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

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ARTHRITIS & RHEUMATISM
Vol. 56, No. 4, April 2007, pp 1273–1285
DOI 10.1002/art.22491
© 2007, American College of Rheumatology
The Clinical Continuum of Cryopyrinopathies
Novel CIAS1 Mutations in North American Patients and a New Cryopyrin Model
Ivona Aksentijevich,1 Christopher D. Putnam,2 Elaine F. Remmers,1 James L. Mueller,2
Julie Le,1 Richard D. Kolodner,2 Zachary Moak,1 Michael Chuang,1 Frances Austin,1
Raphaela Goldbach-Mansky,1 Hal M. Hoffman,2 and Daniel L. Kastner1
cryopyrin or involved in the caspase 1/interleukin-1␤
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.
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
Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program, the National Institute of Allergy and Infectious Diseases (grant R01-AI52430), and the Ludwig Institute of Cancer Research. Dr. Putnam is
recipient of a Postdoctoral Fellowship from the Damon Runyon
Cancer Research Foundation and the Robert Black Charitable Trust.
1
Ivona Aksentijevich, MD, Elaine F. Remmers, PhD, Julie
Le, BS, Zachary Moak, BS, Michael Chuang, BS, Frances Austin, BS,
Raphaela Goldbach-Mansky, MD, Daniel L. Kastner, MD, PhD:
National Institute of Arthritis and Musculoskeletal and Skin Diseases,
Bethesda, Maryland; 2Christopher D. Putnam, PhD, James L. Mueller,
BS, Richard D. Kolodner, PhD, Hal M. Hoffman, MD: University of
California San Diego School of Medicine, La Jolla.
Drs. Aksentijevich and Putnam contributed equally to this
work; Drs. Hoffman and Kastner contributed equally to this work.
Dr. Hoffman has received consulting fees (more than
$10,000) from Regeneron Pharmaceuticals.
Address correspondence and reprint requests to Ivona Aksentijevich, MD, Genetics and Genomics Branch, National Institutes
of Health, Building 9, Room 1N132, 9000 Rockville Pike, Bethesda,
MD 20892-1820. E-mail: aksentii@exchange.nih.gov.
Submitted for publication September 26, 2006; accepted in
revised form December 21, 2006.
The cryopyrinopathies (also known as cryopyrinassociated periodic syndromes [CAPS]) are rare autoinflammatory diseases that have been recently characterized at the molecular level with the identification of
mutations in the gene CIAS1 (cold-induced autoinflammatory syndrome 1). They include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome
(MWS), and neonatal-onset multisystem inflammatory
disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular syndrome [CINCA syndrome]). Although these disorders have been classified
as distinct entities, patients often present with overlapping symptoms that include fevers, urticarial skin rash,
1273
1274
varying degrees of arthralgia/arthritis, neutrophilmediated inflammation, and an intense acute-phase
response. In general, patients with NOMID/CINCA
syndrome (MIM no. 607115) have the most severe
clinical phenotype, patients with FCAS (MIM no.
120100) have the least severe phenotype, and patients
with MWS (MIM no. 191100) present with an intermediate phenotype (1). Several patients have overlapping
phenotypes, e.g., MWS/FCAS and MWS/NOMID.
NOMID/CINCA syndrome is characterized by
nearly continuous symptoms of inflammation presenting
first during the neonatal period or early infancy, with a
migratory and nonpruritic urticaria-like rash and fever.
Later, patients develop symptoms of central nervous
system (CNS) inflammation, including chronic aseptic
meningitis, increased intracranial pressure, cerebral atrophy, seizures, and sometimes mental retardation. Approximately 80% of patients develop progressive sensorineural hearing loss and ocular changes, including
conjunctivitis, anterior and posterior uveitis, optic disc
edema, and optic nerve atrophy with progressive vision
loss. Another feature of the disease is a highly characteristic and sometimes disabling arthropathy caused by
overgrowth of the patella and epiphyses of the long
bones. Approximately 20% of patients with NOMID/
CINCA syndrome die before reaching adulthood (2).
MWS usually presents with more episodic attacks
of inflammation associated with a generalized urticarialike rash, fever, malaise, arthralgia, and progressive
hearing loss. Twenty-five percent of patients also develop serum amyloid A amyloidosis (3,4). FCAS (also
known as familial cold urticaria) is characterized by
cold-induced, daylong episodes of fever associated with
rash, arthralgia, headaches, and less frequently conjunctivitis, but without other signs of CNS inflammation.
Symptoms begin within the first 6 months of life, and
generalized cold exposure is the predominant trigger of
the inflammatory attacks (1).
The cryopyrinopathies are caused by dominantly
inherited or de novo mutations in CIAS1, a gene that
encodes a protein called cryopyrin (also known as
PYPAF1 or NALP3) (3–7). Cryopyrin belongs to the
family of NLR (nucleotide-binding domain, leucine-rich
repeat) proteins (also known as CATERPILLER,
NALP, or PYPAF), with 14 identified members (8).
These proteins have 3 common structural domains: PYD
(an N-terminal pyrin domain), a central NACHT domain (also known as NBD or NOD [nucleotide-binding
or oligomerization domain]), and a C-terminal leucinerich repeat (LRR) domain. The NACHT domain consists of 2 or 3 NACHT subdomains and NAD (a
AKSENTIJEVICH ET AL
NACHT-associated domain). Evolutionary analysis has
shown that cryopyrin is highly conserved among primates and other mammals, including the mouse. With
the exceptions of V198, V262, and M662, all amino acids
mutated in CAPS patients are conserved in the primate
and mouse proteins, suggesting that the functions of
these genes have been under strong evolutionary selection (9).
To date, ⬎40 known disease-associated mutations have been reported, and most of them are found in
exon 3 of CIAS1, encoding the NACHT subdomains and
NAD domain (10). Recently, the first non–exon 3
mutations in patients with NOMID/CINCA syndrome
(G755R, G755A, and Y859C) were identified (11–13).
All but 1 of the known CIAS1 mutations are missense
changes, suggesting that loss-of-function mutations have
a different phenotype. Saito and coworkers described a
NOMID/CINCA syndrome patient with somatic mosaicism for a mutation in exon 3 of CIAS1, with varying
frequencies of the mutant allele in whole blood and
leukocytes. Those authors proposed that somatic mosaicism may account for at least some of the undetected
mutations in CIAS1 mutation–negative patients (14).
Cryopyrin is part of a multiprotein complex
termed the inflammasome (15,16) that plays a critical
role in the regulation of intracellular host defense in
response to bacterial toxins and RNA, small antiviral
compounds (imiquimod [R837] and resiquimod [R848]),
and uric acid crystals. Cryopyrin is essential for activation of caspase 1 and processing of interleukin-1␤ (IL1␤) and IL-18 cytokines (17–20). The mechanism by
which cryopyrin mutations cause inflammatory disease is
still elusive, although in vitro studies suggest that the
mutant protein is constitutively active (21,22). Functional studies of macrophages from NOMID and MWS
patients show a constitutive increase in IL-1␤ and IL-18
secretion (7,16,23). As a result of this finding a new
therapy targeting the IL-1␤ pathway, the IL-1 receptor
antagonist anakinra, has been initiated in patients with
these disorders (24), and has caused a rapid and dramatic improvement of symptoms and a decrease in levels
of acute-phase reactants (12,25–31).
In this study we analyzed 55 NOMID/MWS/
FCAS probands who have not been previously reported,
and identified 7 novel mutations. Fifteen patients were
mutation negative and the rest were carriers for previously reported mutations. We also summarized the
results of genetic testing for CIAS1 mutations in the
North American cohort of 195 patients clinically diagnosed as having NOMID/MWS/FCAS. In the absence of
an experimentally determined cryopyrin structure, we
CLINICAL CONTINUUM OF CRYOPYRINOPATHIES
1275
Table 1. Newly identified CIAS1 mutations and clinical symptoms of patients with NOMID/CINCA syndrome, MWS, and FCAS*
Coldtriggering
factor
Skin
rash
CNS
involvement†
Joint
involvement‡
Deforming
arthropathy
FCAS/57/M
Yes
Yes
No
Yes
No
NOMID/11/F
No
Yes
Yes
Yes
No
NOMID/1.5/F
No
Yes
Yes
Yes
No
NOMID/9/F
No
Yes
Yes
Yes
Yes
NOMID/13/F
No
Yes
Yes
Yes
No
NOMID/16/M
No
Yes
Yes
Yes
No
MWS/7/M
No
Yes
No
Yes
No
FCAS/62/F
Yes
Yes
No
Yes
No
FCAS/40/F
Yes
Yes
No
Yes
No
Diagnosis/age
(years)/sex
CIAS1
mutation
Control
chromosomes
C259W
(777 T⬎G)
V262A
(785 T⬎C)
L264F
(790 C⬎T)
L264F
(790 C⬎T)
V351L
(1051 G⬎C)
F443L
(1329 C⬎G)
F523C
(1568 T⬎G)
Y563N
(1687 T⬎A)
Y563N
(1687 T⬎A)
0/196
0/950
0/924
0/924
0/924
0/930
0/296
0/188
0/188
* NOMID/CINCA syndrome ⫽ neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous articular syndrome;
MWS ⫽ Muckle-Wells syndrome; FCAS ⫽ familial cold-induced autoinflammatory syndrome; CNS ⫽ central nervous system.
† Eye involvement and/or sensorineural hearing loss and/or chronic meningitis.
‡ Arthralgia and/or arthritis.
used modeling to explore the nature of CAPS-associated
mutations on cryopyrin.
PATIENTS AND METHODS
Patients. Patients included in this study fulfilled clinical criteria for NOMID/CINCA syndrome, MWS, or FCAS
(31,32). For participation in the study all patients (or parents
or legal guardians if the patient was a minor child) provided
written informed consent as approved by the respective institutional review boards. Among the NOMID/CINCA syndrome
patients, 10 were Caucasian, 10 were Hispanic, 1 was African
American, and 1 was Asian. All FCAS and MWS patients were
of Caucasian ancestry.
Molecular analysis. All coding exons of CIAS1 were
screened for mutations, using primers that have been described
previously (5,7). Mutation detection was performed by fluorescent sequencing with BigDye Terminator version 3.1 chemistry (Applied Biosystems, Foster City, CA) on an ABI 3100 or
3700 automated sequencer. The sequencing data were analyzed with Sequencher 4.5 (Gene Codes, Ann Arbor, MI). The
allele frequencies of novel mutations were evaluated in a panel
of 376 or 750 Caucasian control DNA samples from the North
American Rheumatoid Arthritis Collection, using mass spectrometry (homogeneous MassExtend assay; Sequenom, San
Diego, CA) or in a panel of 100 normal control DNA samples
from a North American blood bank (5), by automated sequencing. The allele frequencies for novel single-nucleotide
polymorphisms (SNPs) identified in the candidate genes were
evaluated in different panels of control samples (from Caucasian patients in the North American Rheumatoid Arthritis
Collection, from the Coriell human diversity panel, and from
African American patients in the New York Cancer Project
panel).
Sequence analysis and modeling of 3-dimensional
structure. Sequences of exon 3 of cryopyrin were aligned with
NACHT and NAD homologies of NALP1, NALP6, NALP10,
and NALP12, using Sequoia (33). The consensus secondary
structure was determined by comparing the predictions for all
5 proteins using multiple programs (34–37). Models were
generated by threading the cryopyrin sequence onto a known
structure with Swiss-Model (38). Models for both the pyrin
domain and the LRR domain were generated from known
sequence homologs; however, no structures were available for
obvious homologs of the NACHT and NAD domains of
cryopyrin. Using threading algorithms (39,40), multiple members of the AAA⫹ ATPase family were top hits for the first
NACHT subdomain for cryopyrin, NALP2, NALP3, CARD4,
and the mouse MHCII transactivator. These models were the
basis of cycles of automated and manual threading and structure minimization with Swiss-Model and the Swiss
PDB Viewer. All molecular images were generated using
PyMol (41).
RESULTS
Novel CIAS1 mutations. We analyzed 22 patients
with NOMID/CINCA syndrome, 12 with MWS, 18 with
FCAS, and 3 probands with MWS/FCAS overlap, for
mutations in CIAS1. The initial screening included sequencing the 1,753-bp exon 3 of CIAS1, where most of
the previously reported mutations were found. The exon
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3 mutation–negative patients were screened for mutations in the other 8 exons of CIAS1.
We identified 7 novel CIAS1 mutations, occurring in 5 patients with NOMID/CINCA syndrome, 1
with MWS, and 3 with FCAS (Table 1). Seven NOMID/
CINCA syndrome patients were carriers for previously
described CIAS1 mutations (4 patients with the D303N
mutation and 1 patient each with the T436N, G569R,
and L632F mutations). Ten patients were mutation
negative. Their clinical presentations were similar to
those of mutation-positive patients, and they all had an
excellent response to treatment with anakinra. Eight
MWS probands had previously described mutations,
including 2 with R260W and 6 with T348M. Three MWS
patients were mutation negative. Three FCAS patients
were carriers for 2 novel mutations (Table 1), while 2
lacked mutations. The remaining 13 FCAS probands
were carriers for L353P (8 patients), M659K (1 patient),
A439V (2 patients), and L305P (2 patients). Three
patients had MWS/FCAS overlap phenotypes; 2 carried
R260W and 1 had D303N.
Potential reduced-penetrance CIAS1 mutations.
In a family presenting with an atypical autoinflammatory
syndrome we identified the R488K mutation, which was
previously reported in a Spanish family with FCAS-like
symptoms (42). Further investigation of the family in the
present study revealed 2 asymptomatic family members
who were carriers for R488K, supporting the notion that
this is a reduced-penetrance CIAS1 mutation as proposed earlier (42). We screened 740 Caucasian control
chromosomes and found R488K in 1 of 740; we thus
estimated an R488K allele frequency of 0.0014 in the
healthy Caucasian population.
The National Institutes of Health (NIH) Clinical
Research Center and the Department of Pediatrics at
the University of California San Diego are 2 major US
referral centers for patients with various autoinflammatory diseases, including cryopyrinopathies, familial Mediterranean fever (MIM no. 249100), tumor necrosis
factor receptor–associated periodic syndrome (MIM no.
1420680), hyperimmunoglobulinemia D with periodic
fever syndrome (MIM no. 260920), and the syndrome of
pyogenic arthritis with pyoderma gangrenosum and acne
(MIM no. 604416). We screened 125 unrelated patients
with clinically uncharacterized autoinflammatory disease for mutations in exon 3 of CIAS1. This was a cohort
of patients who were referred to the NIH periodic fever
clinic with a history of recurrent fevers with or without
localized inflammation persisting for ⬎6 months, and
who tested negative for mutations in the clinically indicated periodic fever genes.
AKSENTIJEVICH ET AL
Ten patients, including 1 with NOMID/CINCA
syndrome, were found to carry the Q703K (c.2107C⬎A)
missense change (allele frequency 0.04). We evaluated
whether Q703K may be a novel disease-associated mutation with variable expressivity. We found 1 homozygous subject and 34 carriers for the 2107C⬎A nucleotide
transversion in a panel of 374 control Caucasian DNA
samples (allele frequency 0.05).
We investigated the allele frequency for one of
the earliest reported CIAS1 mutations, V198M, in a
large collection of DNA samples from Caucasian subjects. This mutation was originally identified in an FCAS
family that was later found to also have an E525K
mutation (5), and was subsequently reported in Spanish (42) and French (4) FCAS families, in a British
family with MWS and 2 British patients with uncharacterized periodic fevers (3), and in 3 German patients with atypical periodic fevers (43). V198M has
been considered to be a reduced-penetrance CIAS1
mutation because it was found in asymptomatic family
members and in control DNA samples. We did not
identify V198M in any of 125 patients with clinically
uncharacterized autoinflammator y disease. We
screened a panel of 742 Caucasian DNA samples and
found 11 carriers among 1,484 control chromosomes
(allele frequency 0.0074).
Candidate gene screening in mutation-negative
NOMID/CINCA syndrome patients. In our entire cohort
of NOMID/CINCA syndrome patients, 49% were negative for CIAS1 mutations. Based on the report by Saito
et al (14), we considered the possibility that some
mutations might be missed due to undetected somatic
mosaicism. However, we found no evidence of somatic
mosaicism in our CIAS1 mutation–negative patients;
therefore, we believe it is an uncommon mechanism for
the cryopyrinopathies (13).
In a subset of CIAS1 mutation–negative
NOMID/CINCA syndrome patients, we further
screened for mutations in the NACHT domains of 5
NALP proteins that are either highly homologous to
cryopyrin or have similar tissue expression profiles. We
also performed mutational analysis of other genes that
encode proteins that are either described as part of the
inflammasome protein complex or are involved in regulation of the caspase 1/IL-1␤ signaling pathway (Table
2). We identified many missense substitutions in these
genes, including 10 novel nonsynonymous nucleotide
changes, but all of them proved to be polymorphisms
(Table 2). SNPs identified in African American patients
with NOMID/CINCA syndrome were evaluated in samples from African American controls.
NM_052889.2
NM_013258.3
PSEUDO-ICE/COP
PYCARD/ASC
Exons 1–3
Exons 1–3
Exons 1–5
Exon 5
Exon 1
Exons 1–8
Exon 3 (1,702 bp)
Exons 1–2
Exon 4 (1,756 bp)
Exon 3 (1,576 bp)
Exon 6 (1,567 bp)
Exon 4 (1,705 bp)
Exons screened
9
10
5
6
7
12
5
4
7
4
7
7
No. of
patients
Nonsynonymous
identified
Nonsynonymous
identified
Nonsynonymous
identified
Nonsynonymous
identified
Nonsynonymous
identified
SNPs not
SNPs not
SNPs not
SNPs not
SNPs not
Ex5: P280L (c.839C⬎T)¶
F402L (c.1196C⬎G)¶
Ex1: C10X (rs2043211;
c.30T⬎A)
Ex3: I68V (rs11881179;
c.202A⬎G)
Ex2: c.126_127insAA¶
Ex4: A200T (c.598G⬎A)¶
Ex4: P219R (c.656C⬎G)¶
Nonsynonymous SNPs not
identified
D142N (c.414G⬎A)¶
A144T (rs441827; c.430G⬎A)
E383D (rs17857373;
c.1149G⬎C)
M163L (rs6421985;
c.487A⬎C)
P244A (c.730C⬎G)¶
T221M (rs17699678;
c.662C⬎T)
R364K (rs4306647; c.1091
G⬎A)
T529A (c. 1585A⬎G)¶
T782S (c.2345C⬎G)¶
T246S (rs11651595;
c.737C⬎G)
I601F (c. 1801A⬎T)¶
c.126_127insAA all frequency in 371 P1 samples ⫽ 0.05
A200T: A allele frequency in 375 P1 samples ⫽ 0.001
P219R: G allele frequency in 352 P1 samples ⫽ 0.007
G allele frequency in 143 P3 samples ⫽ 0.11
P280L: no carriers in 304 P1 samples
no carriers in 94 P2 samples
T allele frequency in 141 P3 samples ⫽ 0.007
D142N: A allele frequency in 371 P1 samples ⫽ 0.002
A allele frequency in 95 P2 samples ⫽ 0.01
A allele frequency in 143 P3 samples ⫽ 0.04
F402L: G allele frequency in 363 P1 samples ⫽ 0.07
P244A: G allele frequency in 376 P1 samples ⫽ 0.18
G allele frequency in 85 P2 samples ⫽ 0.12
G allele frequency in 140 P3 samples ⫽ 0.05
T529A: G allele frequency in 371 samples ⫽ 0.23
G allele frequency in 89 P2 samples ⫽ 0.10
G allele frequency in 134 P3 samples ⫽ 0.16
I601F: T allele frequency in 348 P1 samples ⫽ 0.02
T allele frequency in 94 P2 samples ⫽ 0.02
T allele frequency in 135 P3 samples ⫽ 0.15
T782S: G allele frequency in 375 P1 samples ⫽ 0.06
G allele frequency in 95 P2 samples ⫽ 0.03
G allele frequency in 146 P3 samples ⫽ 0.10
Allele frequencies of novel SNPs in control chromosomes§
* The following single-nucleotide polymorphisms (SNPs) were identified in African American patients with neonatal-onset multisystem inflammatory disease/chronic infantile
neurologic, cutaneous articular syndrome (NOMID/CINCA syndrome): I601F and T782S (NALP1), D142N (NALP12), P219R and P280L (CARD8). SNPs P244A (NALP6), F402L
(NALP12), and A200T, and c.126_127insAA (CARD8) were identified in Caucasian patients with NOMID/CINCA syndrome.
† Uses a GenBank file as reference sequence (coding DNA).
‡ Using a dbSNP identifier as a reference; “c.” indicates a coding DNA sequence.
§ P1 ⫽ Caucasian control samples (376 samples); P2 ⫽ Human Diversity Panel control samples (96 samples); P3 ⫽ African American samples (150 samples).
¶ Novel nonsynonymous SNPs that were ruled out (proved to be polymorphisms) by screening control chromosomes.
NM_000577.3
NM_014959
CARD8/CARDINAL/TUCAN
IL1-RN
NM_144687.1
NALP12/PYPAF7
NM_021571.2
NM_176821.3
NALP10/PYNOD
NM_021209.3
NM_138329.1
NALP6/PYPAF5
IPAF/CARD12/NOD3
NM_134444.3
NALP4/PYPAF4
ICEBERG
NM_017852.1
NALP2/PYPAF2
RefSeq
DNA†
NM_033004.2
Candidate gene
Nonsynonymous SNPs and
deletions identified in
NOMID/CINCA syndrome
patients‡
Candidate genes screened for mutations in a subset of CIAS1 mutation–negative patients*
NALP1/DEFCAP
Table 2.
CLINICAL CONTINUUM OF CRYOPYRINOPATHIES
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AKSENTIJEVICH ET AL
Figure 1. Sequence alignment of cryopyrin with NALP1, NALP6, NALP10, and NALP12 for most of exon 3 of cryopyrin encoding the NACHT
and NACHT-associated domains. Asterisks below the alignments show positions with perfect identity. AAA⫹ domain functional motifs that are
identifiable in cryopyrin are shown in red. Disease-causing mutations are shown above the sequence; boxed mutations are those newly identified in
this study. The consensus secondary structure prediction for all proteins from multiple prediction programs is depicted using bars for ␣-helices
(␣1–␣22) and arrows for ␤-strands (␤1–␤6). Secondary structural elements shown in dark green correspond to the first subdomain of NACHT, those
shown in light green correspond to the second (and possibly third) subdomain(s) of NACHT, and those shown in yellow-green correspond to the
NACHT-associated domain.
Multiple sequence alignment of the NACHT domain of cryopyrin with homologous human proteins.
We investigated the potential molecular impact of
CAPS-associated CIAS1 mutations on cryopyrin function, using a molecular modeling approach. The vast
majority of mutations underlying FCAS, MWS, and
CLINICAL CONTINUUM OF CRYOPYRINOPATHIES
NOMID are missense mutations in the NACHT and
NACHT-associated (NAD) domains of cryopyrin. Although there are several mutation clusters in exon 3 of
CIAS1, suggesting the presence of functionally important sites, there is no apparent correlation between
mutation cluster position and disease severity. For instance, the mutation cluster adjacent to the conserved
Walker B motif (Mg2⫹-binding site) at residues 300–303
includes NOMID-, MWS-, and FCAS-associated mutations (Figures 1 and 2A).
Phylogenetic studies have identified human
NALP1, NALP6, NALP10, and NALP12 proteins as
being closely related to cryopyrin (9). Recent studies
have shown that NALP1, NALP6, and NALP12 are
expressed in hematopoietic tissue; similar to findings in
cryopyrin, overexpression of these proteins shows that
they also regulate caspase 1 activity (8). Thus, we aligned
the protein sequence of the cryopyrin NACHT domain
with its most homologous human proteins, NALP1,
NALP6, NALP10, and NALP12, to evaluate whether
the CAPS-associated mutations affect amino acids that
are conserved between these proteins (Figure 1). The
sequence alignment showed that only 5 CAPSassociated mutations affected highly conserved amino
acid residues (C259W, G301D, D303N, A352V, and
L632F); 3 mutations were associated with the most
severe NOMID phenotype, while 2 were associated with
the mild FCAS phenotype.
Molecular impact of CIAS1 mutations on protein
function, determined based on predicted modeling for
cryopyrin. CIAS1 mutations (Figure 2A) were placed
onto 3-dimensional structural models of human
cryopyrin threaded onto templates of homologous structures (Figure 2B). The modeling of the N-terminal part
of the NACHT homology (NACHT subdomain 1) was
possible because of the robust identification of this
portion of the NACHT homology as a member of the
AAA⫹ family of proteins, and is consistent with previous models generated for this portion of the NACHT
domain (44,45). These models demonstrate that the
majority of mutations that can be placed in the model
are located on one face of subdomain 1; for most AAA⫹
proteins, this face is where additional domains from the
same protein can interact with subdomain 1 (46). This
intraprotein domain–domain interaction could result in
a closed or nonfunctional state of a modular protein
such as cryopyrin.
More C-terminal portions of the NACHT and
NACHT-associated domains do not robustly identify
any domain by sequence homology or threading; however, the second NACHT of AAA⫹ proteins is typically
1279
4-helix bundles, and the secondary structural predictions
would be consistent with this (Figure 1), although the
possibility of inserted secondary structural elements in
the NACHT family cannot be ruled out. Notably, the
pattern of disease-causing mutations affecting amino
acids at conserved surfaces might continue outside of the
modeled regions. For example, the mutations causing
␣-helix 12 amino acid substitutions (T436P, T436N,
T436I, A439V, A439T, A439P, F443L [Figure 1]) are all
spaced by 3 or 4 residues and would define one face of
this ␣-helix.
Most AAA⫹ proteins assemble into functional
hexamers (47). To gain additional insight into the
disease-causing amino acid substitutions, we superimposed the NACHT subdomain 1 model onto the structure of the HsIU chaperone, which is one of the AAA⫹
proteins whose structure was experimentally determined
in a hexamer assembly (48). Surprisingly, the surface
containing most of the disease-causing amino acid substitutions in the monomer model mapped to a single
inner surface of the assembled hexameric surface, which
would be consistent with the notion of functional multimerization of cryopyrin through the NACHT domain
(Figure 2C).
Close analysis of the NOMID mutations affecting
the LRR domains, G755R and G755A, indicated that
these mutations may function similarly to NACHT domain mutations, by inappropriately exposing LRRs to
assemble inflammasomes (Figure 2B). The internal
packing between leucine-rich repeats of the LRR domain forces every second helix to accommodate a side
chain from an adjacent helix in a pocket lined by a
glycine. Any other residue at the glycine position would
be larger and would disrupt the LRR packing, potentially kinking the arc of the LRR domain or generating
a flexible joint in the LRR at the repeat containing the
substitution. G755 is the first glycine in this position in
the LRR domain, and amino acid substitutions may
decouple the orientation of the LRR domain from the
closed/open status of the NACHT domains (Figure 2D).
The fact that mutations of equivalent glycines in later
repeats have not been observed may suggest that they
may be too disruptive to the LRR binding surface or
may not displace enough of the surface to direct inflammasome assembly.
DISCUSSION
The cryopyrinopathies represent a spectrum of
autoinflammatory diseases that are caused by mutations
in a single gene, and in which severity of the phenotype
1280
AKSENTIJEVICH ET AL
Figure 2. A, The domain and exon arrangements of cryopyrin displayed with the positions of point mutations implicated in familial cold-induced
autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), neonatal-onset multisystem inflammatory disease (NOMID), and other
phenotypes. Domains are displayed as colored boxes; exons are numbered below and delineated by horizontal lines. Point mutations responsible for
various clinical syndromes are displayed from the weakest phenotype (FCAS) on the light yellow portion of the gradient to the strongest phenotype
(NOMID) on the red portion of the gradient. B, Three-dimensional models of the pyrin domain, subdomain 1 of NACHT, and the leucine-rich
repeats (LRRs). Disease-causing mutations are displayed as spheres at the C␣ positions, color-coded as yellow for FCAS, orange for MWS, red for
NOMID, and gray for other. For amino acid positions identified in multiple syndromes, the most severe phenotype is indicated. The pyrin domain
of cryopyrin was threaded onto the pyrin domain of human ASC (Protein Data Bank [PDB] code no. 1ucp [52]). The first domain of NACHT was
generated using the structure of apoptotic protease–activating factor 1 (APAF1; PDB code no. 1z6t [53]). APAF1 and cryopyrin deviate between
␣5 and ␤4 and were modeled using consensus secondary structure predictions. This region includes the positions of the G326E and S331R mutations
(red spheres that do not map to the common mutation surface). The LRR domains were modeled using the porcine ribonuclease inhibitor structure
(PDB code no. 2bnh [54]). C, Superimposition of the model for NACHT subdomain 1 on the hexameric assembly of the AAA⫹ ATPase HslU (PDB
code no. 1doo [48]). Most of the mutations (colored as in B) map to the inner, concave surface of the hexameric ring. In other AAA⫹ ATPases,
this surface is where AAA⫹ subdomains 2 and 3 tend to contact subdomain 1 (46). As in other AAA⫹-ATPases, the hexameric assembly places
nucleotide-binding sites at the interfaces between adjacent protomers. D, Location of the disease-causing mutations in cryopyrin, suggesting a model
for inappropriate inflammasome assembly. In wild-type cryopyrin, opening of the protein to expose the pyrin and LRR domains is normally triggered
due to an external stimulus. The open state of cryopyrin is presumably the active one that assembles a functional inflammasome. With mutations
in the NACHT domain, the closed state is destabilized due to mutations at the interface of the hinge, tending to favor the activated and open state.
The G755 mutations might similarly drive inflammasome assembly by producing a “kink” in the regular LRR structure that inappropriately exposes
the LRR domains either to more readily open the structure or to become competent to directly assemble the inflammasome.
CLINICAL CONTINUUM OF CRYOPYRINOPATHIES
is most likely influenced by a number of other genetic
and environmental modifiers. We report 7 novel
NOMID/MWS/FCAS-causing mutations in exon 3 of
CIAS1. All of these mutations cause missense nucleotide
substitutions and have not been found in any of several
hundred control chromosomes. Thus, with this report
the total number of CIAS1 disease-associated mutations
is 56 (10).
Our entire NOMID/CINCA syndrome cohort
includes 39 patients who fulfill clinical criteria for diagnosis. In the past, we reported 8 mutation-positive and 9
mutation-negative patients (7,49,50); herein we report
an additional 12 mutation-positive and 10 mutationnegative cases. The mutation-negative patients were
screened for mutations in all exons of CIAS1, thus ruling
out mutations in the coding part of cryopyrin as a cause
of the disease. However, our mutation screening
method, although extensive, did not rule out the presence of mutations in the noncoding regulatory sequences of CIAS1. Thus, CIAS1 mutations were identified in only 51% of cases (20 of 39), suggesting
significant genetic heterogeneity among patients with
NOMID/CINCA syndrome.
Similarly, 25% (3 of 12) of the probands in our
MWS cohort lacked mutations in the coding sequence of
CIAS1 exons. In the remaining patients, we found 3
known CIAS1 mutations (R260W, A352V, and T348M).
Interestingly, the prevalence of MWS appears to be
lower in North America than that reported in Europe.
This may result from phenotype assignment preference
in the disease continuum or the presence of larger
families with MWS in Europe and larger families with
FCAS in North America, resulting in a selection bias.
Over the past few years we have identified 137
FCAS patients who belong to 24 families. The vast
majority of them (114 patients from 12 families) are
carriers for the L353P mutation. At least 3 of these
families share a common ancestor, and 1 family has been
confirmed by genotyping to be independent (51). Of the
remaining patients, 21 are carriers for the following
CIAS1 mutations: C259W, L305P, A439V, E525K,
Y563N, E627G, and M659K. Two FCAS patients are
mutation negative.
In this study, we evaluated allele frequencies for
3 CIAS1 mutations that may be considered polymorphisms, V198M, R488K, and Q703K, in a large panel of
DNA samples from Caucasian controls. For V198M and
R488K, we found allele frequencies of 0.0074 and
0.0014, respectively, among 742 and 370 Caucasians.
Previous studies identified V198M in control DNA
samples from 0 of 109 North American Caucasians, 1 of
1281
130 UK Caucasians, 0 of 150 Spanish Caucasians, and 2
of 48 Asian Indians (3,5,42), and thus have raised the
question of whether V198M is a true disease-associated
mutation. R488K was not identified in any of 150
Spanish control DNA samples; however, it was found in
1 unaffected member of a Spanish FCAS family (42). In
the current study, which is the largest survey of healthy
Caucasian controls to date, neither variant was found at
the 1% allele frequency required to be considered
formally as a polymorphism. Nevertheless, given that the
V198M allele frequency approaches this level and that
we have recently observed a patient with V198M and
periodic fever that did not respond to anakinra (Kastner
DL, et al: unpublished observations), we would approach the clinical significance of this variant with
caution. Considering that these substitutions have been
associated with nonspecific autoinflammatory phenotypes, in vitro functional assays may be useful in understanding their pathogenic consequences. Based on the
similar allele frequency of Q703K in patients and control
cohorts (0.04 versus 0.05; P ⫽ 0.84), we conclude that
Q703K is unlikely to be pathogenic.
The vast majority of mutations underlying FCAS,
MWS, and NOMID are dominant mutations. This is
consistent with the notion that cryopyrinopathies are
caused by gain-of-function mutations (21) and is quite
different from the spectrum of frameshift and nonsense
mutations observed in diseases driven by loss of function. We thus sought to understand the structural impact
of these activating mutations. Our modeling of the first
NACHT subdomain yielded essentially similar results
using 2 different templates (Cdc6p from Pyrobaculum
aerophilum [Protein Data Bank code no. 1fnn] and
apoptotic protease–activating factor 1 [Protein Data
Bank code no. 1z6t]). The findings were also consistent
with results of previous studies (44,45) in that most of
the mutations in this subdomain, including C259W,
V262A, L264F, and V351L identified in this study, fall
on one face of the monomer (Figure 2B). Mapping these
mutants onto a model of a cryopyrin hexamer revealed
the surprising result that a single, solvent-exposed surface is affected (Figure 2C). This suggests that the
primary impact of these mutations is to disrupt a surface
and differs from previous proposals that mutations
function via defects in nucleotide hydrolysis, conformational changes, or multimerization.
Although the possibility that the mutated surface
in the hexamer interacts with the LRRs cannot be ruled
out (8), comparisons with other AAA⫹ proteins suggest
that other NACHT subdomains may interact at this
surface. Interaction between NACHT subdomains is
K
M
P
P
K
V
T
P
W
L
P
N
G
M
R
L
C
E
F
F
H
I
N
P
S
R
A
C
F
1†
4
Families
2
5‡
Patient
1
1
2†§
4
12#
2
3**
Families
12
1
3
19
114
4
7
Patient
FCAS
1
4
Families
2
13
Patient
MWS/FCAS
18
2
1
1
1
10
1
1
34
3
4
1
6
3
Patient
1¶
Families
MWS
1
1
1
1
1
1
1
1
1
1
5
1
5
1
2
1
1
2
2
Patient
-
Families
MWS/NOMID
1
1
2
1
1
6
1
1
1
1
1
1
1
1
9
1
Families
2
1
2
1
1
6
1
1
1
1
1
1
1
1
10
1
Patient
NOMID
Refs.
42, P
3, 5, 42, 43
3, 42, P
51, P
10, P
5, 10, P
4
10
4, 10, 16, 27, P
45
45
4, 6, 7, 10, 23, 42, 45, P
45
4, 10, 28, 42, 45, P
4, 25
7
P
10
10
P
7
10
6
10
6, 10
12
13
7, 10, 14
10
* Amino acid (aa) residues for which mutations are only reported once are excluded. Family data are the total number of reported families with ⱖ1 affected patient; patient data
are the total number of reported patients. P ⫽ present study (see Table 1 for other definitions).
† Unaffected family members with mutation.
‡ Uncharacterized periodic fevers.
§ One family also carried E525K.
¶ Patients in family with features of FCAS, MWS, and NOMID.
# Three families confirmed (others presumed) to have common ancestor; 1 family confirmed independent.
**One family with intrafamilial variable phenotype.
Y570
F309
G755
T436
G326
L632
L264
T348
G569
F523
D303
R260
Mutation
aa
Other
Genotype/phenotype of reported CIAS1 mutations*
R488
V198
L305
L353
M659
A439
Table 3.
1282
AKSENTIJEVICH ET AL
CLINICAL CONTINUUM OF CRYOPYRINOPATHIES
consistent with patterns of mutations in other NACHT
domains that suggest that another surface is disrupted
(Figure 1). Similarly, the effect of the G755A/R mutations in the LRRs may be quite similar to those in
NACHT subdomains, even if the mutations affect
cryopyrin in a structurally different way (Figure 2D).
These models are consistent with the notion that
known mutations share a common mechanism whereby
a closed and inactive conformation of cryopyrin is
disrupted, leading to activation of the inflammasome
complex and subsequent activation of caspase 1 and
increased IL-1␤ and IL-18 secretion (Figure 2D). The
fact that most of the disease-causing mutations occur in
the NACHT and NACHT-associated domains suggests
that the gain of function requires intact pyrin and LRR
domains, or that most mutations in the pyrin and LRR
domains cannot activate cryopyrin. These diseasecausing mutations do not need to completely disrupt the
inactive state of cryopyrin, but rather could simply
influence the normal equilibrium between active and
inactive forms of the molecule and the ease by which inflammasome assembly is activated by external stimulus.
Our models, however, cannot directly address the
clinically important problem of the severity of any
particular mutation. And the question remains as to
whether the CAPS mutations show a clear correlation
between genotype and phenotype. If so, then their
defects can be understood primarily in the context of
cryopyrin structure–function relationships. If not, then
other genetic factors likely play a role in the disease
process. Addressing the genotype/phenotype correlation
is complicated by the small number of patients, reporting bias, and variable phenotyping by clinicians. Despite
these limitations, the phenotypes of many patients with
known mutations have been adequately described in the
literature and can be used as a basis for this analysis.
Analysis of all known mutations indicates that
mutational severity is not correlated with mutation
cluster position (Figure 1), the specific residue mutated
(for example, R260 in Table 3), or conservation among
CIAS1 orthologs (Figure 1). Thus, we focused solely on
multiply observed mutations (Table 3). At both ends of
the disease severity continuum, there are mutations with
relatively consistent phenotypes. For example, L353P
and L305P tend to be associated with milder phenotypes, whereas F309S and Y570C tend to be associated
with more severe phenotypes. Other mutations, including those affecting A439, R260, and D303, have significantly variable severities, strongly suggesting that other
genetic factors can play a role in disease severity.
In conclusion, we have identified a number of
novel disease-causing mutations in CIAS1, and our
1283
structural modeling of cryopyrin suggests a common
disease mechanism. But most importantly, several lines
of evidence presented here, including the finding of
patients without cryopyrin mutations, the lack of a clear
genotype/phenotype correlation for many mutations,
and the potential reduced penetrance of V198M and
R488K, strongly suggest the presence of additional
genetic factors that initiate or modulate the cryopyrinopathies. Identification of these genes will be important for understanding innate immunity as well as providing new targets for controlling these diseases.
ACKNOWLEDGMENTS
We would like to thank all of the physicians who
referred their patients to us for molecular diagnostic testing.
We would also like to acknowledge Dr. Peter Gregersen for
sharing the North American Rheumatoid Arthritis Collection
and New York Cancer Project control samples with us, and
Amir Misaghi and Scott Anderson for technical support.
AUTHOR CONTRIBUTIONS
Dr. Aksentijevich had full access to all of the data in the study
and takes responsibility for the integrity of the data and the accuracy
of the data analysis.
Study design. Aksentijevich, Putnam, Remmers, Goldbach-Mansky,
Hoffman, Kastner.
Acquisition of data. Aksentijevich, Remmers, Mueller, Le, Moak,
Chuang, Austin Goldbach-Mansky, Hoffman.
Analysis and interpretation of data. Aksentijevich, Putnam, Remmers,
Mueller, Le, Kolodner Goldbach-Mansky, Hoffman, Kastner.
Manuscript preparation. Aksentijevich, Putnam, Remmers, Mueller,
Kolodner Goldbach-Mansky, Hoffman, Kastner.
Statistical analysis. Aksentijevich, Remmers.
Modeling of cryopyrin structure. Putnam.
REFERENCES
1. Stojanov S, Kastner DL. Familial autoinflammatory diseases:
genetics, pathogenesis and treatment. Curr Opin Rheumatol 2005;
17:586–99.
2. Prieur AM, Griscelli C, Lampert F, Truckenbrodt H, Guggenheim
MA, Lovell DJ, et al. A chronic, infantile, neurological, cutaneous
and articular (CINCA) syndrome: a specific entity analyzed in 30
patients. Scand J Rheumatol Suppl 1987;66:57–68.
3. Aganna E, Martinon F, Hawkins PN, Ross JB, Swan DC, Booth
DR, 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. Arthritis Rheum 2002;46:2445–52.
4. Dode C, Le Du N, Cuisset L, Letourneur F, Berthelot JM,
Vaudour G, et al. New mutations of CIAS1 that are responsible
for Muckle-Wells syndrome and familial cold urticaria: a novel
mutation underlies both syndromes. Am J Hum Genet 2002;70:
1498–506.
5. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner
RD. Mutation of a new gene encoding a putative pyrin-like protein
causes familial cold autoinflammatory syndrome and MuckleWells syndrome. Nat Genet 2001;29:301–5.
6. Feldman J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis S,
et al. Chronic, infantile, neurological, cutaneous and articular
1284
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum
Genet 2002;71:198–203.
Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT,
Hofmann SR, 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. Arthritis Rheum 2002;46:3340–8.
Tschopp J, Martinon F, Burns K. NALPs: a novel protein family
involved in inflammation. Nat Rev Mol Cell Biol 2003;4:95–104.
Anderson JP, Mueller JL, Rosengren S, Boyle DL, Schaner P,
Cannon SB, et al. Structural, expression, and evolutionary analysis
of mouse CIAS1. Gene 2004;338:25–34.
Infevers database. URL: http://fmf.igh.cnrs.fr/infevers.
Frenkel J, van Kempen MJ, Kuis W, van Amstel HK. Variant
chronic infantile neurologic, cutaneous, articular syndrome due to
a mutation within the leucine-reach repeat domain of CIAS1
[letter]. Arthritis Rheum 2004;50:2719–20.
Matsubayashi T, Sugiura H, Arai T, Oh-Ishi T, Inamo Y. Anakinra
therapy for CINCA syndrome with a novel mutation in exon 4 of
the CIAS1 gene. Acta Paediatr 2006;95:246–9.
Aksentijevich I, Remmers EF, Goldbach-Mansky R, Reiff A,
Kastner DL. Mutational analysis in neonatal-onset multisystem
inflammatory disease: comment on the articles by Frenkel et al
and Saito et al [letter]. Arthritis Rheum 2006;54:2703–4.
Saito M, Fujisawa A, Nishikomori R, Kambe N, Nakata-Hizume
M, Yoshimoto M, et al. Somatic mosaicism of CIAS1 in a patient
with chronic infantile neurologic, cutaneous, articular syndrome.
Arthritis Rheum 2005;52:3579–85.
Martinon F, Burns K, Tschopp J. The inflammasome: a molecular
platform triggering activation of inflammatory caspases and processing of proIL-1␤. Mol Cell 2002;10:417–26.
Agostini L, Martinon F, Burns K, McDermott M, Hawkins PN,
Tschopp J. NALP3 forms an IL-1␤-processing inflammasome with
increased activity in Muckle-Wells autoinflammatory disorder.
Immunity 2004;20:319–25.
Kanneganti T, Ozoren N, Body-Malapel M, Amer A, Park JH,
Franchi L, et al. Bacterial RNA and small antiviral compounds
activate caspase-1 through cryopyrin/Nalp3. Nature 2006;440:
233–6.
Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K,
Roose-Girma M, et al. Cryopyrin activates the inflammasome in
response to toxins and ATP. Nature 2006;440:228–32.
Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Goutassociated uric acid crystals activate the NALP3 inflammasome.
Nature 2006;440:237–41.
Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, et al. Critical role for NALP3/CIAS1/
cryopyrin in innate and adaptive immunity through its regulation
of caspase-1. Immunity 2006;24:317–27.
Dowds TA, Masumoto J, Zhu L, Inohara N, Nunez G. Cryopyrininduced interleukin 1␤ secretion in monocytic cells: enhanced
activity of disease-associated mutants and requirement for ASC.
J Biol Chem 2004;279:21924–8.
Yu JW, Wu J, Zhang Z, Datta P, Ibrahimi I, Taniguchi S, et al.
Cryopyrin and pyrin activate caspase-1, but not NF-␬B, via ASC
oligomerization. Cell Death Differ 2006;13:236–49.
Janssen R, Verhard E, Lankester A, ten Cate R, van Dissel JT.
Enhanced interleukin-1␤ and interleukin-18 release in a patient
with chronic infantile neurologic, cutaneous, articular syndrome.
Arthritis Rheum 2004;50:3329–33.
Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. N Engl J Med
2003;348:2583–4.
Hawkins PN, Bybee A, Aganna E, McDermott MF. Response to
AKSENTIJEVICH ET AL
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
anakinra in a de novo case of neonatal-onset multisystem inflammatory disease. Arthritis Rheum 2004;50:2708–9.
Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayer J, Mueller
JL, et al. Prevention of cold-associated acute inflammation in
familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 2004;364:1779–85.
Alexander T, Klotz O, Feist E, Ruther K, Burmester GR, Pleyer
U. Successful treatment of acute visual loss in Muckle-Wells
syndrome with interleukin 1 receptor antagonist. Ann Rheum Dis
2005;64:1245–6.
Seitz M, Kamgang RK, Simon HU, Villiger PM. Therapeutic
interleukin (IL) 1 blockade normalises increased IL1␤ and decreased tumour necrosis factor ␣ and IL-10 production in blood
mononuclear cells of a patient with CINCA syndrome. Ann
Rheum Dis 2005;64:1802–3.
Boschan C, Witt O, Lohse P, Foeldvari I, Zappel H, Schweigerer
L, 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. Am J
Med Genet 2006;140:883–6.
Rynne M, Maclean C, Bybee A, McDermott MF, Emery P.
Hearing improvement in a patient with variant Muckle-Wells
syndrome in response to interleukin 1 receptor antagonist. Ann
Rheum Dis 2006;65:533–4.
Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J,
Rubin BI, et al. Neonatal-onset multisystem inflammatory disease
responsive to interleukin-1␤ inhibition. N Engl J Med 2006;355:
581–92.
Hoffman HM, Wanderer AA, Broide DH. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal
dominant periodic fever. J Allergy Clin Immunol 2001;108:615–20.
Bruns CM, Hubatsch I, Ridderstrom M, Mannervik B, Tainer JA.
Human glutathione transferase A4-4 crystal structures and mutagenesis reveal the basis of high catalytic efficiency with toxic lipid
peroxidation products. J Mol Biol 1999;288:427–39.
Rost B, Sander C. Combining evolutionary information and neural
networks to predict protein secondary structure. Proteins 1994;19:
55–72.
McGuffin LJ, Bryson K, Jones DT. The PSIPRED protein structure prediction server. Bioinformatics 2000;16:404–5.
Cuff JA, Barton GJ. Application of enhanced multiple sequence
alignment profiles to improve protein secondary structure prediction. Proteins 2000;40:502–11.
Ouali M, King RD. Cascaded multiple classifiers for secondary
structure prediction. Protein Sci 2000;9:1162–76.
Schwede T, Kopp J, Guex N, Peitsch MC. SWISS-MODEL: an
automated protein homology-modeling server. Nucl Acid Res
2003;31:3381–5.
Kelley LA, MacCallum RM, Sternberg MJ. Enhanced genome
annotation using structural profiles in the program 3D-PSSM. J
Mol Biol 2003;299:499–520.
Shi J, Blundell TL, Mizuguchi K. FUGUE: sequence-structure
homology recognition using environment-specific substitution tables and structure-dependent gap penalties. J Mol Biol 2001;310:
243–57.
DeLano WL. The PyMOL molecular graphics system. URL:
http://www.pymol.org.
Arostegui JI, Aldea A, Modesto C, Jesus Rua M, Arguellas F,
Gonzalez-Ensenat MA, et al. Clinical and genetic heterogeneity
among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene. Arthritis Rheum 2004;50:4045–50.
Porksen G, Lohse P, Rosen-Wolff A, Heyden S, Forster T,
Wendisch J, 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—
CLINICAL CONTINUUM OF CRYOPYRINOPATHIES
44.
45.
46.
47.
48.
49.
expanding phenotype of CIAS1 related autoinflammatory syndrome. Eur J Haematol 2004;73:123–7.
Albrecht M, Domingues FS, Schreiber S, Lengauer T. Structural
localization of disease-associated sequence variations in the
NACHT and LRR domains of PAYPAF1 and NOD2. FEBS Lett
2003;554:520–8.
Neven B, Callebaut I, Prieur AM, Feldmann J, Bodemer C,
Lepore L, et al. Molecular basis of the spectral expression of
CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. Blood
2004;103:2809–15.
Putnam CD, Clancy CB, Tsuruta H, Gonzalez S, Wetmur JG,
Tainer JA. Structure and mechanism of the RuvB Holliday
junction branch migration motor. J Mol Biol 2001;311:297–310.
Hanson PI, Whitehart SW. AAA⫹ proteins: have engine, will
work. Nat Rev Mol Cell Biol 2005;6:519–29.
Bochtler M, Hartmann C, Song HK, Bourenkov GP, Bartunik HD,
Huber R. The structures of HslU and the ATP-dependent protease HslU-HslV. Nature 2000;403:800–5.
Kallinich T, Hoffman HM, Roth J, Keitzer R. The clinical course
1285
50.
51.
52.
53.
54.
of a child with CINCA/NOMID syndrome improved during and
after treatment with thalidomide. Scand J Rheumatol 2005;34:
246–9.
Matsubara T, Hasegawa M, Shiraishi M, Hoffman HM, Ichiyama
T, Tanaka T, et al. A severe case of chronic infantile neurologic,
cutaneous, articular syndrome treated with biologic agents. Arthritis Rheum 2006;54:2314–20.
Hoffman HM, Gregory S, Mueller J, Tresierras M, Broide D,
Wanderer A, et al. Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation
L353P. Hum Genet 2003;112:209–16.
Liepinsh E, Barbals R, Dahl E, Sharipo A, Staub E, Otting G. The
death-domain fold of the ASC pyrin domain, presenting a basis of
pyrin/pyrin recognition. J Mol Biol 2003;332:1155–63.
Riedel SJ, Li W, Chao Y, Schwarzenbacher R, Shi Y. Structure of
the apoptotic protease-activating factor 1 bound to ADP. Nature
2005;434:926–33.
Kobe B, Deisenhofer J. Crystal structure of porcine ribonuclease
inhibitor, a protein with leucine-rich repeats. Nature 1993;366:
751–6.
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north, mode, patients, mutation, clinical, american, cryopyrinopathiesnovel, continuum, cryopyrin, new, cias
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