Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes

Kenji Nakagawa, Eva Gonzalez-Roca, Alejandro Souto, Toshinao Kawai, Hiroaki Umebayashi, Josep María Campistol, Jeronima Cañellas, Syuji Takei, Norimoto Kobayashi, Jose Luis Callejas-Rubio, Norberto Ortego-Centeno, Estíbaliz Ruiz-Ortiz, Fina Rius, Jordi Anton, Estibaliz Iglesias, Santiago Jimenez-Treviño, Carmen Vargas, Julian Fernandez-Martin, Inmaculada Calvo, José Hernández-RodríguezMaría Mendez, María Teresa Dordal, Maria Basagaña, Segundo Bujan, Masato Yashiro, Tetsuo Kubota, Ryuji Koike, Naoko Akuta, Kumiko Shimoyama, Naomi Iwata, Megumu K. Saito, Osamu Ohara, Naotomo Kambe, Takahiro Yasumi, Kazushi Izawa, Tomoki Kawai, Toshio Heike, Jordi Yagüe, Ryuta Nishikomori, Juan I. Aróstegui

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61 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)603-610
Number of pages8
JournalAnnals of the rheumatic diseases
Volume74
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

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    Nakagawa, K., Gonzalez-Roca, E., Souto, A., Kawai, T., Umebayashi, H., Campistol, J. M., Cañellas, J., Takei, S., Kobayashi, N., Callejas-Rubio, J. L., Ortego-Centeno, N., Ruiz-Ortiz, E., Rius, F., Anton, J., Iglesias, E., Jimenez-Treviño, S., Vargas, C., Fernandez-Martin, J., Calvo, I., ... Aróstegui, J. I. (2015). Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes. Annals of the rheumatic diseases, 74(3), 603-610. https://doi.org/10.1136/annrheumdis-2013-204361