Article Text

PDF
Extended report
Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes
  1. Kenji Nakagawa1,
  2. Eva Gonzalez-Roca2,
  3. Alejandro Souto3,
  4. Toshinao Kawai4,
  5. Hiroaki Umebayashi5,
  6. Josep María Campistol6,
  7. Jeronima Cañellas7,
  8. Syuji Takei8,
  9. Norimoto Kobayashi9,
  10. Jose Luis Callejas-Rubio10,
  11. Norberto Ortego-Centeno10,
  12. Estíbaliz Ruiz-Ortiz2,
  13. Fina Rius2,
  14. Jordi Anton11,
  15. Estibaliz Iglesias11,
  16. Santiago Jimenez-Treviño12,
  17. Carmen Vargas13,
  18. Julian Fernandez-Martin14,
  19. Inmaculada Calvo15,
  20. José Hernández-Rodríguez16,
  21. María Mendez17,
  22. María Teresa Dordal18,
  23. Maria Basagaña19,
  24. Segundo Bujan20,
  25. Masato Yashiro21,
  26. Tetsuo Kubota22,
  27. Ryuji Koike22,
  28. Naoko Akuta23,
  29. Kumiko Shimoyama24,
  30. Naomi Iwata25,
  31. Megumu K Saito26,
  32. Osamu Ohara27,
  33. Naotomo Kambe28,
  34. Takahiro Yasumi1,
  35. Kazushi Izawa1,
  36. Tomoki Kawai1,
  37. Toshio Heike1,
  38. Jordi Yagüe2,
  39. Ryuta Nishikomori1,
  40. Juan I Aróstegui2
  1. 1Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  2. 2Department of Immunology-CDB, Hospital Clínic-IDIBAPS, Barcelona, Spain
  3. 3Department of Rheumatology, Hospital Universitario de Santiago de Compostela, Santiago de Compostela, Spain
  4. 4Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan
  5. 5Department of General Pediatrics, Miyagi Children's Hospital, Sendai, Japan
  6. 6Department of Nephrology, Hospital Clínic-IDIBAPS, Barcelona, Spain
  7. 7Department of Rheumatology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  8. 8Faculty of Medicine, School of Health Sciences, Kagoshima University, Kagoshima, Japan
  9. 9Department of Pediatrics, School of Medicine, Shinshu University, Matsumoto, Japan
  10. 10Department of Internal Medicine, Hospital Universitario San Cecilio, Granada, Spain
  11. 11Department of Pediatric Rheumatology, Hospital Sant Joan de Deu, Esplugues, Spain
  12. 12Department of Pediatrics, Hospital Central de Asturias, Oviedo, Spain
  13. 13Department of Rheumatology, Hospital Virgen de la Macarena, Sevilla, Spain
  14. 14Department of Internal Medicine, Hospital Meixoeiro, Vigo, Spain
  15. 15Department of Pediatric Rheumatology, Hospital Universitario La Fe, Valencia, Spain
  16. 16Department of Autoimmune Diseases, Hospital Clínic-IDIBAPS, Barcelona, Spain
  17. 17Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  18. 18Department of Allergy, Hospital Municipal de Badalona, Badalona, Spain
  19. 19Allergy Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  20. 20Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain
  21. 21Department of Pediatrics, Okayama University Graduate School of Medicine, Okayama, Japan
  22. 22Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  23. 23Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
  24. 24Third Internal Medicine Department, Hamamatsu University School of Medicine, Hamamatsu, Japan
  25. 25Department of Infection and Immunology, Aichi Children's Health and Medical Centre, Obu, Japan
  26. 26Department of Clinical Application, Center for iPS cell research and application, Kyoto University, Kyoto, Japan
  27. 27Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Japan
  28. 28Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan
  1. Correspondence to Dr Juan I Aróstegui, Immunology Department (esc 4-pl 0), Hospital Clínic, Villarroel, 170, Barcelona 08036, Spain; jiaroste{at}clinic.ub.es and Dr Ryuta Nishikomori,Department of Pediatrics, Kyoto University Graduate School of Medicine, 54 Shogoin Sakyo, Kyoto 606-8507, Japan; rnishiko@kuhp.kyoto-u.ac.jp

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
  • somatic mosaicism
  • massively parallel sequencing

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.