Poster presentation | Open | Published:
Somatic NLRP3 mosaicism in Muckle-Wells syndrome
Pediatric Rheumatologyvolume 13, Article number: P61 (2015)
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. All these diseases are currently considered as different phenotypes of the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been recently detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this genetic mechanism in other CAPS phenotypes.
To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with CAPS phenotypes other than CINCA and NLRP3 mutation-negative by conventional, Sanger-based genetic studies.
Materials and methods
NLRP3 analyses were performed by Sanger sequencing and by targeted deep 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.
32 Spanish patients fulfilling clinical inclusion criteria were enrolled. A variable degree (9.4-34.9%) of somatic NLRP3 mosaicism was detected in 9.3% of enrolled patients (3/32). Their clinical phenotypes were identical to that seen in MWS. Three different missense variants (p.D303A, p.L411F and p.F523L) were identified, being two novels (p.D303A and p.L411F). Bioinformatic and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. Treatment with anti-IL-1 drugs showed long-lasting and positive clinical and biochemical responses.
We herein show novel evidence about the role of somatic NLRP3 mosaicism in MWS pathogenesis, which probably represents a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed us to achieve the definitive diagnoses of these patients, which have had serious clinical implications such as gaining access to anti-IL-1 treatments under legal indication and genetic counseling. The detection of somatic gene mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of novel technologies such as targeted deep sequencing.