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Title: Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes
Author: Nakagawa, Kenji
Gonzalez Roca, Eva
Souto, Alejandro
Kawai, Toshinao
Umebayashi, Hiroaki
Campistol Plana, Jaume
Cañellas, Jeronima
Takei, Syuji
Kobayashi, Norimoto
Callejas Rubio, José Luis
Ortego Centeno, Norberto
Ruiz Ortiz, Estíbaliz
Rius, Fina
Antón López, Jordi
Iglesias, Estibaliz
Jiménez Treviño, Santiago
Vargas, Carmen
Fernandez Martin, Julian
Calvo, Inmaculada
Hernández Rodríguez, José
Mendez, María
Dordal, María Teresa
Basagaña, Maria
Bujan, Segundo
Yashiro, Masato
Kubota, Tetsuo
Koike, Ryuji
Akuta, Naoko
Shimoyama, Kumiko
Iwata, Naomi
Saito, Megumu K.
Ohara, Osamu
Kambe, Naotomo
Yasumi, Takahiro
Izawa, Kazushi
Kawai, Tomoki
Heike, Toshio
Yagüe, Jordi
Nishikomori, Ryuta
Aróstegui Gorospe, Juan Ignacio
Keywords: Genètica molecular
Malalties hereditàries
Genètica mèdica
Molecular genetics
Genetic diseases
Medical genetics
Issue Date: Mar-2015
Publisher: BMJ Publishing Group
Abstract: 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
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It is part of: Annals of the Rheumatic Diseases, 2015, vol. 74, num. 3, p. 603-610
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ISSN: 0003-4967
Appears in Collections:Articles publicats en revistes (Cirurgia i Especialitats Medicoquirúrgiques)

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