TY - JOUR
T1 - Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes
AU - Nakagawa, Kenji
AU - Gonzalez-Roca, Eva
AU - Souto, Alejandro
AU - Kawai, Toshinao
AU - Umebayashi, Hiroaki
AU - Campistol, Josep María
AU - Cañellas, Jeronima
AU - Takei, Syuji
AU - Kobayashi, Norimoto
AU - Callejas-Rubio, Jose Luis
AU - Ortego-Centeno, Norberto
AU - Ruiz-Ortiz, Estíbaliz
AU - Rius, Fina
AU - Anton, Jordi
AU - Iglesias, Estibaliz
AU - Jimenez-Treviño, Santiago
AU - Vargas, Carmen
AU - Fernandez-Martin, Julian
AU - Calvo, Inmaculada
AU - Hernández-Rodríguez, José
AU - Mendez, María
AU - Dordal, María Teresa
AU - Basagaña, Maria
AU - Bujan, Segundo
AU - Yashiro, Masato
AU - Kubota, Tetsuo
AU - Koike, Ryuji
AU - Akuta, Naoko
AU - Shimoyama, Kumiko
AU - Iwata, Naomi
AU - Saito, Megumu K.
AU - Ohara, Osamu
AU - Kambe, Naotomo
AU - Yasumi, Takahiro
AU - Izawa, Kazushi
AU - Kawai, Tomoki
AU - Heike, Toshio
AU - Yagüe, Jordi
AU - Nishikomori, Ryuta
AU - Aróstegui, Juan I.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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 chainenhancer of activated B cells (NF-?B) 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.
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 chainenhancer of activated B cells (NF-?B) 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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U2 - 10.1136/annrheumdis-2013-204361
DO - 10.1136/annrheumdis-2013-204361
M3 - Article
C2 - 24326009
AN - SCOPUS:84922464191
VL - 74
SP - 603
EP - 610
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
SN - 0003-4967
IS - 3
ER -