Periodic fever, mild arthralgias, and reversible moderate and severe organ inflammation associated with the V198M mutation in the <i>CIAS1</i> gene in three German patients – expanding phenotype of <i>CIAS1</i> related autoinflammatory syndrome

Pörksen, G; Lohse, Peter; Rösen‐Wolff, Angela; Heyden, Stefan; Förster, Theresa; Wendisch, J.; Heubner, Georg; Bernuth, Horst von; Sallmann, Svea; Gahr, Manfred; Roesler, Joachim

doi:10.1111/j.1600-0609.2004.00270.x

Cited by 30 publications

(19 citation statements)

References 24 publications

(49 reference statements)

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“…Paediatric and NOMID/CINCA patients required more dose or frequency adjustments to control their disease activity. One paediatric MWS patient on an increased canakinumab dose, a non-responder to previous anakinra treatment, was a carrier of a V198M mutation, which is related to a heterogeneous CAPS phenotype with variable response to increasing doses of anti-IL-1 medication 1 13…”

Section: Discussionmentioning

confidence: 99%

Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes

Kuemmerle‐Deschner¹,

Hachulla

Cartwright³

et al. 2011

Annals of the Rheumatic Diseases

196

159

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Section: Discussionmentioning

confidence: 99%

Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes

Kuemmerle‐Deschner¹,

Hachulla

Cartwright³

et al. 2011

Annals of the Rheumatic Diseases

196

159

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“…This mutation was originally identified in an FCAS family that was later found to also have an E525K mutation (5), and was subsequently reported in Spanish (42) and French (4) FCAS families, in a British family with MWS and 2 British patients with uncharacterized periodic fevers (3), and in 3 German patients with atypical periodic fevers (43). V198M has been considered to be a reduced-penetrance CIAS1 mutation because it was found in asymptomatic family members and in control DNA samples.…”

Section: Resultsmentioning

confidence: 99%

The clinical continuum of cryopyrinopathies: Novel CIAS1 mutations in North American patients and a new cryopyrin model

Aksentijevich

Putnam

Remmers

et al. 2007

Arthritis & Rheumatism

367

300

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Objective. The cryopyrinopathies are a group of rare autoinflammatory disorders that are caused by mutations in CIAS1, encoding the cryopyrin protein. However, cryopyrin mutations are found only in 50% of patients with clinically diagnosed cryopyrinopathies. This study was undertaken to investigate the structural effect of disease-causing mutations on cryopyrin, in order to gain better understanding of the impact of disease-associated mutations on protein function.Methods. We tested for CIAS1 mutations in 22 patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome, 12 with Muckle-Wells syndrome (MWS), 18 with familial cold-induced autoinflammatory syndrome (FCAS), and 3 probands with MWS/FCAS. In a subset of mutation-negative patients, we screened for mutations in proteins that are either homologous to cryopyrin or involved in the caspase 1/interleukin-1␤ signaling pathway. CIAS1 and other candidate genes were sequenced, models of cryopyrin domains were constructed using structurally homologous proteins as templates, and disease-causing mutations were mapped.Results. Forty patients were mutation positive, and 7 novel mutations, V262A, C259W, L264F, V351L, F443L, F523C, and Y563N, were found in 9 patients. No mutations in any candidate genes were identified. Most mutations mapped to an inner surface of the hexameric ring in the cryopyrin model, consistent with the hypothesis that the mutations disrupt a closed form of cryopyrin, thus potentiating inflammasome assembly. Disease-causing mutations correlated with disease severity only for a subset of known mutations.Conclusion. Our modeling provides insight into potential molecular mechanisms by which cryopyrin mutations can inappropriately activate an inflammatory response. A significant number of patients who are clinically diagnosed as having cryopyrinopathies do not have identifiable disease-associated mutations.

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“…Although the related drug research is still limited in this area, research on other diseases is inspiring. Mutations in the gene encoding NLRP3 have been recognized to be associated with various autoinflammatory syndromes, including familial cold autoinflammatory syndrome, the Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease, which also belongs to cryopyrin-associated periodic syndrome [64]; nephropathy was also involved [65,66]. Excessive production of IL-1 by monocytes/macrophages triggered by the NLRP3 inflammasome is the central pathophysiology of cryopyrin-associated periodic syndrome.…”

Section: Treatmentmentioning

confidence: 99%

Inflammasomes in the Pathophysiology of Kidney Diseases

2015

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Background: The inflammasome is a complex of proteins in the cytoplasm that consists of three main components: a sensor protein (receptor), an adapter protein and caspase-1. Inflammasomes are the critical components of innate immunity and have been gradually recognized as a critical mediator in various autoimmune diseases; also, their role in chronic kidney disease and acute kidney injury has been gradually accepted. Summary: Inflammasomes triggered by infectious or sterile injuries transfer proinflammatory mediators into mature ones through innate danger-signaling platforms. Information on inflammasomes in kidney disease will help to uncover the underlying mechanisms of nephropathy and provide novel therapeutic targets in the future. Key Messages: The inflammasomes can be activated by a series of exogenous and endogenous stimuli, including pathogen-and danger-associated molecular patterns released from or caused by damaged cells. The NACHT, LRR and PYD domain-containing protein 3 (NLRP3) in the kidney exerts its effect not only by the ‘canonical' pathway of IL-1β and IL-18 secretion but also by ‘noncanonical' pathways, such as tumor growth factor-β signaling, epithelial-mesenchymal transition and fibrosis. In both clinical and experimental data, the NLRP3 inflammasome was reported to be involved in the pathogenesis of chronic kidney disease and acute kidney injury. However, the underlying mechanisms are not fully understood. Therapies targeting the activation of the NLRP3 inflammasome or blocking its downstream effectors appear attractive for the pursuit of neuropathy treatments.

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Periodic fever, mild arthralgias, and reversible moderate and severe organ inflammation associated with the V198M mutation in the CIAS1 gene in three German patients – expanding phenotype of CIAS1 related autoinflammatory syndrome

Cited by 30 publications

References 24 publications

Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes

Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes

The clinical continuum of cryopyrinopathies: Novel CIAS1 mutations in North American patients and a new cryopyrin model

Inflammasomes in the Pathophysiology of Kidney Diseases

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