The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model.

OBJECTIVE The cryopyrinopathies are a group of rare autoinflammatory disorders that are caused by mutations in CIAS1, encoding the cryopyrin protein. However, cryopyrin mutations are found only in 50% of patients with clinically diagnosed cryopyrinopathies. This study was undertaken to investigate the structural effect of disease-causing mutations on cryopyrin, in order to gain better understanding of the impact of disease-associated mutations on protein function. METHODS We tested for CIAS1 mutations in 22 patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome, 12 with Muckle-Wells syndrome (MWS), 18 with familial cold-induced autoinflammatory syndrome (FCAS), and 3 probands with MWS/FCAS. In a subset of mutation-negative patients, we screened for mutations in proteins that are either homologous to cryopyrin or involved in the caspase 1/interleukin-1beta signaling pathway. CIAS1 and other candidate genes were sequenced, models of cryopyrin domains were constructed using structurally homologous proteins as templates, and disease-causing mutations were mapped. RESULTS Forty patients were mutation positive, and 7 novel mutations, V262A, C259W, L264F, V351L, F443L, F523C, and Y563N, were found in 9 patients. No mutations in any candidate genes were identified. Most mutations mapped to an inner surface of the hexameric ring in the cryopyrin model, consistent with the hypothesis that the mutations disrupt a closed form of cryopyrin, thus potentiating inflammasome assembly. Disease-causing mutations correlated with disease severity only for a subset of known mutations. CONCLUSION Our modeling provides insight into potential molecular mechanisms by which cryopyrin mutations can inappropriately activate an inflammatory response. A significant number of patients who are clinically diagnosed as having cryopyrinopathies do not have identifiable disease-associated mutations.

[1]  S. Sicherer,et al.  Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1β Inhibition , 2007, Pediatrics.

[2]  E. Remmers,et al.  Mutational analysis in neonatal-onset multisystem inflammatory disease: comment on the articles by Frenkel et al and Saito et al. , 2006, Arthritis and rheumatism.

[3]  Takeo Tanaka,et al.  A severe case of chronic infantile neurologic, cutaneous, articular syndrome treated with biologic agents. , 2006, Arthritis and rheumatism.

[4]  O. Witt,et al.  Neonatal‐onset multisystem inflammatory disease (NOMID) due to a novel S331R mutation of the CIAS1 gene and response to interleukin‐1 receptor antagonist treatment , 2006, American journal of medical genetics. Part A.

[5]  P. Emery,et al.  Hearing improvement in a patient with variant Muckle-Wells syndrome in response to interleukin 1 receptor antagonism , 2006, Annals of the rheumatic diseases.

[6]  V. Dixit,et al.  Cryopyrin activates the inflammasome in response to toxins and ATP , 2006, Nature.

[7]  S. Akira,et al.  Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3 , 2006, Nature.

[8]  F. Martinon,et al.  Gout-associated uric acid crystals activate the NALP3 inflammasome , 2006, Nature.

[9]  J. Bertin,et al.  Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. , 2006, Immunity.

[10]  T. Matsubayashi,et al.  Anakinra therapy for CINCA syndrome with a novel mutation in exon 4 of the CIAS1 gene. , 2006, Acta paediatrica.

[11]  E. Alnemri,et al.  Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization , 2006, Cell Death and Differentiation.

[12]  T. Nakahata,et al.  Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome. , 2006, Arthritis and rheumatism.

[13]  H. Simon,et al.  Therapeutic interleukin (IL) 1 blockade normalises increased IL1β and decreased tumour necrosis factor α and IL10 production in blood mononuclear cells of a patient with CINCA syndrome , 2005, Annals of the rheumatic diseases.

[14]  D. Kastner,et al.  Familial autoinflammatory diseases: genetics, pathogenesis and treatment , 2005, Current opinion in rheumatology.

[15]  G. Burmester,et al.  Successful treatment of acute visual loss in Muckle-Wells syndrome with interleukin 1 receptor antagonist , 2005, Annals of the rheumatic diseases.

[16]  P. Hanson,et al.  AAA+ proteins: have engine, will work , 2005, Nature Reviews Molecular Cell Biology.

[17]  J. Roth,et al.  The clinical course of a child with CINCA/NOMID syndrome improved during and after treatment with thalidomide , 2005, Scandinavian journal of rheumatology.

[18]  Yigong Shi,et al.  Structure of the apoptotic protease-activating factor 1 bound to ADP , 2005, Nature.

[19]  J. Yagüe,et al.  Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene. , 2004, Arthritis and rheumatism.

[20]  G. Firestein,et al.  Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist , 2004, The Lancet.

[21]  R. Janssen,et al.  Enhanced interleukin-1β and interleukin-18 release in a patient with chronic infantile neurologic, cutaneous, articular syndrome , 2004 .

[22]  S. Cannon,et al.  Structural, expression, and evolutionary analysis of mouse CIAS1. , 2004, Gene.

[23]  M. Gahr,et al.  Periodic fever, mild arthralgias, and reversible moderate and severe organ inflammation associated with the V198M mutation in the CIAS1 gene in three German patients – expanding phenotype of CIAS1 related autoinflammatory syndrome , 2004, European journal of haematology.

[24]  W. Kuis,et al.  Variant chronic infantile neurologic, cutaneous, articular syndrome due to a mutation within the leucine-rich repeat domain of CIAS1. , 2004, Arthritis and rheumatism.

[25]  P. Hawkins,et al.  Response to anakinra in a de novo case of neonatal-onset multisystem inflammatory disease. , 2004, Arthritis and rheumatism.

[26]  G. Núñez,et al.  Cryopyrin-induced interleukin 1beta secretion in monocytic cells: enhanced activity of disease-associated mutants and requirement for ASC. , 2004, The Journal of biological chemistry.

[27]  A. Fischer,et al.  Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. , 2004, Blood.

[28]  F. Martinon,et al.  NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. , 2004, Immunity.

[29]  Thomas Lengauer,et al.  Structural localization of disease‐associated sequence variations in the NACHT and LRR domains of PYPAF1 and NOD2 , 2003, FEBS letters.

[30]  E. Dahl,et al.  The death-domain fold of the ASC PYRIN domain, presenting a basis for PYRIN/PYRIN recognition. , 2003, Journal of molecular biology.

[31]  Manuel C. Peitsch,et al.  SWISS-MODEL: an automated protein homology-modeling server , 2003, Nucleic Acids Res..

[32]  P. Hawkins,et al.  Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. , 2003, The New England journal of medicine.

[33]  F. Martinon,et al.  NALPs: a novel protein family involved in inflammation , 2003, Nature Reviews Molecular Cell Biology.

[34]  S. Gregory,et al.  Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P , 2003, Human Genetics.

[35]  E. Remmers,et al.  De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. , 2002, Arthritis and rheumatism.

[36]  G. Hitman,et al.  Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. , 2002, Arthritis and rheumatism.

[37]  F. Martinon,et al.  The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. , 2002, Molecular cell.

[38]  A. Fischer,et al.  Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. , 2002, American journal of human genetics.

[39]  D. Scott,et al.  New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. , 2002, American journal of human genetics.

[40]  W. Delano.  The PyMOL Molecular Graphics System , 2002 .

[41]  R. Kolodner,et al.  Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome , 2001, Nature Genetics.

[42]  D. Broide,et al.  Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. , 2001, The Journal of allergy and clinical immunology.

[43]  J. Tainer,et al.  Structure and mechanism of the RuvB Holliday junction branch migration motor. , 2001, Journal of molecular biology.

[44]  T L Blundell,et al.  FUGUE: sequence-structure homology recognition using environment-specific substitution tables and structure-dependent gap penalties. , 2001, Journal of molecular biology.

[45]  G J Barton,et al.  Application of multiple sequence alignment profiles to improve protein secondary structure prediction , 2000, Proteins.

[46]  M. Sternberg,et al.  Enhanced genome annotation using structural profiles in the program 3D-PSSM. , 2000, Journal of molecular biology.

[47]  Liam J. McGuffin,et al.  The PSIPRED protein structure prediction server , 2000, Bioinform..

[48]  Robert Huber,et al.  The structures of HslU and the ATP-dependent protease HslU–HslV , 2000, Nature.

[49]  M Ouali,et al.  Cascaded multiple classifiers for secondary structure prediction , 2000, Protein science : a publication of the Protein Society.

[50]  J. Tainer,et al.  Human glutathione transferase A4-4 crystal structures and mutagenesis reveal the basis of high catalytic efficiency with toxic lipid peroxidation products. , 1999, Journal of molecular biology.

[51]  B. Rost,et al.  Combining evolutionary information and neural networks to predict protein secondary structure , 1994, Proteins.

[52]  Bostjan Kobe,et al.  Crystal structure of porcine ribonuclease inhibitor, a protein with leucine-rich repeats , 1993, Nature.

[53]  C. Griscelli,et al.  A chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients. , 1987, Scandinavian journal of rheumatology. Supplement.