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

Research output: Contribution to journalArticle

58 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

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Cryopyrin-Associated Periodic Syndromes
Mosaicism
Phenotype
Cell death
Bioinformatics
Interleukin-1
Assays
Chemical activation
Cells
Apoptosis
Mutation
Pharmaceutical Preparations
Joints
Proteins
High-Throughput Nucleotide Sequencing
Skin
Genetic Counseling
Computational Biology
Transfection
B-Lymphocytes

ASJC Scopus subject areas

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

Cite this

Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes. / Nakagawa, Kenji; Gonzalez-Roca, Eva; Souto, Alejandro; Kawai, Toshinao; Umebayashi, Hiroaki; Campistol, Josep María; Cañellas, Jeronima; Takei, Syuji; Kobayashi, Norimoto; Callejas-Rubio, Jose Luis; Ortego-Centeno, Norberto; Ruiz-Ortiz, Estíbaliz; Rius, Fina; Anton, Jordi; Iglesias, Estibaliz; Jimenez-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, Juan I.

In: Annals of the Rheumatic Diseases, Vol. 74, No. 3, 01.03.2015, p. 603-610.

Research output: Contribution to journalArticle

Nakagawa, K, Gonzalez-Roca, E, Souto, A, Kawai, T, Umebayashi, H, Campistol, JM, Cañellas, J, Takei, S, Kobayashi, N, Callejas-Rubio, JL, Ortego-Centeno, N, Ruiz-Ortiz, E, Rius, F, Anton, J, Iglesias, E, Jimenez-Treviño, S, Vargas, C, Fernandez-Martin, J, Calvo, I, Hernández-Rodríguez, J, Mendez, M, Dordal, MT, Basagaña, M, Bujan, S, Yashiro, M, Kubota, T, Koike, R, Akuta, N, Shimoyama, K, Iwata, N, Saito, MK, Ohara, O, Kambe, N, Yasumi, T, Izawa, K, Kawai, T, Heike, T, Yagüe, J, Nishikomori, R & Aróstegui, JI 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, vol. 74, no. 3, pp. 603-610. https://doi.org/10.1136/annrheumdis-2013-204361
Nakagawa, Kenji ; Gonzalez-Roca, Eva ; Souto, Alejandro ; Kawai, Toshinao ; Umebayashi, Hiroaki ; Campistol, Josep María ; Cañellas, Jeronima ; Takei, Syuji ; Kobayashi, Norimoto ; Callejas-Rubio, Jose Luis ; Ortego-Centeno, Norberto ; Ruiz-Ortiz, Estíbaliz ; Rius, Fina ; Anton, Jordi ; Iglesias, Estibaliz ; Jimenez-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, Juan I. / Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes. In: Annals of the Rheumatic Diseases. 2015 ; Vol. 74, No. 3. pp. 603-610.
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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.",
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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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