A rare case of uncharacterized autoinflammatory disease: Patient carrying variations in NLRP3 and TNFRSF1A genes.
CAPS
NLRP3
TNFRSF1A
TRAPS
autoinflammatory diseases
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
20 May 2024
20 May 2024
Historique:
revised:
15
04
2024
received:
10
02
2024
accepted:
03
05
2024
medline:
20
5
2024
pubmed:
20
5
2024
entrez:
20
5
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38766920
doi: 10.1002/ajmg.a.63715
doi:
Types de publication
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
e63715Subventions
Organisme : Acibadem University Research Funds (ABAPKO)
ID : 2022/01-14
Informations de copyright
© 2024 Wiley Periodicals LLC.
Références
Aksentijevich, I., & Schnappauf, O. (2021). Molecular mechanisms of phenotypic variability in monogenic autoinflammatory diseases. Nature Reviews Rheumatology, 17(7), 405–425.
Ayla, A. Y., Eren, H., Zare, J., Calhan, S. S., Karacan, I., Seven, M., & Ugurlu, S. (2021). A rare case of an NLRP12‐associated autoinflammatory disease. European Journal of Medical Genetics, 64(4), 104168.
Best, R. B., Zhu, X., Shim, J., Lopes, P. E. M., Mittal, J., Feig, M., & MacKerell, A. D., Jr. (2012). Optimization of the additive CHARMM all‐atom protein force field targeting improved sampling of the backbone phi, psi and side‐chain chi(1) and chi(2) dihedral angles. Journal of Chemical Theory and Computation, 8(9), 3257–3273.
Cudrici, C., Deuitch, N., & Aksentijevich, I. (2020). Revisiting TNF receptor‐associated periodic syndrome (TRAPS): Current perspectives. International Journal of Molecular Sciences, 21(9), 3263.
Feller, S. E., Zhang, Y. H., Pastor, R. W., & Brooks, B. R. (1995). Constant‐pressure molecular‐dynamics simulation – the Langevin piston method. Journal of Chemical Physics, 103(11), 4613–4621.
Fu, J., & Wu, H. (2023). Structural mechanisms of NLRP3 inflammasome assembly and activation. Annual Review of Immunology, 41, 301–316.
Grateau, G., Hentgen, V., Stojanovic, K. S., Jéru, I., Amselem, S., & Steichen, O. (2013). How should we approach classification of autoinflammatory diseases? Nature Reviews Rheumatology, 9(10), 624–629.
Hansmann, S., Lainka, E., Horneff, G., Holzinger, D., Rieber, N., Jansson, A. F., Rösen‐Wolff, A., Erbis, G., Prelog, M., Brunner, J., Benseler, S. M., & Kuemmerle‐Deschner, J. B. (2020a). Consensus protocols for the diagnosis and management of the hereditary autoinflammatory syndromes CAPS, TRAPS and MKD/HIDS: A German PRO‐KIND initiative. Pediatric Rheumatology, 18(1), 1–11.
Hansmann, S., Lainka, E., Horneff, G., Holzinger, D., Rieber, N., Jansson, A. F., Rösen‐Wolff, A., Erbis, G., Prelog, M., Brunner, J., Benseler, S. M., & Kuemmerle‐Deschner, J. B. (2020b). Consensus protocols for the diagnosis and management of the hereditary autoinflammatory syndromes CAPS, TRAPS and MKD/HIDS: A German PRO‐KIND initiative. Pediatric Rheumatology, 18(1), 17.
Hochheiser, I. V., Pilsl, M., Hagelueken, G., Moecking, J., Marleaux, M., Brinkschulte, R., Latz, E., Engel, C., & Geyer, M. (2022). Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3. Nature, 604(7904), 184–189.
Hoover, W. G. (1985). Canonical dynamics: Equilibrium phase‐space distributions. Physical Review A, 31(3), 1695–1697.
Huang, J., Rauscher, S., Nawrocki, G., Ran, T., Feig, M., de Groot, B. L., Grubmüller, H., & MacKerell, A. D., Jr. (2017). CHARMM36m: An improved force field for folded and intrinsically disordered proteins. Nature Methods, 14(1), 71–73.
Humphrey, W., Dalke, A., & Schulten, K. (1996). VMD: Visual molecular dynamics. Journal of Molecular Graphics, 14(1), 33–38.
Ioannidis, N. M., Rothstein, J. H., Pejaver, V., Middha, S., McDonnell, S. K., Baheti, S., Musolf, A., Li, Q., Holzinger, E., Karyadi, D., Cannon‐Albright, L. A., Teerlink, C. C., Stanford, J. L., Isaacs, W. B., Xu, J., Cooney, K. A., Lange, E. M., Schleutker, J., Carpten, J. D., … Sieh, W. (2016). REVEL: An ensemble method for predicting the pathogenicity of rare missense variants. The American Journal of Human Genetics, 99(4), 877–885.
Jo, E. K., Kim, J. K., Shin, D. M., & Sasakawa, C. (2016). Molecular mechanisms regulating NLRP3 inflammasome activation. Cellular & Molecular Immunology, 13(2), 148–159.
Jorgensen, W. L., & Madura, J. D. (1983). Quantum and statistical mechanical studies of liquids. 25. Solvation and conformation of methanol in water. Journal of the American Chemical Society, 105(6), 1407–1413.
Karacan, İ., Balamir, A., Uğurlu, S., Aydın, A. K., Everest, E., Zor, S., Önen, M. Ö., Daşdemir, S., Özkaya, O., Sözeri, B., Tufan, A., Yıldırım, D. G., Yüksel, S., Ayaz, N. A., Ömeroğlu, R. E., Öztürk, K., Çakan, M., Söylemezoğlu, O., Şahin, S., … Turanlı, E. T. (2019). Diagnostic utility of a targeted next‐generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: A multi‐center study. Rheumatology International, 39(5), 911–919.
Krainer, J., Siebenhandl, S., & Weinhäusel, A. (2020). Systemic autoinflammatory diseases. Journal of Autoimmunity, 109, 102421.
Louvrier, C., Assrawi, E., El Khouri, E., Melki, I., Copin, B., Bourrat, E., Lachaume, N., Cador‐Rousseau, B., Duquesnoy, P., Piterboth, W., Awad, F., Jumeau, C., Legendre, M., Grateau, G., Georgin‐Lavialle, S., Karabina, S. A., Amselem, S., & Giurgea, I. (2020). NLRP3‐associated autoinflammatory diseases: Phenotypic and molecular characteristics of germline versus somatic mutations. The Journal of Allergy and Clinical Immunology, 145(4), 1254–1261.
MacKerell, A. D., Bashford, D., Bellott, M., et al. (1998). All‐atom empirical potential for molecular modeling and dynamics studies of proteins. The Journal of Physical Chemistry. B, 102(18), 3586–3616.
Mackerell, A. D., Jr., Feig, M., & Brooks, C. L., 3rd. (2004). Extending the treatment of backbone energetics in protein force fields: Limitations of gas‐phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. Journal of Computational Chemistry, 25(11), 1400–1415.
Martyna, G. J., Hughes, A., & Tuckerman, M. E. (1999). Molecular dynamics algorithms for path integrals at constant pressure. Journal of Chemical Physics, 110(7), 3275–3290.
Meng, T., Wu, D., Luo, Y., Wu, N., Zhao, M., Shen, M., & Yu, W. (2021). Ocular manifestations in Chinese adult patients with NLRP3‐associated autoinflammatory disease. Scientific Reports, 11(1), 11904.
Oziębło, D., Leja, M. L., Jeznach, A., Orzechowska, M., Skirecki, T., Więsik‐Szewczyk, E., Furmanek, M., Bałdyga, N., Skarżyński, H., & Ołdak, M. (2022). Hearing loss as the Main clinical presentation in NLRP3‐associated autoinflammatory disease. Frontiers in Immunology, 26(13), 904632.
Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J., & Kircher, M. (2019). CADD: Predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Research, 47(D1), D886–D894.
Rubartelli, A. (2014). Autoinflammatory diseases. Immunology Letters, 161(2), 226–230.
Sivapriya, K. V., Rathinam, V. A. K., & Fitzgerald, K. A. (2015). Mechanisms of inflammasome activation: Recent advances and novel insights. Trends in Cell Biology, 25, 308–315.
South, S. T., Lee, C., Lamb, A. N., Higgins, A. W., & Kearney, H. M. (2013). ACMG standards and guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: Revision 2013. Genetics in Medicine, 15(11), 901–909.
Weber, A. N. R., Tortola, M. M., & Kuemmerle‐Deschner, J. B. (2024). Cracking the NLRP3 code: Pioneering precision medicine for inflammation. The Journal of Experimental Medicine, 221(5), e20240221. https://doi.org/10.1084/jem.20240221
Zhou, Y., Wang, W., Zhong, L., Wang, L., Ma, M., Tang, X., Li, Z., Wang, C., Gou, L., Zhang, T., & Song, H. (2022). Clinical and genetic spectrum of 14 cases of NLRP3‐associated autoinflammatory disease (NLRP3‐AID) in China and a review of the literature. Orphanet Journal of Rare Diseases, 17(1), 214.