title: Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes.
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.
authors: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Kenji
authors: K
authors: Nakagawa
authors: Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors: Eva
authors: E
authors: Gonzalez-Roca
authors: Department of Rheumatology, Hospital Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
authors: Alejandro
authors: A
authors: Souto
authors: Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
authors: Toshinao
authors: T
authors: Kawai
authors: Department of General Pediatrics, Miyagi Children's Hospital, Sendai, Japan.
authors: Hiroaki
authors: H
authors: Umebayashi
authors: Department of Nephrology, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors: Josep María
authors: JM
authors: Campistol
authors: Department of Rheumatology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
authors: Jeronima
authors: J
authors: Cañellas
authors: Faculty of Medicine, School of Health Sciences, Kagoshima University, Kagoshima, Japan.
authors: Syuji
authors: S
authors: Takei
authors: Department of Pediatrics, School of Medicine, Shinshu University, Matsumoto, Japan.
authors: Norimoto
authors: N
authors: Kobayashi
authors: Department of Internal Medicine, Hospital Universitario San Cecilio, Granada, Spain.
authors: Jose Luis
authors: JL
authors: Callejas-Rubio
authors: Department of Internal Medicine, Hospital Universitario San Cecilio, Granada, Spain.
authors: Norberto
authors: N
authors: Ortego-Centeno
authors: Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors: Estíbaliz
authors: E
authors: Ruiz-Ortiz
authors: Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors: Fina
authors: F
authors: Rius
authors: Department of Pediatric Rheumatology, Hospital Sant Joan de Deu, Esplugues, Spain.
authors: Jordi
authors: J
authors: Anton
authors: Department of Pediatric Rheumatology, Hospital Sant Joan de Deu, Esplugues, Spain.
authors: Estibaliz
authors: E
authors: Iglesias
authors: Department of Pediatrics, Hospital Central de Asturias, Oviedo, Spain.
authors: Santiago
authors: S
authors: Jimenez-Treviño
authors: Department of Rheumatology, Hospital Virgen de la Macarena, Sevilla, Spain.
authors: Carmen
authors: C
authors: Vargas
authors: Department of Internal Medicine, Hospital Meixoeiro, Vigo, Spain.
authors: Julian
authors: J
authors: Fernandez-Martin
authors: Department of Pediatric Rheumatology, Hospital Universitario La Fe, Valencia, Spain.
authors: Inmaculada
authors: I
authors: Calvo
authors: Department of Autoimmune Diseases, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors: José
authors: J
authors: Hernández-Rodríguez
authors: Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
authors: María
authors: M
authors: Mendez
authors: Department of Allergy, Hospital Municipal de Badalona, Badalona, Spain.
authors: María Teresa
authors: MT
authors: Dordal
authors: Allergy Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
authors: Maria
authors: M
authors: Basagaña
authors: Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain.
authors: Segundo
authors: S
authors: Bujan
authors: Department of Pediatrics, Okayama University Graduate School of Medicine, Okayama, Japan.
authors: Masato
authors: M
authors: Yashiro
authors: Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Tetsuo
authors: T
authors: Kubota
authors: Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Ryuji
authors: R
authors: Koike
authors: Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: Naoko
authors: N
authors: Akuta
authors: Third Internal Medicine Department, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors: Kumiko
authors: K
authors: Shimoyama
authors: Department of Infection and Immunology, Aichi Children's Health and Medical Centre, Obu, Japan.
authors: Naomi
authors: N
authors: Iwata
authors: Department of Clinical Application, Center for iPS cell research and application, Kyoto University, Kyoto, Japan.
authors: Megumu K
authors: MK
authors: Saito
authors: Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Japan.
authors: Osamu
authors: O
authors: Ohara
authors: Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan.
authors: Naotomo
authors: N
authors: Kambe
authors: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Takahiro
authors: T
authors: Yasumi
authors: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Kazushi
authors: K
authors: Izawa
authors: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Tomoki
authors: T
authors: Kawai
authors: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Toshio
authors: T
authors: Heike
authors: Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors: Jordi
authors: J
authors: Yagüe
authors: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Ryuta
authors: R
authors: Nishikomori
authors: Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors: Juan I
authors: JI
authors: Aróstegui
mesh_terms: D000293:Adolescent; D044466:Asian People / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002675:Child, Preschool; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009030:Mosaicism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human
keywords: CAPS; NLRP3; massively parallel sequencing; somatic mosaicism