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

Am J Hum Genet. 2002 Jun;70(6):1498-506. doi: 10.1086/340786. Epub 2002 Apr 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Alleles
  • Amino Acid Sequence
  • Arthralgia / genetics
  • Base Sequence
  • Blood Proteins / genetics*
  • Carrier Proteins / genetics*
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Exons / genetics
  • Female
  • Fever / genetics
  • Haplotypes / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation / genetics*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pedigree
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Syndrome
  • Urticaria / genetics*
  • Urticaria / physiopathology


  • Blood Proteins
  • Carrier Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human

Associated data

  • GENBANK/AF418985
  • GENBANK/AF427617
  • OMIM/MIM120100
  • OMIM/MIM134610
  • OMIM/MIM142680
  • OMIM/MIM191900
  • OMIM/MIM249100
  • OMIM/MIM260920