RT Journal Article SR Electronic T1 Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes JF Annals of the Rheumatic Diseases JO Ann Rheum Dis FD BMJ Publishing Group Ltd and European League Against Rheumatism SP 603 OP 610 DO 10.1136/annrheumdis-2013-204361 VO 74 IS 3 A1 Nakagawa, Kenji A1 Gonzalez-Roca, Eva A1 Souto, Alejandro A1 Kawai, Toshinao A1 Umebayashi, Hiroaki A1 Campistol, Josep María A1 Cañellas, Jeronima A1 Takei, Syuji A1 Kobayashi, Norimoto A1 Callejas-Rubio, Jose Luis A1 Ortego-Centeno, Norberto A1 Ruiz-Ortiz, Estíbaliz A1 Rius, Fina A1 Anton, Jordi A1 Iglesias, Estibaliz A1 Jimenez-Treviño, Santiago A1 Vargas, Carmen A1 Fernandez-Martin, Julian A1 Calvo, Inmaculada A1 Hernández-Rodríguez, José A1 Mendez, María A1 Dordal, María Teresa A1 Basagaña, Maria A1 Bujan, Segundo A1 Yashiro, Masato A1 Kubota, Tetsuo A1 Koike, Ryuji A1 Akuta, Naoko A1 Shimoyama, Kumiko A1 Iwata, Naomi A1 Saito, Megumu K A1 Ohara, Osamu A1 Kambe, Naotomo A1 Yasumi, Takahiro A1 Izawa, Kazushi A1 Kawai, Tomoki A1 Heike, Toshio A1 Yagüe, Jordi A1 Nishikomori, Ryuta A1 Aróstegui, Juan I YR 2015 UL http://ard.bmj.com/content/74/3/603.abstract AB Familial 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.