New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes

Abstract

Mutations of CIAS1 have recently been shown to underlie familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS), in three families and one family, respectively. These rare autosomal dominant diseases are both characterized by recurrent inflammatory crises that start in childhood and that are generally associated with fever, arthralgia, and urticaria. The presence of sensorineural deafness that occurs later in life is characteristic of MWS. Amyloidosis of the amyloidosis-associated type is the main complication of MWS and is sometimes associated with FCU. In FCU, cold exposure is the triggering factor of the inflammatory crisis. We identified CIAS1 mutations, all located in exon 3, in nine unrelated families with MWS and in three unrelated families with FCU, originating from France, England, and Algeria. Five mutations--namely, R260W, D303N, T348M, A439T, and G569R--were novel. The R260W mutation was identified in two families with MWS and in two families with FCU, of different ethnic origins, thereby demonstrating that a single CIAS1 mutation may cause both syndromes. This result indicates that modifier genes are involved in determining either a MWS or a FCU phenotype. The finding of the G569R mutation in an asymptomatic individual further emphasizes the importance of such modifier a gene (or genes) in determining the disease phenotype. Identification of this gene (or these genes) is likely to have significant therapeutic implications for these severe diseases.

Figure 1

Pedigree of the 12 families with MWS or FCU, with mutation analysis of CIAS1. Affected individuals are shown as blackened circles (females) or blackened squares (males). Deceased individuals are denoted by diagonal slashes. A gray circle represents an asymptomatic individual carrying an MWS mutation.

Figure 2

DNA-sequence electrophoregrams for the five novel CIAS1 mutations identified in the present study. Upper electrophoregrams correspond to the patients, lower ones to the control. Arrows indicate the position of the mutation. Sequences showing mutations R260W and A439T are on the coding strand, and D303N, T348M, and G569R are on the opposite strand.

Figure 3

Physical map of the region surrounding the CIAS1 gene, between microsatellite markers AFMB358wg1 and D1S2682 (UCSC Human Genome Project Working Draft).

Figure 4

A, Exon 3 of CIAS1 (GenBank accession number AF427617). The blackened box represents the NACHT domain, and all mutations involved in MWS and FCU are shown. Mutations in italics are those described in the present study. B, Alignment of the NACHT-domain amino acid sequence from human cryopyrin, NALP2, and NALP3 (GenBank accession numbers AAG30289 and AF418985). Asterisks (*) represent positions of mutations in the NACHT domain. Amimo acid homologies are represented by boldface characters.