[email protected] (受疫情影响,东南亚目前只开放曼谷诊所)
全周 (9AM - 5PM)

我们和你在一起

Extra info thumb
  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
  • [email protected]
NLR FAMILY, PYRIN DOMAIN-CONTAINING 1; NLRP1

NLR FAMILY, PYRIN DOMAIN-CONTAINING 1; NLRP1

Alternative titles; symbolsNACHT DOMAIN-, LEUCINE-RICH REPEAT-, AND PYD-CONTAINING PROTEIN 1; NALP1DEATH EFFECTOR FILAMENT-FORMING CED4-LIKE APOPTOSIS PROTEIN; D...

Alternative titles; symbols

  • NACHT DOMAIN-, LEUCINE-RICH REPEAT-, AND PYD-CONTAINING PROTEIN 1; NALP1
  • DEATH EFFECTOR FILAMENT-FORMING CED4-LIKE APOPTOSIS PROTEIN; DEFCAP
  • KIAA0926
  • CARD7
  • NLRP1A, MOUSE, HOMOLOG OF; NLRP1A

Other entities represented in this entry:

  • DEFCAP-L, INCLUDED
  • DEFCAP-S, INCLUDED

HGNC Approved Gene Symbol: NLRP1

Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38): 17:5,501,395-5,584,508 (from NCBI)

▼ Description
Genes encoding Ced proteins in worms are crucial for initiating apoptosis during development. Mammalian Ced4 homologs include APAF1 (602233) and NOD1/CARD4 (605980). DEFCAP is a member of the mammalian family of Ced4 proteins and is capable of inducing apoptosis (Hlaing et al., 2001).

▼ Cloning and Expression
By screening for cDNAs encoding large proteins expressed in brain, Nagase et al. (1999) identified a cDNA encoding KIAA0926. The deduced 1,429-amino acid protein is predicted to be 42% identical to a placental ribonuclease inhibitor (RNH; 173320). RT-PCR analysis detected weak expression in most tissues, with highest expression in spleen.

By protein database searching for pyrin (608107) domain (PYD)-containing proteins, Martinon et al. (2001) identified NALP1 and NALP2 (609364), so symbolized for 'NACHT-, LRR-, and PYD-containing proteins.' The authors noted that NACHT and LRR domains are found in proteins involved in inflammation or apoptosis, such as NAIP (600355) and CIITA (600005). Sequence analysis suggested that PYD, along with the domains DED, CARD, and DD, is a fourth potential member of the death-domain-fold superfamily. However, binding analysis indicated that PYD-containing proteins interact only with other PYD proteins.

By database searching and PCR of a chronic myelogenous leukemia (K562) cDNA library with primers based on KIAA0926, Hlaing et al. (2001) isolated cDNAs encoding short and long isoforms of death effector filament-forming Ced4-like apoptosis protein, or DEFCAP-S and DEFCAP-L. The longer isoform includes a 132-bp insertion encoding an additional leucine-rich repeat (LRR) in a 1,473-amino acid protein. Sequence analysis predicted that both proteins contain a C-terminal CARD domain, LRRs, and a nucleotide-binding domain, in different positions from those of NOD1 and APAF1. An N-terminal pyrin-like motif (PLM) is conserved with other mammalian proteins such as ASC (CARD5), and is evolutionarily conserved, as seen in sequence alignments with zebrafish ASC1. Northern blot analysis revealed expression of approximately 7.0- and 8.0-kb transcripts in most tissues, with highest levels in peripheral blood leukocytes, heart, thymus, and spleen, but none in brain. High levels were detected in K562 cells, with weaker or no expression in other cancer cell lines. Semiquantitative RT-PCR analysis detected both isoforms in normal tissue and cancer cell lines. Fluorescence microscopy demonstrated a diffuse cytoplasmic localization.

Soler et al. (2013) examined NLRP1 expression in human fetal and adult ocular tissues obtained from dissected whole globes, and observed expression in adult cornea as well as adult and 24-week fetal tissues, including choroid, sclera, cornea, optic nerve, and adult retina and fetal retina/retinal pigment epithelium. In addition, NLRP1 was expressed in corneal epithelia obtained during photorefractive keratectomy.

Zhong et al. (2016) examined the tissue expression profile of NLRP1 in the Human Protein Atlas RNA-seq database and observed that NLRP1 is widely expressed, with skin having the highest expression of all tissues tested. Analysis of transcript levels in the 3 major skin cell types showed that NLRP1 was readily detectable by RT-PCR in keratinocytes and fibroblasts, but not in melanocytes. Using RNAscope in situ staining in paraffin-preserved primary human skin samples, Zhong et al. (2016) observed that NLRP1 mRNA is expressed throughout the epidermis and in dermal fibroblasts in both glabrous and plantar skin, as well as in epidermal appendages such as hair follicles. These findings confirmed the RT-PCR results, and were corroborated by immunohistochemical staining.

▼ Mapping
By radiation hybrid analysis, Nagase et al. (1999) mapped the KIAA0926 gene to chromosome 17. By the same method, Hlaing et al. (2001) mapped the DEFCAP gene to chromosome 17p13.

▼ Gene Function
By immunoprecipitation analysis, Hlaing et al. (2001) demonstrated that both DEFCAP isoforms interacted strongly with CASP2 (600639), but only weakly with CASP9 (602234). Transient overexpression of full-length DEFCAP-L, but not DEFCAP-S, in breast adenocarcinoma cells resulted in significant apoptosis.

Decreasing oocyte competence with maternal aging is a major factor in human infertility. To investigate the age-dependent molecular changes in a mouse model, Hamatani et al. (2004) compared the expression profiles of metaphase II oocytes collected from 5- to 6-week-old mice with those collected from 42- to 45-week-old mice using a 22K oligo microarray. Among approximately 11,000 genes whose transcripts were detected, about 5% showed statistically significant expression changes. Among the transcripts decreased with aging was a group of oocyte-specific genes, members of the human NACHT, leucine-rich repeat and PYD-containing (NALP) gene family.

Using purified recombinant proteins, Faustin et al. (2007) reconstituted the NALP1 inflammasome to characterize the requirements for inflammasome assembly and CASP1 (147678) activation. NALP1 oligomerized in a 2-step process that required a microbial product, muramyl-dipeptide, followed by ribonucleotide triphosphates. CASP1 activation by NALP1 was enhanced by ASC (PYCARD; 606838). Faustin et al. (2007) concluded that NALP1 is a direct sensor of bacterial components in host defense against pathogens.

Guarda et al. (2009) incubated mouse splenocyte naive, memory, and regulatory T-cell subsets with bone marrow-derived macrophages and stimulated them with anti-Cd3 (see 186740), followed by lipopolysaccharide activation and ATP stimulation. They found that inflammasome-mediated Casp1 activation and secretion of mature Il1b (147720) was blocked in the presence of memory Cd4 (186940)-positive T cells, but not other T-cell subsets. Subsequent investigation showed that multiple activators of Nalp1 and Nalp3 (NLRP3; 606416), but not Nlrc4 (606831), were inhibited in inflammasome function by memory or in vitro-activated Cd4-positive T cells. Suppression of Nalp3 inflammasome function required cell-to-cell contact. Effector Cd4-positive T cells also decreased neutrophil recruitment in an Nalp3-dependent peritonitis mouse model. Guarda et al. (2009) concluded that effector and memory CD4-positive T cells selectively inhibit NALP1 and NALP3 inflammasomes.

Gregory et al. (2011) found that the Kaposi sarcoma-associated herpesvirus (KSHV) Orf63 is a viral homolog of human NLRP1. Orf63 blocked NLRP1-dependent innate immune responses, including CASP1 activation and processing of interleukins IL1B and IL18 (600953). KSHV Orf63 interacted with NLRP1, NLRP3, and NOD2 (605956). Inhibition of Orf63 expression resulted in increased expression of IL1B during the KSHV life cycle. Furthermore, inhibition of NLRP1 was necessary for efficient reactivation and generation of progeny virus. The viral homolog subverts the function of cellular NLRs, which suggested to Gregory et al. (2011) that modulation of NLR-mediated innate immunity is important for the lifelong persistence of herpesviruses.

In their biochemical analysis of NLRP1, Zhong et al. (2016) observed that the NLRP1 PYD functions as an autoinhibitory domain, unlike the PYDs of other known inflammasome sensors. They proposed that, despite having both a PYD and a CARD domain, NLRP1 should be classified functionally as an NOD-, LRR-, and CARD-containing (NLRC) protein rather than as an NOD-, LRR-, and pyrin domain-containing (NLRP) protein. Zhong et al. (2016) also demonstrated that the NLRP1 PYD functions nonredundantly with the LRR domain to maintain NLRP1 in an inactive monomeric form, and that the monomer-to-oligomer transition is an obligatory step for NLRP1 inflammasome activation, requiring the autoproteolytic cleavage of the FIIND domain.

Sandstrom et al. (2019) found that cleavage of NLRP1B results in proteasome-mediated degradation of the amino-terminal domains of NLRP1B, liberating a carboxyl-terminal fragment that is a potent activator of CASP1. Proteasome-mediated degradation of NLRP1B is both necessary and sufficient for NLRP1B activation. Sandstrom et al. (2019) identified IpaH7.8, a Shigella flexneri ubiquitin ligase secreted effector, as an enzyme that induces NLRP1B degradation and activation.

Chui et al. (2019) used genomewide CRISPR-Cas9 knockout screens to identify genes required for NLRP1B-mediated pyroptosis and discovered that the anthrax lethal factor metalloprotease induces cell death via the N-end rule proteasomal degradation pathway. Anthrax lethal factor directly cleaves NLRP1B, inducing the N-end rule-mediated degradation of the NLRP1B N terminus and freeing the NLRP1B C terminus to activate caspase-1. Small molecule DPP8/9 (606819/608258) inhibitors also induce proteasomal degradation of the NLRP1B N terminus, but not via the N-end rule pathway.

Robinson et al. (2020) reported that human NLRP1 is activated by 3C proteases of enteroviruses, such as human rhinovirus (HRV). 3C proteases directly cleave human NLRP1 at a single site between glu130 and gly131. This cleavage triggers N-glycine-mediated degradation of the autoinhibitory NLRP1 N-terminal fragment via the cullin/ZER1/ZYG11B complex (see 618673), which liberates the activating C-terminal fragment. Infection of primary human airway epithelial cells by live human HRV triggers NLRP1-dependent inflammasome activation and interleukin-18 (IL18; 600953) secretion. These findings established 3C proteases as a pathogen-derived trigger for the human NLRP1 inflammasome and suggested that NLRP1 may contribute to inflammatory diseases of the airway.

▼ Molecular Genetics
Vitiligo-Associated Autoimmune Disease Susceptibility

Among patients with generalized vitiligo there is an increased frequency of several autoimmune and autoinflammatory diseases (Jin et al., 2007). There is also an increased frequency of these same disorders among first-degree relatives of patients with vitiligo, suggesting that some families have a genetic predisposition to this group of autoimmune and autoinflammatory diseases. To identify the gene responsible for vitiligo-related autoimmune disease susceptibility associated with the 17p13 region (VAMAS1; 606579), Jin et al. (2007) performed fine-scale genetic association and DNA sequence analyses in 114 families with vitiligo and associated autoimmune and autoinflammatory diseases. Association analyses resulted in identification of NALP1 as a candidate gene. Fine-scale association mapping using DNA from affected families and additional SNPs in and around NALP1 showed an association of specific variants with vitiligo alone, with an extended autoimmune and autoinflammatory disease phenotype, or with both. Conditional logistic-regression analysis of NALP1 SNPs indicated that at least 2 variants contribute independently to the risk of disease. Jin et al. (2007) identified 15 SNPs in the NALP1 region predicted to result in nonsynonymous amino acid substitutions in the NALP1 protein. Only 1 of these (leu155 to his; 606636.0001) showed evidence in association, both with vitiligo alone and with autoimmune inflammatory diseases (p = 0.002 and p = 0.001, respectively, by pedigree disequilibrium test). Five of 6 tightly linked SNPs in the promoter region of NALP1 that were associated with disease were found to affect high-probability mammalian transcription factor binding sites.

Multiple Self-Healing Palmoplantar Carcinoma

In an affected mother and son from a Caucasian French family originally diagnosed with corneal intraepithelial dyskeratosis and ectodermal dysplasia, but later diagnosed with multiple self-healing palmoplantar carcinoma (MSPC; 615225) by Zhong et al. (2016), Soler et al. (2013) identified heterozygosity for a missense mutation in the NLRP1 gene (M77T; 606636.0002) that segregated with the disease and was not found in 672 controls or in 61 exome-sequenced subjects' DNA.

In 2 large unrelated multigenerational families segregating autosomal dominant MSPC and known to be negative for mutation in the TGFBR1 gene (190181), Zhong et al. (2016) identified 2 different heterozygous missense mutations in the NLRP1 gene, A54T (606636.0003) and A66V (606636.0004), that segregated with disease in each of the families. Functional analysis of the 3 MSPC-associated mutations, all located within the pyrin domain (PYD), revealed that all 3 increased inflammasome activation, likely by disrupting PYD-dependent autoinhibition. Experiments using blue-native PAGE to visualize the native conformations of wildtype and patient-derived mutant NLRP1 proteins suggested that wildtype NLRP1 exists as an inactive monomer in the absence of a ligand, and that binding to a putative ligand rapidly causes NLRP1 to self-oligomerize in a manner that is dependent on autoproteolytic cleavage within the FIIND domain. However, this self-inhibitory mechanism is lost with mutation in the PYD domain, triggering constitutive self-oligomerization and spontaneous inflammasome activation.

Zhong et al. (2016) reported a consanguineous family in which a sister and brother with clinical features of MSPC as well as multiple discrete and semiconfluent lichenoid papules on the arms, legs, and lower trunk were homozygous for an in-frame deletion in the NLRP1 gene (606636.0005). The deletion was present in heterozygosity in their parents, who exhibited milder skin defects, and was not found in their unaffected sibs. Functional analysis demonstrated that the deletion is a gain-of-function variant that causes increased inflammasome activation. The authors diagnosed the patients with familial keratosis lichenoides chronica (Nekam disease).

Autoinflammation with Arthritis and Dyskeratosis

In 2 double first cousins from a consanguineous Algerian family segregating autosomal recessive autoinflammation with arthritis and dyskeratosis (AIADK; 617388), Grandemange et al. (2016) identified homozygosity for a missense mutation in the NLRP1 gene (R726W; 606636.0006). Sanger sequencing of NLRP1 in a similarly affected Dutch girl revealed heterozygosity for a de novo missense mutation (P1214R; 606636.0007).

Congenital Juvenile Recurrent Respiratory Papillomatosis

In 2 brothers, born of consanguineous parents, with autosomal recessive congenital juvenile recurrent respiratory papillomatosis (JRRP; 618803), Drutman et al. (2019) identified a homozygous missense mutation in the NLRP1 gene (T755N; 606636.0008). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient-derived keratinocytes and HEK293 cells transfected with the mutation showed expression of the mutant protein, which had undergone spontaneous oligomerization. Patient cells and cultured immortalized keratinocytes overexpressing the mutation both showed increased production of IL1B (147720), consistent with increased activation of the inflammasome and a gain-of-function effect.

▼ Evolution
Using a population genetics approach to define the ways in which natural selection has driven evolution of NOD-like microbial receptors (NLRs) in various human populations, Vasseur et al. (2012) identified 2,084 SNPs, including 396 nonsynonymous SNPs, 4 nonsense variants, and 12 coding region insertion/deletions. Overall, members of the NALP subfamily, which includes NLRP1 through NLRP14 (609665), had undergone strong purifying selection with little functional diversity. In contrast, members of the NOD/IPAF subfamily, which includes NOD1 through NOD4 (NLRC5; 613537), as well as NOD9 (NLRX1; 611947), CIITA, and NLRC4, had undergone weak negative selection. After expanding their studies to include other major families of microbial sensors, Vasseur et al. (2012) distinguished 3 groups of innate immunity genes that differed in their evolutionary patterns: those under strong selective constraints (most NALPs and endosomal Toll-like receptors (e.g., TLR3; 603029)), those under weaker constraints (most NOD/IPAFs and cytosolic RIGI-like receptors (e.g., DDX58; 609631)), and those that did not appear to deviate from neutrality (most cell surface Toll-like receptors (e.g., TLR1, 601194)).

▼ Animal Model
Using chemical mutagenesis, Masters et al. (2012) generated mice with an activating glu593-to-pro (Q593P) mutation in Nlrp1a. The mutation likely occurred in a flex linker region of the protein between the NACHT and LRR domains. Although grossly normal, mice homozygous for the Q593P mutation had neutrophilic inflammatory disease in multiple organs. The disease was dependent on Il1b and Casp1, but independent of Asc and Casp11 (CASP4; 602664). Homozygous Q593P mice had elevated levels of Il18. Histologic analysis showed that Q593P mice that also lacked Il18 had increased circulating neutrophils and mortality, which was associated with increased myocarditis. In contrast, hepatitis was absent in these mice, suggesting that IL18 is protective against myocarditis but enhances liver inflammation. Hemopoietic stress induced in Q593P mice by chemotherapy or lymphocytic choriomeningitis infection caused prolonged cytopenia, bone marrow hyperplasia, and immunosuppression. Mice lacking Nlrp1a showed enhanced recovery from these stresses, indicating that NLRP1 acts as a cellular sentinel to alert CASP1 to hemopoietic stress and infection.

▼ ALLELIC VARIANTS ( 8 Selected Examples):

.0001 VITILIGO-ASSOCIATED MULTIPLE AUTOIMMUNE DISEASE SUSCEPTIBILITY 1
NLRP1, LEU155HIS
In a study of families with vitiligo-associated multiple autoimmune disease (VAMAS1; 606579), Jin et al. (2007) identified association of a nonsynonymous change in the coding region of the NALP1 gene, leu155 to his (L155H; rs12150220), with susceptibility both to vitiligo alone and to autoimmune and autoinflammatory diseases. The L155H substitution occurs between the N-terminal pyrin and NACHT domains of the NALP1 polypeptide, within a region highly conserved through primate evolution. An association was also identified with another SNP in the promoter region.

.0002 PALMOPLANTAR CARCINOMA, MULTIPLE SELF-HEALING
NLRP1, MET77THR
In an affected mother and son from a Caucasian French family (MSPC-FR-1) originally diagnosed with corneal intraepithelial dyskeratosis and ectodermal dysplasia, but later diagnosed with multiple self-healing palmoplantar carcinoma (MSPC; 615225) by Zhong et al. (2016), Soler et al. (2013) identified heterozygosity for a c.230T-C transition in exon 1 of the NRLP1 gene, resulting in a met77-to-thr (M77T) substitution at a conserved residue at the end of the fourth alpha helix, predicted to destabilize the protein structure. The mutation was not present in the unaffected maternal grandparents, and was not found in 672 controls or in 61 exome-sequenced subjects' DNA.

.0003 PALMOPLANTAR CARCINOMA, MULTIPLE SELF-HEALING
NLRP1, ALA54THR
In a large 5-generation Tunisian family (MSPC-TN-1) with multiple self-healing palmoplantar carcinoma (MSPC; 615225), originally studied by Mamai et al. (2015), Zhong et al. (2016) identified heterozygosity for a G-A transition (chr17.5,487,118G-A, GRCh37) in exon 1 of the NLRP1 gene, resulting in an ala54-to-thr (A54T) substitution at a highly conserved residue within the PYD domain. The authors noted that 1 member of the Tunisian family was reported to be asymptomatic despite being a carrier of the A54T mutation, suggesting the existence of possible modifier alleles. Functional analysis in transfected 293T cells demonstrated increased inflammasome activation with the A54T mutant compared to wildtype NLRP1. Analysis of the native conformations of wildtype and mutant NLRP1 suggested that the wildtype protein exists as a monomer that self-oligomerizes only in the presence of a ligand, whereas the A54T mutant undergoes constitutive self-oligomerization that results in spontaneous inflammasome activation. Next-generation RNA sequencing to characterize the effects of the A54T mutation on keratinocyte gene expression showed remarkable enrichment of IL1 (see 147760)/NFKB (164011) signaling pathway genes, including stress-responsive secreted factors and known proinflammatory cytokines, as well as keratinocyte differentiation markers. Zhong et al. (2016) concluded that the recurrent focal hyperkeratotic growth seen in these patients is a direct result of IL1-driven proinflammatory and proproliferative paracrine signaling.

.0004 PALMOPLANTAR CARCINOMA, MULTIPLE SELF-HEALING
NLRP1, ALA66VAL
In affected members of a 4-generation family (MSPC-RO-1) with multiple self-healing palmoplantar carcinoma (MSPC; 615225), Zhong et al. (2016) identified heterozygosity for an ala66-to-val (A66V) substitution at a highly conserved residue within the PYD domain of NLRP1. The mutation segregated fully with disease in the family. Functional analysis in transfected 293T cells demonstrated increased inflammasome activation with the A66V mutant compared to wildtype NLRP1. Analysis of the native conformations of wildtype and mutant NLRP1 suggested that the wildtype protein exists as a monomer that self-oligomerizes only in the presence of a ligand, whereas the A66V mutant undergoes constitutive self-oligomerization that results in spontaneous inflammasome activation. Next-generation RNA sequencing to characterize the effects of the A66V mutation on keratinocyte gene expression showed remarkable enrichment of IL1 (see 147760)/NFKB (164011) signaling pathway genes, including stress-responsive secreted factors and known proinflammatory cytokines, as well as keratinocyte differentiation markers. Zhong et al. (2016) concluded that the recurrent focal hyperkeratotic growth seen in these patients is a direct result of IL1-driven proinflammatory and proproliferative paracrine signaling.

.0005 PALMOPLANTAR CARCINOMA, MULTIPLE SELF-HEALING
NLRP1, EX5DEL
In 2 affected sibs from a consanguineous family with features of multiple self-healing palmoplantar carcinoma (MSPC; 615225) as well as multiple discrete and semiconfluent lichenoid papules, Zhong et al. (2016) identified homozygosity for a deletion of exon 5 of the NLRP1 gene, resulting in an internal in-frame deletion (Phe787_Arg843del) that removes the first of 6 leucine-rich repeats (LRRs) and part of the preceding linker region. The deletion was present in heterozygosity in their parents, who exhibited milder skin defects, and was not found in their unaffected sibs. Functional analysis in transfected 293T cells demonstrated increased inflammasome activation with the F787_R843del mutant compared to wildtype NLRP1. Analysis of the native conformations of wildtype and mutant NLRP1 suggested that the wildtype protein exists as a monomer that self-oligomerizes only in the presence of a ligand, whereas the F787_R843del mutant undergoes constitutive self-oligomerization that results in spontaneous inflammasome activation. Zhong et al. (2016) diagnosed the patients with familial keratosis lichenoides chronica (Nekam disease, FKLC).

.0006 AUTOINFLAMMATION WITH ARTHRITIS AND DYSKERATOSIS
NLRP1, ARG726TRP (rs776245016)
In a 16-year-old boy and an 8-year-old girl who were double first cousins from a consanguineous Algerian family segregating autosomal recessive autoinflammation with arthritis and dyskeratosis (AIADK; 617388), Grandemange et al. (2016) identified homozygosity for a c.2176C-T transition (c.2176C-T, NM_033004.3) in the NLRP1 gene, resulting in an arg726-to-trp (R726W) substitution at a residue within a conserved region between the NACHT and LRR domains. The boy was originally described by Girard et al. (2006). The mutation segregated with disease in the family and was not found in 95 Algerian controls or in the 1000 Genomes Project or Exome Variant Server databases. However, the variant was reported in heterozygous state in 5 individuals in the ExAC database.

.0007 AUTOINFLAMMATION WITH ARTHRITIS AND DYSKERATOSIS
NLRP1, PRO1214ARG
In a 10-year-old Dutch girl who had autoinflammation with arthritis and dyskeratosis (AIADK; 617388), Grandemange et al. (2016) identified heterozygosity for a de novo c.3641C-G transversion (c.3641C-G, NM_033004.3) in the NLRP1 gene, resulting in a pro1214-to-arg (P1214R) substitution within the FIIND domain. The mutation was not present in her unaffected parents, in 110 control chromosomes, or in the 1000 Genomes Project, Exome Variant Server, or ExAC databases.

.0008 RESPIRATORY PAPILLOMATOSIS, JUVENILE RECURRENT, CONGENITAL (1 family)
NLRP1, THR755ASN
In 2 brothers, born of consanguineous parents, with autosomal recessive congenital juvenile recurrent respiratory papillomatosis (JRRP; 618803), Drutman et al. (2019) identified a homozygous c.2819C-A transversion (c.2819C-A, NM_033004) in the NLRP1 gene, resulting in a thr755-to-asn (T755N) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient-derived keratinocytes and HEK293 cells transfected with the mutation showed expression of the mutant protein, which had undergone spontaneous oligomerization. Patient cells and cultured immortalized keratinocytes overexpressing the mutation both showed increased production of IL1B (147720), consistent with increased activation of the inflammasome and a gain-of-function effect.

Tags: 17p13.2