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Ann Rheum Dis. 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.

Author information

1
Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
2
Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain.
3
Department of Rheumatology, Hospital Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
4
Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
5
Department of General Pediatrics, Miyagi Children's Hospital, Sendai, Japan.
6
Department of Nephrology, Hospital Clínic-IDIBAPS, Barcelona, Spain.
7
Department of Rheumatology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
8
Faculty of Medicine, School of Health Sciences, Kagoshima University, Kagoshima, Japan.
9
Department of Pediatrics, School of Medicine, Shinshu University, Matsumoto, Japan.
10
Department of Internal Medicine, Hospital Universitario San Cecilio, Granada, Spain.
11
Department of Pediatric Rheumatology, Hospital Sant Joan de Deu, Esplugues, Spain.
12
Department of Pediatrics, Hospital Central de Asturias, Oviedo, Spain.
13
Department of Rheumatology, Hospital Virgen de la Macarena, Sevilla, Spain.
14
Department of Internal Medicine, Hospital Meixoeiro, Vigo, Spain.
15
Department of Pediatric Rheumatology, Hospital Universitario La Fe, Valencia, Spain.
16
Department of Autoimmune Diseases, Hospital Clínic-IDIBAPS, Barcelona, Spain.
17
Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
18
Department of Allergy, Hospital Municipal de Badalona, Badalona, Spain.
19
Allergy Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
20
Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain.
21
Department of Pediatrics, Okayama University Graduate School of Medicine, Okayama, Japan.
22
Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
23
Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
24
Third Internal Medicine Department, Hamamatsu University School of Medicine, Hamamatsu, Japan.
25
Department of Infection and Immunology, Aichi Children's Health and Medical Centre, Obu, Japan.
26
Department of Clinical Application, Center for iPS cell research and application, Kyoto University, Kyoto, Japan.
27
Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Japan.
28
Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan.

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

PMID:
24326009
DOI:
10.1136/annrheumdis-2013-204361
[Indexed for MEDLINE]
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