at CpG islands. Most changes were related to hypermethylation, but methylation at germline DMRs was generally unchanged. Mahadevan et al. (2014) concluded that NLRP7 has an important noninflammasome function affecting DNA methylation, possibly in conjunction with YY1.

Nguyen et al. (2014) found variable expression of CDKN1C (600856) in 35 conceptuses from 17 patients with HYDM1 due to biallelic mutations in the NLRP7 gene. Of the informative samples, 19 (59%) did not express CDKN1C and 13 (41%) displayed variable levels (20-100%) of CDKN1C. All tissue contained a diploid biparental genome. Some NLRP7 missense mutations did not completely repress CDKN1C expression, and these samples were associated with the presence of embryonic tissue of inner cell mass origin, mild trophoblastic proliferation, and low expression of CDKN1C. In contrast, truncating NLRP7 mutations were associated with lack of CDKN1C expression, absence of embryonic tissue of inner cell mass origin, and the presence of excessive trophoblastic proliferation. The findings suggested that NLRP7 regulates the imprinted expression of CDKN1C and consequently the balance between tissue differentiation and proliferation during early human development.

▼ Molecular Genetics
Recurrent Hydatidiform Mole 1

Hydatidiform mole (see 231090) is an abnormal human pregnancy with no embryo and cystic degeneration of placental villi. Moglabey et al. (1999) mapped a maternal recessive locus responsible for familial hydatidiform moles to 19q13.4 (HYDM1; 231090). Murdoch et al. (2006) fine-mapped the hydatidiform mole candidate region to 0.65 Mb and identified 5 mutations in the maternal gene NALP7 in individuals with familial and recurrent hydatidiform moles (609661.0001-609661.0005, respectively).

NALP7 is a negative regulator of interleukin-1-beta (IL1B; 147720), a pleiotropic cytokine that activates a number of immunologic and inflammatory pathways. IL1-beta is abundant in the uterine milieu during the periimplantation period, during which it facilitates the implantation of the blastocyst, regulates the protease network and controls the extent to which the trophoblast may invade the endometrium. Deregulation of the inflammatory pathways in the reproductive tract or the uterus of women with defects in NALP7 would explain the wide variability in the phenotype of their conceptuses, mainly late spontaneous abortions, stillbirths, and normal pregnancies with intrauterine growth defect (Murdoch et al., 2006).

Djuric et al. (2006) analyzed molar tissues from 2 Lebanese sisters, in whom Murdoch et al. (2006) previously identified a splice site mutation in the NALP7 gene (609661.0001), and demonstrated normal postzygotic DNA methylation patterns at major repetitive and long interspersed nuclear elements, genes on the inactive X chromosome, 3 cancer-related genes, and CpG-rich areas surrounding the PEG3 (601483) differentially methylated region (DMR). Djuric et al. (2006) concluded that postzygotic DNA methylation and de novo methylation are normal in familial hydatidiform moles with defects in NALP7, and that abnormal DNA methylation in these tissues is restricted to imprinted DMRs.

Deveault et al. (2009) reported 10 novel nonsynonymous variants/mutations and 1 novel truncation mutation (609661.0006) of the NLRP7 gene in sporadic and familial patients with hydatidiform mole. Diploid biparental, diploid androgenetic, triploid, and tetraploid conceptions were seen in patients. In vitro and in vivo early embryo cleavage abnormalities were documented in 3 patients. The authors proposed a 2-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 may then be subject to the maternal immune response. Because of the patients' impaired inflammatory response, androgenetic cells, which are complete allograft, may grow and proliferate.

Wang et al. (2009) analyzed the NLRP7 gene in affected individuals from 20 families with a confirmed diagnosis of familial recurrent hydatidiform mole and identified 16 different mutations in 17 of the families (see, e.g., 609661.0003-609661.0012). Affected members from 14 of the 17 mutation-positive families were homozygous for the identified mutation, even though only 1 family reported consanguinity. Wang et al. (2009) noted that 3 different mutations had been identified at codon 693 (R693W, 609661.0003; R693P, 609661.0004; and R693Q, 609661.0008), suggesting that position 693, located in the C-terminal LRR domain, represents a hotspot for mutation in the NLRP7 gene.

In 10 unrelated Indian women with recurrent hydatidiform moles and reproductive wastage, Slim et al. (2009) analyzed the NLRP7 gene and identified homozygosity or compound heterozygosity for the R693P and N913S (609661.0005) mutations in 7 patients. Haplotype analysis showed a common haplotype carrying each of the mutations, demonstrating a strong founder effect for both mutations in the Indian population; this was further supported by the fact that 4 of the patients were homozygotes despite the absence of known consanguinity between their parents. The brother of 1 of the probands, who had 1 child and no reproductive problems, was found to be compound heterozygous for the R693P and N913S mutations; Slim et al. (2009) stated that he was the third reported male patient with 2 mutations in NLRP7 and no reproductive problems.

In a Danish woman with a biparental diploid hydatidiform mole, Andreasen et al. (2012) identified homozygosity for a splice site mutation in the NLRP7 gene (609661.0001).

Fallahian et al. (2013) performed genetic analysis of tissue from the complete hydatidiform mole pregnancies of a woman who was previously studied by Wang et al. (2009) and found to be homozygous for a 14-bp duplication in the NLRP7 gene (609661.0011). Her first and third were diploid biparental HYDMs, whereas the second was a digynic triploid conceptus, with 1 paternal and 2 maternal alleles. Fallahian et al. (2013) stated that these findings were consistent with a role for NLRP7 in setting and/or maintaining the maternal imprint.

Possible Association with Recurrent Pregnancy Loss

Huang et al. (2013) analyzed SNPs in the NLRP7 gene in 143 Taiwanese Han women with recurrent miscarriages (see 614389) and identified 1 SNP, rs269949, that showed a significant difference between patients and controls in a recessive model (p = 0.0456; odds ratio = 16.49 for the GG genotype).

Aghajanova et al. (2015) analyzed the NLRP7 gene in 24 women with a mean of 4.7 miscarriages of unknown etiology, 22 of Caucasian origin and 2 of Asian origin, as well as in 94 Swedish or Finnish women with primary unexplained infertility, but identified no disease-causing mutations in either group.

▼ ALLELIC VARIANTS ( 12 Selected Examples):

.0001 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, IVS3DS, G-A, +1
In the Lebanese family originally reported by Vejerslev et al. (1991), Murdoch et al. (2006) found that recurrent hydatidiform moles (HYDM1; 231090) were associated with a homozygous donor splice site mutation, IVS3+1G-A, in the NALP7 gene. Stillbirth, spontaneous abortion at 7 to 20 weeks, both complete and partial hydatidiform mole, and persistent trophoblastic disease were also observed in this family, which had been reported by Moglabey et al. (1999).

In a Danish woman with biparental diploid hydatidiform mole, who was born of consanguineous parents, Andreasen et al. (2012) identified homozygosity for the IVS3+1G-A mutation in the NLRP7 gene. The woman had a positive family history and had experienced 7 HYDMs.

.0002 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, IVS7DS, G-A, +1
In a Pakistani family, Murdoch et al. (2006) observed that recurrent hydatidiform moles (HYDM1; 231090) were associated with homozygosity for a G-to-A transition in the intron 7 donor splice site (2471+1G-A) in the NALP7 gene, resulting in premature termination. Spontaneous abortion also occurred in this family.

.0003 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, ARG693TRP
In a German family, Murdoch et al. (2006) found homozygosity for an arg693-to-trp (R693W) mutation in the NALP7 gene as the basis of recurrence of complete hydatidiform mole (HYDM1; 231090). The amino acid substitution resulted from a 2077C-T transition in exon 5.

In 2 unrelated Caucasian probands with recurrent hydatidiform mole pregnancies, 1 of whom was previously reported by Ozalp et al. (2001), Wang et al. (2009) identified homozygosity for the R693W mutation in the NLRP7 gene. The mutation was not found in 390 unrelated control chromosomes.

.0004 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, ARG693PRO
In an Indian family reported by Agarwal et al. (2004), Murdoch et al. (2006) found that recurrent hydatidiform moles (HYDM1; 231090) were associated with homozygosity for a 2078G-C transversion in exon 5 of the NALP7 gene that resulted in an arg693-to-pro (R693P) substitution. Amino acid arg693 is a conserved residue in chimpanzee and cow NALP7 as well as in human, cow, and dog NALP2 (609364).

In 2 Asian sisters with recurrent complete hydatidiform mole pregnancies, Wang et al. (2009) identified homozygosity for the R693P mutation in the NLRP7 gene. Their brother, who was also homozygous for the mutation, had a normal son. In another Asian proband with recurrent HYDM, Wang et al. (2009) identified homozygosity for R693P as well as a single copy of the N913S mutation in the NLRP7 gene (609661.0005). Analysis of family members confirmed inheritance of R693P from her mother and both R693P and N913S from her father. In addition, a Caucasian HYDM proband was found to be compound heterozygous for R693P and a frameshift mutation in NLRP7 (609661.0007). None of the mutations were found in 390 unrelated control chromosomes.

Of 10 Indian probands with recurrent hydatidiform moles and reproductive wastage, Slim et al. (2009) identified 3 who were homozygous for R693P and 3 who were compound heterozygous for the R693P and N913S mutations. Haplotype analysis revealed a strong founder effect for both mutations in the Indian population. The brother of 1 proband was found to be compound heterozygous for R693P and N913S, although he had 1 child and no reproductive problems. Slim et al. (2009) stated that he was the third reported male patient with 2 mutations in NLRP7 and no reproductive problems.

.0005 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, ASN913SER
In a single Indian patient with recurrent hydatidiform moles (HYDM1; 231090), Murdoch et al. (2006) found compound heterozygosity for 2 mutations of the NALP7 gene: R693P in exon 5 (609661.0004) and asn913-to-ser (N913S) in exon 9. The N913S substitution arose from a 2738A-G transition.

For discussion of the N913S mutation in the NLRP7 gene that was found in compound heterozygous state in a patient with HYDM by Wang et al. (2009), see 609661.0004.

Of 10 Indian probands with recurrent hydatidiform moles and reproductive wastage, Slim et al. (2009) identified 1 who was homozygous for the N913S mutation in the NLRP7 gene and 3 who were compound heterozygous for the N913S and R693P mutations. Haplotype analysis revealed a strong founder effect for both mutations in the Indian population.

.0006 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, ARG432TER
In affected members of a Chinese family with recurrent hydatidiform moles (231090), Deveault et al. (2009) identified compound heterozygosity for a 1294C-T transition in exon 4 of the NLRP7 gene, resulting in an arg432-to-ter (R432X) substitution, and the intron 7 donor splice site mutation (609661.0002). Spontaneous abortion also occurred in this family.

See 609661.0008 and Wang et al. (2009).

.0007 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, 1-BP INS, 337G
In a Caucasian proband with a history of 3 complete hydatidiform mole pregnancies (231090), Wang et al. (2009) identified compound heterozygosity for a 1-bp insertion (337insG) in the NLRP7 gene, predicted to result in a frameshift and premature termination, and the R693P mutation (609661.0004). The 1-bp insertion was not found in 390 unrelated control chromosomes.

.0008 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, ARG693GLN
In a Chinese proband with recurrent complete hydatidiform mole (HYDM; 231090), previously studied by Zhao et al. (2006), Wang et al. (2009) identified compound heterozygosity for the R432X mutation (609661.0006) and a 2078G-A transition in the NLRP7 gene, resulting in an arg693-to-gln (R693Q) substitution. The proband's sister, who also had recurrent HYDM, was unavailable for screening. The unaffected parents were each heterozygous for 1 of the mutations, respectively; neither mutation was found in 192 Caucasian or 198 Asian control chromosomes.

.0009 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, LEU398ARG
In 2 Asian sisters with recurrent complete hydatidiform mole (HYDM1; 231090), previously reported by Fisher et al. (2002), Wang et al. (2009) identified homozygosity for a 1193T-G transversion in the NLRP7 gene, resulting in a leu398-to-arg (L398R) substitution. Their parents were heterozygous for the mutation, which was not found in 192 Caucasian or 198 Asian control chromosomes.

.0010 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, PRO651SER
In 2 Italian sisters with recurrent complete hydatidiform mole (HYDM1; 231090), previously reported by Sensi et al. (2000), Wang et al. (2009) identified homozygosity for a 1951C-T transition in the NLRP7 gene, resulting in a pro651-to-ser (P651S) substitution. Their parents were heterozygous for the mutation, which was not found in 192 Caucasian or 198 Asian control chromosomes.

.0011 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, 14-BP DUP, NT939
In 2 Caucasian probands with recurrent complete hydatidiform mole pregnancies (HYDM1; 231090), Wang et al. (2009) identified homozygosity for a 14-bp duplication (939_952dup14) in the NLRP7 gene, causing a frameshift predicted to result in premature termination (Tyr318CysfsTer7). Both of the probands had 3 HYDMs, and 1 also had a spontaneous abortion. In addition, in 2 sisters with HYDM, Wang et al. (2009) detected the 14-bp duplication in compound heterozygosity with a 1-bp deletion in NLRP7 (2030delT; 609661.0012); one sister had 3 HYDMs and 1 spontaneous abortion, whereas the other had 1 HYDM.

Fallahian et al. (2013) performed genetic analysis of tissue from the HYDMs of 1 of the women previously studied by Wang et al. (2009) and found to be homozygous for the 14-bp duplication. Her first and third were diploid biparental HYDMs, whereas the second was a digynic triploid conceptus, with 1 paternal and 2 maternal alleles.

.0012 HYDATIDIFORM MOLE, RECURRENT, 1
NLRP7, 1-BP DEL, 2030T
For discussion of the 1-bp deletion in the NLRP7 gene (2030delT) that was found in compound heterozygous state in a woman with hydatidiform moles (HYDM1; 231090) by Wang et al. (2009), see 609661.0011.

Tags: 19q13.42