title: A new CARD15 mutation in Blau syndrome.
abstract: The caspase recruitment domain gene CARD15/NOD2, encoding a cellular receptor involved in an NF-kappaB-mediated pathway of innate immunity, was first identified as a major susceptibility gene for Crohn's disease (CD), and more recently, as responsible for Blau syndrome (BS), a rare autosomal-dominant trait characterized by arthritis, uveitis, skin rash and granulomatous inflammation. While CARD15 variants associated with CD are located within or near the C-terminal leucine-rich repeat domain and cause decreased NF-kappaB activation, BS mutations affect the central nucleotide-binding NACHT domain and result in increased NF-kappaB activation. In an Italian family with BS, we detected a novel mutation E383K, whose pathogenicity is strongly supported by cosegregation with the disease in the family and absence in controls, and by the evolutionary conservation and structural role of the affected glutamate close to the Walker B motif of the nucleotide-binding site in the NACHT domain. Interestingly, substitutions at corresponding positions in another NACHT family member cause similar autoinflammatory phenotypes.
authors.affiliation: Department of Clinical and Biological Sciences, Division of Medical Genetics, University of Torino, Orbassano, Italy.
authors.forename: Marjan M
authors.initials: MM
authors.lastname: van Duist
authors.forename: Mario
authors.initials: M
authors.lastname: Albrecht
authors.forename: Marta
authors.initials: M
authors.lastname: Podswiadek
authors.forename: Daniela
authors.initials: D
authors.lastname: Giachino
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.forename: Leonardo
authors.initials: L
authors.lastname: Punzi
authors.forename: Mario
authors.initials: M
authors.lastname: De Marchi
mesh_terms: D000595:Amino Acid Sequence; D001168:Arthritis / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005076:Exanthema / Q000235:genetics*; D005260:Female; D006099:Granuloma / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D053473:Nod2 Signaling Adaptor Protein; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D013577:Syndrome; D014605:Uveitis / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein