Brief Report: Late-Onset Cryopyrin-Associated Periodic Syndrome Due to Myeloid-Restricted Somatic NLRP3 Mosaicism.
Gain-of-function NLRP3 mutations cause cryopyrin-associated periodic syndrome (CAPS), with gene mosaicism playing a relevant role in the pathogenesis. This study was undertaken to characterize the genetic cause underlying late-onset but otherwise typical CAPS.



We studied a 64-year-old patient who presented with recurrent episodes of urticaria-like rash, fever, conjunctivitis, and oligoarthritis at age 56 years. DNA was extracted from both unfractionated blood and isolated leukocyte and CD34+ subpopulations. Genetic studies were performed using both the Sanger method of DNA sequencing and next-generation sequencing (NGS) methods. In vitro and ex vivo analyses were performed to determine the consequences that the presence of the variant have in the normal structure or function of the protein of the detected variant.



NGS analyses revealed the novel p.Gln636Glu NLRP3 variant in unfractionated blood, with an allele frequency (18.4%) compatible with gene mosaicism. Sanger sequence chromatograms revealed a small peak corresponding to the variant allele. Amplicon-based deep sequencing revealed somatic NLRP3 mosaicism restricted to myeloid cells (31.8% in monocytes, 24.6% in neutrophils, and 11.2% in circulating CD34+ common myeloid progenitor cells) and its complete absence in lymphoid cells. Functional analyses confirmed the gain-of-function behavior of the gene variant and hyperactivity of the NLRP3 inflammasome in the patient. Treatment with anakinra resulted in good control of the disease.



We identified the novel gain-of-function p.Gln636Glu NLRP3 mutation, which was detected as a somatic mutation restricted to myeloid cells, as the cause of late-onset but otherwise typical CAPS. Our results expand the diversity of CAPS toward milder phenotypes than previously reported, including those starting during adulthood.
Hospital Clínic de Barcelona, Barcelona, Spain.
Anna
A
Mensa-Vilaro
Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain.
María
M
Teresa Bosque
Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.
Giuliana
G
Magri
Kyoto University, Kyoto, Japan.
Yoshitaka
Y
Honda
Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
Helios
H
Martínez-Banaclocha
Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain.
Marta
M
Casorran-Berges
Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.
Jordi
J
Sintes
Hospital Clínic de Barcelona, Barcelona, Spain.
Eva
E
González-Roca
Hospital Clínic de Barcelona, Barcelona, Spain.
Estibaliz
E
Ruiz-Ortiz
Kyoto University, Kyoto, Japan.
Toshio
T
Heike
Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
Juan J
JJ
Martínez-Garcia
Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
Alberto
A
Baroja-Mazo
Institut Hospital del Mar d'Investigacions Mèdiques and Catalan Institute for Research and Advanced Studies, Barcelona, Spain.
Andrea
A
Cerutti
Kyoto University, Kyoto, Japan.
Ryuta
R
Nishikomori
Hospital Clínic de Barcelona, Barcelona, Spain.
Jordi
J
Yagüe
Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
Pablo
P
Pelegrín
Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain.
Concha
C
Delgado-Beltran
Hospital Clínic de Barcelona, Barcelona, Spain.
Juan I
JI
Aróstegui
D000483:Alleles; D018501:Antirheumatic Agents / Q000627:therapeutic use; D003198:Computer Simulation; D056587:Cryopyrin-Associated Periodic Syndromes / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D000067562:Late Onset Disorders / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009030:Mosaicism; D022423:Myeloid Cells / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics*; D009504:Neutrophils / Q000378:metabolism; D017422:Sequence Analysis, DNA
D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human