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dc.contributor.authorNakagawa, Kenji-
dc.contributor.authorGonzalez Roca, Eva-
dc.contributor.authorSouto, Alejandro-
dc.contributor.authorKawai, Toshinao-
dc.contributor.authorUmebayashi, Hiroaki-
dc.contributor.authorCampistol Plana, Jaume-
dc.contributor.authorCañellas, Jeronima-
dc.contributor.authorTakei, Syuji-
dc.contributor.authorKobayashi, Norimoto-
dc.contributor.authorCallejas Rubio, José Luis-
dc.contributor.authorOrtego Centeno, Norberto-
dc.contributor.authorRuiz Ortiz, Estíbaliz-
dc.contributor.authorRius, Fina-
dc.contributor.authorAntón López, Jordi-
dc.contributor.authorIglesias, Estibaliz-
dc.contributor.authorJiménez Treviño, Santiago-
dc.contributor.authorVargas, Carmen-
dc.contributor.authorFernandez Martin, Julian-
dc.contributor.authorCalvo, Inmaculada-
dc.contributor.authorHernández Rodríguez, José-
dc.contributor.authorMendez, María-
dc.contributor.authorDordal, María Teresa-
dc.contributor.authorBasagaña, Maria-
dc.contributor.authorBujan, Segundo-
dc.contributor.authorYashiro, Masato-
dc.contributor.authorKubota, Tetsuo-
dc.contributor.authorKoike, Ryuji-
dc.contributor.authorAkuta, Naoko-
dc.contributor.authorShimoyama, Kumiko-
dc.contributor.authorIwata, Naomi-
dc.contributor.authorSaito, Megumu K.-
dc.contributor.authorOhara, Osamu-
dc.contributor.authorKambe, Naotomo-
dc.contributor.authorYasumi, Takahiro-
dc.contributor.authorIzawa, Kazushi-
dc.contributor.authorKawai, Tomoki-
dc.contributor.authorHeike, Toshio-
dc.contributor.authorYagüe, Jordi-
dc.contributor.authorNishikomori, Ryuta-
dc.contributor.authorAróstegui Gorospe, Juan Ignacio-
dc.description.abstractFamilial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. OBJECTIVE: To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. METHODS: NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. RESULTS: A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. CONCLUSIONS: We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools-
dc.format.extent9 p.-
dc.publisherBMJ Publishing Group-
dc.relation.isformatofReproducció del document publicat a:
dc.relation.ispartofAnnals of the Rheumatic Diseases, 2015, vol. 74, num. 3, p. 603-610-
dc.rights(c) BMJ Publishing Group, 2015-
dc.subject.classificationGenètica molecular-
dc.subject.classificationMalalties hereditàries-
dc.subject.classificationGenètica mèdica-
dc.subject.otherMolecular genetics-
dc.subject.otherGenetic diseases-
dc.subject.otherMedical genetics-
dc.titleSomatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes-
Appears in Collections:Articles publicats en revistes (Cirurgia i Especialitats Medicoquirúrgiques)

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