title: Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P.
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.
authors.affiliation: Division of Rheumatology, Allergy, and Immunology, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093-0635, USA. hahoffman@ucsd.edu
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.forename: James L
authors.initials: JL
authors.lastname: Mueller
authors.forename: Mark
authors.initials: M
authors.lastname: Tresierras
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wanderer
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kolodner
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics*; D001798:Blood Proteins / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D022202:Chromosomes, Artificial, Bacterial; D003080:Cold Temperature; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D010505:Familial Mediterranean Fever / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D020125:Mutation, Missense / Q000235:genetics*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010375:Pedigree; D020161:Physical Chromosome Mapping; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D001798:Blood Proteins; D002352:Carrier Proteins; D017931:DNA Primers; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human