Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU.
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.
Neven
Bénédicte
B
INSERM U429, Hôpital Necker-Enfants Malades, Paris, France.
Callebaut
Isabelle
I
Prieur
Anne-Marie
AM
Feldmann
Jérôme
J
Bodemer
Christine
C
Lepore
Loredana
L
Derfalvi
Beata
B
Benjaponpitak
Suata
S
Vesely
Richard
R
Sauvain
Marie Jose
MJ
Oertle
Stefan
S
Allen
Roger
R
Morgan
Gareth
G
Borkhardt
Arndt
A
Hill
Clare
C
Gardner-Medwin
Janet
J
Fischer
Alain
A
de Saint Basile
Geneviève
G
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
D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human