Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis

Abstract

Objective. Familial cold urticaria (FCU) andMuckle-Wells syndrome (MWS) are dominantly inherited autoinflammatory disorders that cause rashes, fever, arthralgia, and in some subjects, AA amyloidosis, and have been mapped to chromosome 1q44. Sensorineural deafness in MWS, and provocation of symptoms by cold in FCU, are distinctive features. This study was undertaken to characterize the genetic basis of FCU, MWS, and an overlapping disorder in French Canadian, British, and Indian families, respectively.Methods. Mutations in the candidate gene NALP3, which has also been named CIAS1 and PYPAF1, were sought in the study families, in a British/Spanish patient with apparent sporadic MWS, and in matched population controls. Identified variants were sought in 50 European subjects with uncharacterized, apparently sporadic periodic fever syndromes, 48 subjects with rheumatoid arthritis (RA), and 19 subjects with juvenile idiopathic arthritis (JIA).Results. Point mutations, encoding putative protein variants R262W and L307P, were present in all affected members of the Indian and French Canadian families, respectively, but not in controls. The R262W variant was also present in the subject with sporadic MWS. The V200M variant was present in all affected members of the British family with MWS, in 2 of the 50 subjects with uncharacterized periodic fevers, and in 1 of 130 Caucasian and 2 of 48 Indian healthy controls. No mutations were identified among the subjects with RA or JIA.Conclusion. These findings confirm that mutations in the NALP3/CIAS1/PYPAF1 gene are associated with FCU and MWS, and that disease severity and clinical features may differ substantially within and between families. Analysis of this gene will improve classification of patients with inherited or apparently sporadic periodic fever syndromes.

Inflammatory caspases and inflammasomes: master switches of inflammation

“…Alternative splicing of the LRR region is evident for virtually all NALPs as detected by EST analysis and the cloning of various NALPs. 66,67 Moreover, it is interesting to note that exon-exon junctions disrupt the b-strand that is predicted in binding targets. Therefore, alternative splicing not only reorganize the numbers of bstrand but generate completely new b-strands allowing maximal variability in the ligand recognition region.…”

“…66,86,87 All three disorders are closely related autoinflammatory syndromes characterized by periodic fever, skin rashes, amyloidosis and in the case of CINCA, the eventual development of neurological complications. Mutations in NALP3 confer a gain of function to the protein, resulting in constitutively active NALP3 in Muckle Wells patients.…”

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

“…69 These pathologies are listed in order of increasing disease severity and life-threatening potential, and are characterized by recurrent episodes of fever, rush, arthropathies and various degrees of neurological complications. [70][71][72] Genetic studies of CAPS identified more than 90 disease-associated genetic variants of the NLRP3 gene, the majority of which are autosomal dominant missense point mutations located in exon 3, encoding the NATCH domain ( Figure 3 and Table 1). 73,74 Despite the familial recurrence, some genetic variants inducing CAPS phenotypes result from de novo mutations.…”

The genetics of the amyloidoses: interactions with immunity and inflammation

“…68 Similar analyses have been performed in populations defined by the mutations in genes that are responsible for the hereditary inflammatory diseases FMF, Familial Cold Urticaria (FCAS), Muckle-Wells Syndrome (MWS), Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), TNF-receptor associated periodic syndromes (TRAPS), Neonatal-onset inflammatory disease/ chronic infantile neurologic cutaneous and articular syndrome (NOMID/CINCA) and Pyogenic arthritis with pyoderma gangrenosum and acne (PAPA). [76][77][78][79] All of these are characterized by recurrent febrile episodes with various constellations of clinical features. AA amyloidosis is common in FMF, rare in HIDS, uncommon in FCAS, present in about 10% of cases of TRAPS, and 25% of MWS.…”

“…The relationship of this gene to intrinsic inflammatory processes is unclear. 77,78,[80][81][82][83] The prototypic and most frequently described of these disorders, FMF is autosomal recessive as is HIDS. The others appear to have dominant inheritance.…”