Somatic Mosaicism of CIAS1 in a Patient with Chronic Infantile Neurologic, Cutaneous, Articular Syndrome

Saito, Mitsuru; Nishikomori, Ryuta; Fujisawa, Akihiro; Kambe, Naotomo; Hizume, M.N.; Okafuji, Ikuo; Yoshioka, Takakazu; Yoshimoto, Momoko; Omori, Kao; Kusunoki, Takashi; Heike, Toshio; Nakahata, Tatsutoshi

doi:10.1016/j.jaci.2005.12.074

Cited by 46 publications

(78 citation statements)

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“…Un polymorphisme de NLRP3 interférant avec le processus de phosphorylation de la sérine (S198N) a été identifié chez un patient présen-tant un CAPS. Néanmoins, ce patient était également porteur d'une autre mutation, bien caractérisée dans ce syndrome (Y570C), et sans doute responsable de la pathologie [34]. Ces résultats sont cohérents avec l'observation plus ancienne d'une déubiquitination de NLRP3 dépendant des ROS mitochondriales produites lors du priming non-transcriptionnel induit par un bref engagement de TLR4 [20].…”

Section: Les Voies De Signalisation Qui Contrôlent L'assemblage De L'unclassified

NLRP3, un inflammasome sous contrôle

Groslambert

2018

Med Sci (Paris)

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> La réponse immunitaire innée protège l'organisme par la détection rapide des agents pathogènes et des lésions via des récepteurs spéciali-sés, dont NLRP3. Celui-ci assemble un inflammasome, un complexe cytosolique de signalisation qui active la caspase-1, contrôle la libération de cytokines et de facteurs inflammatoires produits dans le cytosol comme les interleukines 1 / . Les pathologies inflammatoires associées à NLRP3, dont la goutte, révèlent la nécessité d'un contrôle étroit de son activité. Cette revue présente les avancées sur la signalisation du priming (ou amorçage) du complexe puis de son activation avec une attention particulière sur le rôle des modifications post-traductionnelles de NLRP3. < cytokines et d'autres facteurs intracellulaires pro-inflammatoires dont l'IL-1 La mort par pyroptose de cellules infectées permet d'éliminer en parallèle les niches de réplication des pathogènes intracellulaires. La structure des inflammasomes dits non-canoniques, associés à la caspase-11, ou 4 et 5 chez l'homme, reste mal connue. Les inflammasomes canoniques, qui sont eux, associés à la caspase-1, sont assemblés par des récepteurs cytosoliques de la famille des NLR (nucleotide-binding domain leucin-rich repeat) ou ALR (Aim2-like receptors). Ces récepteurs s'oligomérisent pour former une plateforme de nucléation pour des filaments formés par la protéine adaptatrice ASC (apoptosis-associated speck-like protein containing a CARD domain, aussi appelé PYCARD, CARD5, TMS1, Q9ULZ3), dont la surface permet, à son tour, la nucléation de filaments de pro-caspase-1 [4]. Ces inflammasomes forment des specks (ou structures ponctiformes) d'une taille de l'ordre du micron, visibles en microscopie, et qui sont uniques pour une cellule. NLRP3 (nucleotide-binding domain leucin-rich repeat [LRR] and pyrin-containing receptor 3, nommé également cryopyrin, CIAS1 [cold autoinflammatory syndrome 1 protein] ou NALP3 [NACHT, LRR and PYD domains-containing protein 3]) a été initialement décrit pour son association génétique avec des syndromes auto-inflammatoires héréditaires monogéniques dominants, nommés CAPS (cryopyrin-associated periodic syndrome) ou cryopyrinopathies [5]. Depuis, NLRP3 a été impliqué dans de nombreuses pathologies multifactorielles à composante inflammatoire, dont l'arthrite goutteuse, l'athérosclérose, le diabète de type 2 et la stéatose hépatique non-alcoolique [6,7]. Il est également impliqué dans plusieurs maladies neurodégénéra-tives, dont la sclérose en plaques et les maladies d'Alzheimer et de Parkinson, ainsi que dans les pathologies associées au vieillissement [6][7][8][9]. NLRP3 est aussi important au cours des infections par diffé-rents pathogènes. Il intervient en effet dans la reconnaissance de

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Section: Les Voies De Signalisation Qui Contrôlent L'assemblage De L'unclassified

NLRP3, un inflammasome sous contrôle

Groslambert

2018

Med Sci (Paris)

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“…NOMID has the most severe clinical phenotype and worst prognosis; FCAS is relatively mild with a good prognosis, and MWS lies in between. Only half of all patients with clinical NOMID have a demonstrable mutation in CIAS, which led to the exploration of the role of somatic mosaicism in causing NOMID [9]. In one NOMID patient with CNS disease, a somatic mutation resulted in the presence of Y570C change in only 16.7% of cells in whole blood.…”

Section: Update On the Genetics Underlying Monogenic Autoinflammatorymentioning

confidence: 99%

The spectrum of autoinflammatory diseases: recent bench to bedside observations

Ryan¹,

Goldbach‐Mansky

2008

Current Opinion in Rheumatology

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Purpose of review-The autoinflammatory diseases are a group of conditions that include the hereditary fever syndromes, and result from upregulated innate immune responses. The discovery of the genetic basis for these conditions led to the description of novel intracellular receptors for infectious and noninfectious danger signals. This article focuses on recent progress in our understanding of autoinflammatory syndromes, and how insights into these conditions have triggered the exploration of the role of innate immunity in common rheumatologic diseases.Recent findings-New models for the pathogenesis of several autoinflammatory syndromes have been proposed, including the role of pyrin and cryopyrin in regulating inflammation. Robust evidence has emerged that IL-1β oversecretion is pivotal in cryopyrin-associated periodic syndromes, and that IL-1 inhibition ameliorates the clinical features of these syndromes. Monosodium urate crystals stimulate IL-1β secretion via cryopyrin, which led to the addition of gout to the spectrum of autoinflammatory diseases.Summary-Advances in our understanding of the autoinflammatory diseases have led to renewed interest in the innate immune system, and its role in the pathogenesis of more common rheumatic diseases.

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“…Saito and coworkers described a NOMID/CINCA syndrome patient with somatic mosaicism for a mutation in exon 3 of CIAS1, with varying frequencies of the mutant allele in whole blood and leukocytes. Those authors proposed that somatic mosaicism may account for at least some of the undetected mutations in CIAS1 mutation-negative patients (14).…”

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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

373

299

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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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Somatic Mosaicism of CIAS1 in a Patient with Chronic Infantile Neurologic, Cutaneous, Articular Syndrome

Cited by 46 publications

References 0 publications

NLRP3, un inflammasome sous contrôle

NLRP3, un inflammasome sous contrôle

The spectrum of autoinflammatory diseases: recent bench to bedside observations

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

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