Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU

• Published in: Blood Vol. 103; no. 7; pp. 2809 - 2815
• Main Authors: NEVEN, Bénédicte, CALLEBAUT, Isabelle, OERTLE, Stefan, ALLEN, Roger, MORGAN, Gareth, BORKHARDT, Arndt, HILL, Clare, GARDNER-MEDWIN, Janet, FISCHER, Alain, DE SAINT BASILE, Geneviève, PRIEUR, Anne-Marie, FELDMANN, Jérome, BODEMER, Christine, LEPORE, Loredana, DERFALVI, Beata, BENJAPONPITAK, Suata, VESELY, Richard, SAUVAIN, Marie Jose
• Format: Journal Article
• Language: English
• Published: Washington, DC The Americain Society of Hematology 01.04.2004; American Society of Hematology
• Subjects: Adolescent; Adult; Amino Acid Sequence; Amino Acid Substitution; Biological and medical sciences; Carrier Proteins - chemistry; Carrier Proteins - genetics; Child; Child, Preschool; Female; Gene Frequency; Humans; Infant; Joint Diseases - genetics; Joint Diseases - pathology; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Multiple System Atrophy - genetics; Multiple System Atrophy - pathology; Mutation; NLR Family, Pyrin Domain-Containing 3 Protein; Parents; Phagocytes - pathology; Protein Conformation; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sequence Alignment; Sequence Homology, Amino Acid; Syndrome; Human; Familial cold urticaria; Skin disease; Urinary system disease; Molecular structure; Urticaria; Diseases of the osteoarticular system; Muckle syndrome; Metabolic diseases; Autoimmune disease; Inflammation; Enzymopathy; Genetic disease; Signal transduction; CINCA syndrome; Nucleotide; ENT disease; Affinity; Mutation; Apoptosis; Phagocyte
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-07-2531

NALP proteins are recently identified members of the CATERPILLER (CARD, transcription enhancer, R(purine)-binding, pyrin, lots of LRR) family of proteins, thought to function in apoptotic and inflammatory signaling pathways. Mutations in the CIAS1 gene, which encodes a member of the NALP (NACHT-, LRR-, and PYD-containing proteins) family, the cryopyrin/NALP3/PYPAF1 protein, expressed primarily in phagocytic cells, were recently found to be associated with a spectrum of autoinflammatory disorders. These include chronic infantile neurologic cutaneous and articular (CINCA) syndrome (also known as neonatal-onset multisystem inflammatory disease [NOMID]), Muckle-Wells syndrome (MWS), and familial cold urticaria (FCU). We describe herein 7 new mutations in 13 unrelated patients with CINCA syndrome and identify mutational hotspots in CIAS1 on the basis of all mutations described to date. We also provide evidence of genotype/phenotype correlations. A 3-dimensional model of the nucleotide-binding domain (NBD) of cryopyrin suggested that this molecule is structurally and functionally similar to members of the AAA+ protein family of ATPases. According to this model, most of the mutations known to affect residues of the NBD are clustered on one side of this domain in a region predicted to participate in intermolecular contacts, suggesting that this model is likely to be biologically relevant and that defects in nucleotide binding, nucleotide hydrolysis, or protein oligomerization may lead to the functional dysregulation of cryopyrin in the MWS, FCU, and CINCA/NOMID disorders.