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. 2015 Mar;74(3):603-10.
doi: 10.1136/annrheumdis-2013-204361. Epub 2013 Dec 10.

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

Kenji Nakagawa  1 , Eva Gonzalez-Roca  2 , Alejandro Souto  3 , Toshinao Kawai  4 , Hiroaki Umebayashi  5 , Josep María Campistol  6 , Jeronima Cañellas  7 , Syuji Takei  8 , Norimoto Kobayashi  9 , Jose Luis Callejas-Rubio  10 , Norberto Ortego-Centeno  10 , Estíbaliz Ruiz-Ortiz  2 , Fina Rius  2 , Jordi Anton  11 , Estibaliz Iglesias  11 , Santiago Jimenez-Treviño  12 , Carmen Vargas  13 , Julian Fernandez-Martin  14 , Inmaculada Calvo  15 , José Hernández-Rodríguez  16 , María Mendez  17 , María Teresa Dordal  18 , Maria Basagaña  19 , Segundo Bujan  20 , Masato Yashiro  21 , Tetsuo Kubota  22 , Ryuji Koike  22 , Naoko Akuta  23 , Kumiko Shimoyama  24 , Naomi Iwata  25 , Megumu K Saito  26 , Osamu Ohara  27 , Naotomo Kambe  28 , Takahiro Yasumi  1 , Kazushi Izawa  1 , Tomoki Kawai  1 , Toshio Heike  1 , Jordi Yagüe  2 , Ryuta Nishikomori  1 , Juan I Aróstegui  2
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Free article

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

Kenji Nakagawa et al. Ann Rheum Dis. 2015 Mar.
Free article

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.

Keywords: CAPS; NLRP3; massively parallel sequencing; somatic mosaicism.

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