Clinical Characteristics of Patients Carrying the Q703K Variant of the <i>NLRP3</i> Gene: A 10-year Multicentric National Study

Naselli, Aldo; Penco, Federica; Cantarini, Luca; Insalaco, Antonella; Alessio, M; Tommasini, Alberto; Maggio, Claudia; Obici, Laura; Gallizi, Romina; Cimmino, Marco A.; Signa, Sara; Lucherini, Orso Maria; Carta, Sonia; Caroli, Francesco; Martini, Alberto; Rubartelli, Anna; Ceccherini, Isabella; Gattorno, Marco

doi:10.3899/jrheum.150962

Cited by 32 publications

(20 citation statements)

References 26 publications

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“…These results support recent reports of patients with low-penetrance variants treated effectively with IL-1 inhibitors (12). Similar to known pathogenetic NLRP3 variants, children had a higher likelihood of complete response (70% versus 30%) (13,14).…”

Section: Discussionsupporting

confidence: 89%

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Brief Report: Clinical and Molecular Phenotypes of Low‐Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges

Kuemmerle‐Deschner¹,

Verma

Endres³

et al. 2017

Arthritis & Rheumatology

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Section: Discussionsupporting

confidence: 89%

“…IL-1b secretion was decreased in cells from patients with low-penetrance NLRP3 variants as compared to confirmed pathogenetic CAPS mutations (12).…”

Section: Discussionmentioning

confidence: 65%

Brief Report: Clinical and Molecular Phenotypes of Low‐Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges

Kuemmerle‐Deschner¹,

Verma

Endres³

et al. 2017

Arthritis & Rheumatology

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“…Naselli et al. analysed the clinical and functional effect of the p.Gln703Lys, and they suggested that the effect of the p.Gln703Lys variant was weak (Naselli et al., ). Kuemmerle‐Deschner et al.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is later suggested as a functional variant or low-penetrance mutation (Lidar et al, 2015;Verma et al, 2012). Naselli et al analysed the clinical and functional effect of the p.Gln703Lys, and they suggested that the effect of the p.Gln703Lys variant was weak (Naselli et al, 2016). Val198Met (c.592G>A) is classified as "conflicting interpretations of pathogenicity" with likely benign and pathogenic references in ClinVar database (Landrum et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Molecular genetic evaluation of NLRP3, MVK and TNFRSF1A associated periodic fever syndromes

Özyılmaz

Kırbıyık

Koç

et al. 2019

Int J Immunogenetics

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Periodic fever syndromes (PFSs) are a family of clinical disorders, which are characterized by recurrent episodes of fever in the absence of microbial, autoimmune or malign conditions. Most common types of PFSs are associated with four genes: MEFV, MVK, TNFRSF1A and NLRP3. This paper aims to add new data to the genotype–phenotype association of MVK-, TNFRSF-1A- and NLRP3‐associated PFSs. A total number of 211 patients were evaluated. Two different approaches were used for the molecular genetic evaluation of MVK-, TNFRSF-1A- and NLRP3‐associated PFSs. For the first 147 patients, Sanger sequence analysis of selected exons of MVK, TNFRSF1A and NLRP3 genes was done. For subsequent 64 patients, targeted NGS panel analysis, covering all exons of MVK, TNFRSF1A and NLRP3 genes, was used. A total number of 48 variants were detected. The “variant detection rate in index patients” was higher in the NGS group than Sanger sequencing group (19% vs. 15,1%). For the variant positive patients, a detailed genotype–phenotype table was built. In PFSs, lack of correlation exists between genotype and phenotype in the general population and even within the families. In some cases, mutations behave differently and yield unexpected phenotypes. In this study, we discussed the clinical effects of eight different variants we have detected in the MVK, TNFRSF1A and NLRP3 genes. Four of them were previously identified in patients with PFS. The remaining four were not reported in patients with PFS. Thus, we had to interpret their clinical effects by analysing their frequencies and in silico analysis predictions. We suggest that new studies are needed to evaluate the effects of these variants more clearly. To be able to demonstrate a clearer genotype–phenotype relationship, all PFS‐related genes should be analysed together and the possibility of polygenic inheritance should be considered.

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“…Other mutations, including those affecting the codons p.A439, p.R260, and p.D303, are related to different levels of disease severity, suggesting the involvement of other unknown genetic factors in the development of the CAPS phenotype [101][102][103]. On the other hand, finding mutations such as Moreover, monocytes isolated from these patients and stimulated with LPS showed a pattern of cytokine secretion (including IL-1β, IL-6, and IL-1 receptor antagonist) similar to that displayed by healthy controls, suggesting that the variant p.Q703K has a limited functional and clinical impact [106]. The NLRP3 gene encodes an intracellular sensor protein known as cryopyrin, NALP3, or PYPAF1, which is expressed in several cell types, such as monocytes, macrophages, neutrophils, and chondrocytes, and is directly involved in the inflammatory response, being a key component of the multimolecular complex called NLRP3-inflammasome [107][108][109].…”

Section: Cryopyrin-associated Periodic Syndrome (Caps)mentioning

confidence: 93%

Hints for Genetic and Clinical Differentiation of Adult-Onset Monogenic Autoinflammatory Diseases

Gaggiano

Rigante

Vitale

et al. 2019

Mediators of Inflammation

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Monogenic autoinflammatory diseases (mAIDs) are inherited errors of innate immunity characterized by systemic inflammation recurring with variable frequency and involving the skin, serosal membranes, synovial membranes, joints, the gastrointestinal tube, and/or the central nervous system, with reactive amyloidosis as a potential severe long-term consequence. Although individually uncommon, all mAIDs set up an emerging chapter of internal medicine: recent findings have modified our knowledge regarding mAID pathophysiology and clarified that protean inflammatory symptoms can be variably associated with periodic fevers, depicting multiple specific conditions which usually start in childhood, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, and mevalonate kinase deficiency. There are no evidence-based studies to establish which potential genotype analysis is the most appropriate in adult patients with clinical phenotypes suggestive of mAIDs. This review discusses genetic and clinical hints for an ideal diagnostic approach to mAIDs in adult patients, as their early identification is essential to prompt effective treatment and improve quality of life, and also highlights the most recent developments in the diagnostic work-up for the most frequent hereditary periodic febrile syndromes worldwide.

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Clinical Characteristics of Patients Carrying the Q703K Variant of the NLRP3 Gene: A 10-year Multicentric National Study

Abstract: The present study confirms the weak clinical and functional effect of the p.Q703K variant.

Cited by 32 publications

References 26 publications

Brief Report: Clinical and Molecular Phenotypes of Low‐Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges

Brief Report: Clinical and Molecular Phenotypes of Low‐Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges

Molecular genetic evaluation of NLRP3, MVK and TNFRSF1A associated periodic fever syndromes

Hints for Genetic and Clinical Differentiation of Adult-Onset Monogenic Autoinflammatory Diseases

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