title: Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU.
abstract: 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.
authors: INSERM U429, Hôpital Necker-Enfants Malades, Paris, France.
authors: Bénédicte
authors: B
authors: Neven
authors: Isabelle
authors: I
authors: Callebaut
authors: Anne-Marie
authors: AM
authors: Prieur
authors: Jérôme
authors: J
authors: Feldmann
authors: Christine
authors: C
authors: Bodemer
authors: Loredana
authors: L
authors: Lepore
authors: Beata
authors: B
authors: Derfalvi
authors: Suata
authors: S
authors: Benjaponpitak
authors: Richard
authors: R
authors: Vesely
authors: Marie Jose
authors: MJ
authors: Sauvain
authors: Stefan
authors: S
authors: Oertle
authors: Roger
authors: R
authors: Allen
authors: Gareth
authors: G
authors: Morgan
authors: Arndt
authors: A
authors: Borkhardt
authors: Clare
authors: C
authors: Hill
authors: Janet
authors: J
authors: Gardner-Medwin
authors: Alain
authors: A
authors: Fischer
authors: Geneviève
authors: G
authors: de Saint Basile
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D007592:Joint Diseases / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D019578:Multiple System Atrophy / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010290:Parents; D010586:Phagocytes / Q000473:pathology*; D011487:Protein Conformation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
chemical_list: D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human