A rare case of an NLRP12-associated autoinflammatory disease

Ayla, Ali Yagiz; Eren, Hatice; Zare, Jale; Calhan, Sevgi S.; Karacan, Ilker; Seven, Mehmet; Uğurlu, Serdal

doi:10.1016/j.ejmg.2021.104168

Cited by 7 publications

(8 citation statements)

References 13 publications

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“…We interpreted these data as an additional example of possible low penetrance of NLRP12 variants, as recently discussed. 17 …”

Section: Resultsmentioning

confidence: 99%

“…11 To date, few such patients were identified (see ref. 17 for the most recent description) but the association between NLRP12 variants and spontaneous inflammation is not yet firmly established, nor is the molecular role of this inflammasome in the establishment of systemic inflammatory settings. 1 9 In this work, we described a patient with late onset autoinflammatory syndromes which was diagnosed a likely FCAS2 based on the identification, by targeted gene resequencing, of a NLRP12 variant of unknown significance (although several bioinformatics programmes suggest potential damaging consequences of this mutation, see online supplemental table II) which has not been ascribed so far as causal for any disease.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Contrasting role of NLRP12 in autoinflammation: evidence from a case report and mouse models

et al. 2021

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ObjectiveTo explore at the molecular level the phenotype of a patient suffering an autoinflammatory syndrome which was diagnosed as familial cold autoinflammatory syndrome type 2 (FCAS-2). To explore the functions of Nlrp12 in inflammation using mouse models.MethodsWhole exome sequencing and Nlrp12 targeted resequencing were performed on DNA isolated from the patient and her family members. In vivo and ex vivo models of inflammation (urate crystals-dependent acute joint inflammation and urate crystals-induced peritonitis) were analysed in Nlrp12-deficient and Nlrp12-competent mice.ResultsA rare missense NLRP12 variant (c.857C>T, p.P286L) was identified in the patient and her healthy relatives. Nlrp12-deficient mice exhibit reduced systemic inflammation and neutrophilic infiltration.ConclusionNlrp12 mediates proinflammatory functions in mice. In humans, the identification of Nlrp12 variants must be cautiously interpreted depending on clinical and paraclinical data to diagnose FCAS-2.

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“…We interpreted these data as an additional example of possible low penetrance of NLRP12 variants, as recently discussed. 17 …”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Contrasting role of NLRP12 in autoinflammation: evidence from a case report and mouse models

et al. 2021

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“… 1 This gene encodes for NLRP12 protein, a member of the larger family of NOD-like receptor, which acts as a negative regulator of inflammation, suppressing nuclear factor-κB activation and subsequent production of proinflammatory cytokines and chemokines, such as interleukin (IL)-1, IL-6, and IL-8. 1 , 4 , 6 Since the first report of NLRP12 as a causative gene of AIDs, at least 62 cases of FCAS-2 have been discovered worldwide. 6 Our patient carried simultaneously 2 mutations: c.625G>A (p.Ala218Thr) and c.910C>T (p.His304Tyr).…”

Section: Discussionmentioning

confidence: 99%

“… 1 , 4 , 6 Since the first report of NLRP12 as a causative gene of AIDs, at least 62 cases of FCAS-2 have been discovered worldwide. 6 Our patient carried simultaneously 2 mutations: c.625G>A (p.Ala218Thr) and c.910C>T (p.His304Tyr). The age at onset of FCAS-2 is variable, ranging from the first year of life to middle age, with a slight male prevalence.…”

Section: Discussionmentioning

confidence: 99%

NLRP12 and IL36RN mutations in a Portuguese woman with autoinflammatory syndrome

et al. 2022

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A rare case of uncharacterized autoinflammatory disease: Patient carrying variations in NLRP3 and TNFRSF1A genes

Kilinc,

Gayibova,

Onen

et al. 2024

American J of Med Genetics Pt A

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Tumor necrosis factor type 1A receptor‐associated periodic syndrome (TRAPS) and cryopyrin‐associated autoinflammatory syndrome (CAPS) are rare monogenic autoinflammatory diseases (AIDs) mainly caused by pathogenic variations in the TNFRSF1A and NLRP3 genes, respectively. Here, we describe a unique patient presenting with symptoms overlapping both TRAPS and CAPS, without known pathogenic variants in the respective genes. The patient harbored the p.Val200Met variation in NLRP3 and the p.Ser226Cys variation in TNFRSF1A, prompting us to delve deeper into the functional analysis due to conflicting or inconclusive pathogenicity interpretations of the variants across various databases. Molecular dynamics analysis of the p.Val200Met variation in NLRP3 revealed a rigid conformation in the helical domain 2 subdomain of the NACHT domain. This increased rigidity suggests a potential mechanism by which this variation supports the assembly of the NLRP3 inflammasome. Notably, the patient's peripheral mononuclear blood cells demonstrated an elevated IL‐1β response upon lipopolysaccharides (LPS) induction. Subsequent initiation of anti‐IL‐1β therapy resulted in a significant alleviation of the patient's symptoms, further supporting our hypothesis. We interpret these findings as suggestive of a potential pathophysiological role for the NLPR3 p.Val200Met variation in shaping the patient's clinical phenotype, which was also supported by clinical and genetic analysis of the family. This case underscores the complexity of the genetic landscape in AIDs and highlights the value of combining family genetic and functional data to refine the understanding and management of such challenging cases.

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A rare case of an NLRP12-associated autoinflammatory disease

Cited by 7 publications

References 13 publications

Contrasting role of NLRP12 in autoinflammation: evidence from a case report and mouse models

Contrasting role of NLRP12 in autoinflammation: evidence from a case report and mouse models

NLRP12 and IL36RN mutations in a Portuguese woman with autoinflammatory syndrome

A rare case of uncharacterized autoinflammatory disease: Patient carrying variations in NLRP3 and TNFRSF1A genes

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