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Two adult siblings with atypical cryopyrin-associated periodic syndrome due to a novel M299V mutation in NLRP3
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002.3555-7162
Örebro universitet, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
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2010 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 7, 2138-2143 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: The NALP3 inflammasome is a multiprotein complex that triggers caspase 1-mediated interleukin-1beta (IL-1beta) release. Mutations in the gene encoding NALP3 (NLRP3) underlie the cryopyrin-associated periodic syndrome (CAPS). The aim of this study was to report a novel NLRP3 mutation in 2 siblings of Swedish descent in whom symptoms first presented in adulthood.

METHODS: Mutation analysis of NLRP3 was performed on DNA from patients with CAPS and 100 control subjects. For assessment of caspase 1 and IL-1beta, blood was collected from patients and age- and sex-matched healthy control subjects. Genetic constructs containing mutant or wild-type NLRP3 were transduced into THP-1 cells, followed by assessment of IL-1beta levels in cell supernatant.

RESULTS: Both siblings carried a novel M299V mutation in NLRP3, which was not present in the control population. The samples obtained from the patients displayed increased caspase 1 activity and elevated IL-1beta levels at basal conditions as compared with healthy control subjects. THP-1 cells expressing mutated M299V revealed almost 10-fold higher IL-1beta production compared with the wild-type construct.

CONCLUSION: M299V is an activating mutation in NLRP3 resulting in elevated spontaneous caspase 1 activity and IL-1beta levels. The classic CAPS phenotype was lacking in these adult siblings. Whereas one sibling displayed a milder phenotype that has so far responded satisfactorily to oral nonsteroidal antiinflammatory drugs in combination with low-dose corticosteroids, the inflammatory symptoms in the sibling with the more severe case responded well to IL-1beta blockade. Understanding the pathogenic mechanism underlying such disorders can be helpful for the physician. Our study reinforces the importance of genetic testing and laboratory investigations in combination with careful phenotypic evaluation for the diagnosis of such patients.

Place, publisher, year, edition, pages
2010. Vol. 62, no 7, 2138-2143 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-58807DOI: 10.1002/art.27489ISI: 000282758500034PubMedID: 20506209OAI: diva2:345840
Available from: 2010-08-27 Created: 2010-08-27 Last updated: 2013-10-25Bibliographically approved
In thesis
1. Genetic Variations in the NLRP3 Inflammasome: Susceptibility Factor for Chronic Inflammation
Open this publication in new window or tab >>Genetic Variations in the NLRP3 Inflammasome: Susceptibility Factor for Chronic Inflammation
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

NLRP3 has been recognized as one of the key components of innate immunity. Upon activation, NLRP3 forms a multiprotein complex called as the ‘inflammasome’ which leads to the activation of pro-inflammatory caspase-1 which subsequently results in the formation of Interleukin (IL)-1β and IL-18. Mutations in the NLRP3 gene can lead to its constitutive activation resulting in an uncontrolled production of IL-1β. These mutations have been implicated in hereditary inflammatory diseases, often grouped under Cryopyrin associated periodic syndromes (CAPS, cryopyrin being an alternative name for NLRP3).

Paper I in this thesis presents the case of a patient with a long history of arthritis and antibiotic resistant fever, but without the typical symptoms of CAPS. The patient was a heterozygous carrier of two common polymorphisms, Q705K in NLRP3 and C10X in CARD-8. Experimental studies indicated elevated activity of caspase-1 and IL-1β levels in the patient and a total clinical remission was achieved by IL-1β blockade. These two polymorphisms simultaneously occur in almost 4% of the control population, suggesting the possibility of a genetic predisposition for inflammation in these individuals. We, therefore, investigated a cohort of rheumatoid arthritis (RA) patients in paper II, and found that carrying the combined polymorphisms resulted in increased RA susceptibility and a more severe disease course. Hypothetically, this subgroup might benefit from IL-1β blockade. Paper III presents two patients: siblings, who did not fit into a typical CAPS phenotype. The inflammatory symptoms in both the patients appeared in adult life. A novel and functional M299V mutation in NLRP3 was detected in the siblings who neither had common symptoms nor the same disease severity. Consequent with inflammasome activation, abnormally elevated caspase-1 activity and IL-1β levels were seen. Patients in papers I and III highlight the risk of missing out such patients if attempting a very conventional diagnosis. Paper IV dissects the functional role of Q705K in NLRP3 using THP-1 cells in an in vitro model. Moderately elevated IL-1β and IL-18 levels could be observed in the THP-1 cells expressing Q705K, as compared to the wild type expressing cells, indicating a gain-of-function. Due to the presence of this alteration in healthy individuals it can be classified as a low-penetrance alteration. Additional studies are warranted to elucidate the mechanistic details of this polymorphism.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 69 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1250
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-70077 (URN)978-91-7393-116-8 (ISBN)
Public defence
2011-09-09, Linden, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2011-08-18 Created: 2011-08-18 Last updated: 2011-10-03Bibliographically approved

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