Abstract
IntroductionMutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS). The significance of the V198M variant is unclear; it has been reported in association with various CAPS phenotypes and as a variant of uncertain consequence. The aim of this study was to characterize the clinical phenotypes and treatments in individuals with V198M assessed in a single UK center.MethodsDNA samples from 830 subjects with fever syndromes or a family history of CAPS were screened for mutations in the NLRP3 gene with polymerase chain reaction (PCR) and sequencing. A detailed medical history was available in all cases. Inflammatory disease activity was monitored monthly with measurements of serum amyloid A protein (SAA) and C-reactive protein (CRP) in symptomatic individuals.ResultsNLRP3 V198M was identified in 19 subjects. It was found in association with CAPS in five cases, in one patient with Schnitzler syndrome, in three patients who also had a nucleotide alteration in another fever gene, and in three other patients with evidence of an autoinflammatory phenotype. Seven asymptomatic individuals were detected during screening of family members.ConclusionsThe NLRP3 V198M variant shows variable expressivity and reduced penetrance. It may be associated with classical inherited or apparently sporadic CAPS and with atypical autoinflammatory disease of varying severity, intriguingly including Schnitzler syndrome. The factors that influence the pathogenic consequences of this variant remain unknown. However, the remarkable response to interleukin 1 (IL-1) blockade in all but one individual in our series confirms that their clinical features are indeed mediated by IL-1.
Highlights
Mutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS)
Symptomatic CAPS is accompanied by a striking acute-phase response, with serum concentrations of C-reactive protein (CRP) and serum amyloid A protein (SAA) frequently elevated by 100- to 1,000fold, underlying the high risk of AA amyloidosis [10,12]
We describe here the clinical phenotypes and treatments in individuals with V198M characterized in a single UK center and review the published literature regarding the clinical spectrum associated with this variant
Summary
Mutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS). 138 sequence variants of NLRP3 have been identified, of which 110 have been associated with CAPS, and 28 are either nonpathogenic or of undetermined significance [13], the commonest of which is the Q703K variant ( described as Q705K in older literature) [14] that has been reported in 5% of healthy Caucasian alleles [11]. The NLRP3 V198M variant (previously described as V200M) [10] is of particular interest because it has been reported in both individual patients and families with apparently classical CAPS [4,10,15]; in association with other autoinflammatory syndromes [16,17]; in patients with apparently acquired autoinflammatory disorders including the IgM paraprotein-related Schnitzler syndrome [18]; and in healthy Caucasian controls with an allele frequency of between 0.0038 [10] and 0.0074 [11]
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