Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene

Abstract

Objective. To investigate the involvement of the CIAS1/PYPAF1/NALP3 gene in 7 unrelated Spanish families with recurrent autoinflammatory diseases characterized by early onset, recurrent fever, and a chronic urticarial rash, in whom a clinical diagnosis of cryopyrin-associated periodic syndromes (CAPS) is suspected.Methods. Clinical symptoms, results of laboratory analyses, and data on previous treatments in members of the 7 families were recorded on a questionnaire specific for hereditary autoinflammatory diseases. All coding regions and intronic flanking boundaries of the CIAS1/PYPAF1/NALP3 gene were amplified by polymerase chain reaction and sequenced.Results. Five different missense mutations, including 2 de novo and 1 previously unreported mutation (R488K), were identified in exon 3 of the CIAS1/ PYPAF1/NALP3 gene in 5 of the 7 affected families. Expanded genetic analysis among the healthy individuals identified incomplete penetrance in 2 families. No mutations were found in 2 of the 3 patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome/neonatal-onset multisystem inflammatory disease (NOMID).Conclusion. The clinical data suggested a diagnosis of familial cold-induced autoinflammatory syndrome in 3 families, CINCA/NOMID syndrome in 3 others, and a possible Muckle-Wells syndrome, whereas mutational analysis showed different CIAS1/PYPAF1/NALP3 missense mutations in 5 families. These data are consistent with a common molecular basis of these diseases and highlights the phenotypic heterogeneity among CIAS1/ PYPAF1/NALP3 gene-associated syndromes. The previously unreported mutation and the incomplete penetrance found in 2 families expand the genetic basis underlying these autoinflammatory syndromes. These findings should alert clinicians to the possible genetic basis of these conditions, even in the absence of a family history, in their attempts to establish an accurate diagnosis and the optimal therapeutic approach.

PYPAF1 nonsense mutation in a patient with an unusual autoinflammatory syndrome: Role of PYPAF1 in inflammation

“…In this regard, the identification of a nonsense mutation in PYPAF1 (c.1660CϾT, exon 3) calls into question the current nosology of hereditary recurrent fever syndromes and suggests that defects in PYPAF1 may also underlie "FMF-like" disorders. Of note, the mutation was also found in the patient's mother, who did not exhibit any clinical manifestations; this finding is consistent with the notion of incomplete penetrance of the disease phenotype, an observation already reported in several families with PYPAF1 mutations (8,25,27).…”

The clinical continuum of cryopyrinopathies: Novel CIAS1 mutations in North American patients and a new cryopyrin model

“…In a family presenting with an atypical autoinflammatory syndrome we identified the R488K mutation, which was previously reported in a Spanish family with FCAS-like symptoms (42). Further investigation of the family in the present study revealed 2 asymptomatic family members who were carriers for R488K, supporting the notion that this is a reduced-penetrance CIAS1 mutation as proposed earlier (42). We screened 740 Caucasian control chromosomes and found R488K in 1 of 740; we thus estimated an R488K allele frequency of 0.0014 in the healthy Caucasian population.…”

Síndromes autoinflamatórias hereditárias na faixa etária pediátrica

“…60 Roughly 85% of CIAS1 mutations occur in exon 3. 62,63 Cryopyrin is one of the constituents of the inflammasome, which plays a key role in the regulation of intracellular defense in response to bacterial toxins and compounds released during cell injury or stress. 22,64,65 This protein is essential for activation of caspase-1, the enzyme that cleaves pro-IL1-β into its active form, IL1-beta, which in turn is a major proinflammatory cytokine.…”