title: Periodic Fever with Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome Is Associated with a CARD8 Variant Unable To Bind the NLRP3 Inflammasome.
abstract: Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is a relatively common autoinflammatory condition that primarily affects children. Although tendencies were reported for this syndrome, genetic variations influencing risk and disease progression are poorly understood. In this study, we performed next-generation sequencing for 82 unrelated PFAPA patients and identified a frameshift variant in theCARD8gene (CARD8-FS). Subsequently, we compared the frequency of CARD8-FS carriers in our PFAPA cohort (13.9%) with a healthy local population group (3.2%) and found a significant association between the CARD8-FS polymorphism and risk for PFAPA syndrome (p= 0.012; odds ratio: 4.96 [95% confidence interval, 1.33-18.47]). Moreover, CARD8-FS carriers display a distinct PFAPA phenotype that is characterized by a higher prevalence of symptoms out of flares and oral aphthosis (bothp= 0.02 compared with PFAPA patients without the frameshift variant). CARD8 encodes a protein component of the NLRP3 inflammasome, which plays an important role in inflammation and contributes to the pathology of various autoinflammatory diseases. We found that the CARD8-FS variant led to a truncated CARD8 protein lacking the FIIND and CARD domains. As a result, the mutant CARD8 protein lost the ability to interact with the NOD domain of NLRP3. In summary, these results identify a new CARD8 variant associated with PFAPA and further suggest that disruption of the interaction between CARD8 and NLRP3 can regulate autoinflammation in patients.
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Ming Sin
authors.identifier: 0000-0003-3423-4609
authors.initials: MS
authors.lastname: Cheung
authors.affiliation: Pediatric Rheumatology Unit of Western Switzerland, Pediatric Department, University Hospital Center Vaudois, University of Lausanne, 1011 Lausanne, Switzerland.|Pediatric Department, Geneva University Hospitals, 1211 Geneva, Switzerland.
authors.forename: Katerina
authors.initials: K
authors.lastname: Theodoropoulou
authors.affiliation: Department of Biochemistry, University of Lausanne, 1011 Lausanne, Switzerland; and.
authors.forename: Jérôme
authors.identifier: 0000-0002-1178-2752
authors.initials: J
authors.lastname: Lugrin
authors.affiliation: Department of Biochemistry, University of Lausanne, 1011 Lausanne, Switzerland; and.
authors.forename: Fabio
authors.identifier: 0000-0002-6969-822X
authors.initials: F
authors.lastname: Martinon
authors.affiliation: Service of Rheumatology, Department of Musculoskeletal Health, Lausanne University Hospital, University Hospital Center Vaudois, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Busso
authors.affiliation: Pediatric Rheumatology Unit of Western Switzerland, Pediatric Department, University Hospital Center Vaudois, University of Lausanne, 1011 Lausanne, Switzerland; michael.hofer@chuv.ch.|Pediatric Department, Geneva University Hospitals, 1211 Geneva, Switzerland.
authors.forename: Michaël
authors.initials: M
authors.lastname: Hofer
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D004252:DNA Mutational Analysis; D005334:Fever / Q000235:genetics*; D016368:Frameshift Mutation / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D008199:Lymphadenitis; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010612:Pharyngitis; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding / Q000235:genetics; D012306:Risk; D013281:Stomatitis, Aphthous; D013577:Syndrome
chemical_list: D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009363:Neoplasm Proteins