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. 2011 Nov;63(11):3625-32.
doi: 10.1002/art.30512.

High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study

Naoko Tanaka  1 , Kazushi Izawa, Megumu K Saito, Mio Sakuma, Koichi Oshima, Osamu Ohara, Ryuta Nishikomori, Takeshi Morimoto, Naotomo Kambe, Raphaela Goldbach-Mansky, Ivona Aksentijevich, Geneviève de Saint Basile, Bénédicte Neven, Mariëlle van Gijn, Joost Frenkel, Juan I Aróstegui, Jordi Yagüe, Rosa Merino, Mercedes Ibañez, Alessandra Pontillo, Hidetoshi Takada, Tomoyuki Imagawa, Tomoki Kawai, Takahiro Yasumi, Tatsutoshi Nakahata, Toshio Heike
Affiliations

High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study

Naoko Tanaka et al. Arthritis Rheum. 2011 Nov.

Abstract

Objective: Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in ∼40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome.

Methods: An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations.

Results: Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean ± SD 12.1 ± 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms.

Conclusion: Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.

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Figures

Figure 1
Figure 1
In vitro functional assessment of the identified NLRP3 mosaicism mutations. A, Necrotic cell death of THP-1 cells induced by the identified somatic NLRP3 mosaicism mutations. Green fluorescent protein (GFP)–fused mutant NLRP3 was transfected into THP-1 cells. The percentage of dead cells (7-aminoactinomycin D positive) among GFP-positive cells is shown. Values are the mean ± SD of triplicate experiments, and data are representative of 2 independent experiments. None = nothing transfected; mock = vector without NLRP3; WT = wild-type NLRP3; R260W = NLRP3 with p.R260W (frequent mutations in patients with cryopyrin-associated periodic syndromes). B, ASC-dependent NF-κB activation induced by the identified somatic NLRP3 mosaicism mutations. HEK 293FT cells were cotransfected with WT or mutant NLRP3 in the presence or absence of ASC. The induction of NF-κB is shown as the fold change compared with cells that were transfected with a control vector without ASC (set at 1). Values are the mean ± SD of triplicate experiments, and data are representative of 2 independent experiments.
Figure 2
Figure 2
Comparison of the clinical profiles of patients carrying somatic NLRP3 mutations and patients carrying the same mutation, but with germline status. Clinical profiles of patients with mosaicism and those of patients with heterozygous germline mutations are compared for each protein variant (L264F, D303H, G307V, Y570C, and G755R). The data on 4 typical clinical symptoms are shown. Total numbers of patients with mosaicism and total numbers of patients with heterozygous mutation examined are shown as a bar for each protein variant. Each bar is stratified according to the presence or absence of the symptom. For the protein variant L264F, no data on mental retardation were available for the patient with a heterozygous germline mutation.
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