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

Autor: Kilinc OC; Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey., Gayibova K; Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey., Onen MO; Faculty of Science and Letters, Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, Turkey., Onat UI; Graduate School of Natural and Applied Sciences, Acibadem University, Istanbul, Turkey.; Faculty of Engineering and Natural Sciences, Department of Molecular Biology and Genetics, Acibadem University, Istanbul, Turkey., Bülbül A; Graduate School of Health Sciences, Bioinformatics and Biostatistics Department, Acibadem University, Istanbul, Turkey., Timucin AC; Graduate School of Natural and Applied Sciences, Acibadem University, Istanbul, Turkey.; Faculty of Engineering and Natural Sciences, Department of Molecular Biology and Genetics, Acibadem University, Istanbul, Turkey., Ugurlu S; Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey., Turanli ET; Graduate School of Natural and Applied Sciences, Acibadem University, Istanbul, Turkey.; Faculty of Engineering and Natural Sciences, Department of Molecular Biology and Genetics, Acibadem University, Istanbul, Turkey.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2024 Oct; Vol. 194 (10), pp. e63715. Date of Electronic Publication: 2024 May 20.
DOI: 10.1002/ajmg.a.63715
Abstrakt: 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.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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