Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P

Hum Genet. 2003 Feb;112(2):209-16. doi: 10.1007/s00439-002-0860-x. Epub 2002 Nov 16.

Abstract

Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant inflammatory disease with a high degree of penetrance that is characterized by episodes of rash, arthralgia, fever, conjunctivitis, and leukocytosis after generalized exposure to cold. FCAS was previously mapped to a 10-cM region on chromosome 1q44, and subsequently the gene ( CIAS1) responsible for FCAS was identified. In this paper, we describe the physical and genetic mapping of the FCAS locus, and we report a large ancestral haplotype and a new disease-causing mutation. A BAC contig of approximately 3 Mb was developed and subsequently used for high throughput sequencing. We identified a critical region of 4 cM using rare crossover events in four large North American FCAS families. An unusually large shared haplotype (40 cM) was identified in three of the four families. We found a single heterozygous missense mutation (T1058C=L353P) in exon 3 of CIAS1 in all four families that is responsible for the large majority of FCAS cases described in the literature. We also report a comprehensive list of intragenic single nucleotide polymorphisms. The data provided here will assist others researching the 1q44 region and will aid clinicians in the diagnosis of FCAS.

MeSH terms

  • Autoimmune Diseases / genetics*
  • Blood Proteins / genetics*
  • Blood Proteins / metabolism
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Chromosome Mapping
  • Chromosomes, Artificial, Bacterial
  • Cold Temperature
  • DNA Mutational Analysis
  • DNA Primers / chemistry
  • Familial Mediterranean Fever / genetics*
  • Female
  • Genetic Linkage
  • Haplotypes
  • Humans
  • Lod Score
  • Male
  • Microsatellite Repeats
  • Mutation, Missense / genetics*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pedigree
  • Physical Chromosome Mapping
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide / genetics

Substances

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