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Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic cutaneous articular syndrome.

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Vol. 52, No. 11, November 2005, pp 3579–3585
DOI 10.1002/art.21404
© 2005, American College of Rheumatology
Somatic Mosaicism of CIAS1 in a Patient With
Chronic Infantile Neurologic, Cutaneous, Articular Syndrome
Megumu Saito, Akihiro Fujisawa, Ryuta Nishikomori, Naotomo Kambe, Mami Nakata-Hizume,
Momoko Yoshimoto, Katsuyuki Ohmori, Ikuo Okafuji, Takakazu Yoshioka, Takashi Kusunoki,
Yoshiki Miyachi, Toshio Heike, and Tatsutoshi Nakahata
Chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is a severe inflammatory disease that was recently found to be associated
with mutations in CIAS1. However, CIAS1 mutations
have been detected in only half of CINCA syndrome
patients, and it remains unclear which genes are responsible for the syndrome in the remaining patients.
We describe here a patient with CINCA syndrome who
exhibited CIAS1 somatic mosaicism. We genetically
analyzed the CIAS1 gene in various blood cells and the
buccal mucosa of the patient. The production of
interleukin-1␤ (IL-1␤) by peripheral blood mononuclear cells (PBMCs) was measured by enzyme-linked
immunosorbent assay, and the ability of the mutant
CIAS1 gene to enhance ASC-dependent NF-␬B activation was assessed to confirm that the mutations of
CIAS1 found were responsible for the patient’s clinical
manifestations of the CINCA syndrome. The patient
had 1 heterologous single-nucleotide polymorphism,
587G>A (S196N), and 1 heterologous mutation,
1709A>G (Y570C), in exon 3 of CIAS1. The latter
mutation was found to occur as somatic mosaicism. The
patient’s PBMCs produced a large amount of IL-1␤ in
the absence of stimulation, unlike those from controls or
from his mother, who also bore the S196N polymorphism. In addition, the Y570C mutation (with or without the S196N polymorphism) increased the ability of
CIAS1 to induce ASC-dependent NF-␬B activation, unlike the wild-type gene or the gene bearing the S196N
polymorphism alone. The findings in this patient indicate that somatic mosaicism is one reason CIAS1 mutations have not been detected in some patients with
CINCA syndrome.
Chronic infantile neurologic, cutaneous, articular
syndrome (CINCA syndrome) (MIM no. #607115), also
known as neonatal-onset multisystem inflammatory disease, is a recently recognized disorder characterized by
recurrent episodes of inflammation (1–5). Patients with
CINCA syndrome exhibit recurrent fever, an urticarial
rash beginning in the neonatal period, arthropathy characterized particularly by epiphyseal patellar overgrowth,
chronic meningitis, papilledema, hearing loss, and
growth retardation. The gene responsible for the syndrome is reported to be CIAS1, which has also been
associated with 2 less severe but phenotypically similar
syndromes, familial cold autoinflammatory syndrome
(FCAS) (MIM no. #120100) and Muckle-Wells syndrome (MWS) (MIM no. #191900) (6–10).
CIAS1 (also designated PYPAF1 and NALP3) has
been reported to be expressed in polymorphonuclear
cells, monocytes, chondrocytes, and activated T cells
(9,11,12). Its product is cryopyrin, which contains an
amino-terminal pyrin domain, a centrally located
NACHT domain, and carboxy-terminal leucine-rich repeats (LRRs). Cryopyrin localizes in the cytosol and is
believed to function as a pattern recognition receptor. It
can activate caspase 1 in the presence of an adaptor
protein called ASC, and it converts the proform of
interleukin-1␤ (IL-1␤) into the mature and biologically
Supported in part by the Morinaga Hoshi-Kai, the Sapporo
Bioscience Foundation, the Ministry of Education, Science, Sports,
and Culture, and the Ministry of Health, Labor, and Welfare, Japan.
Megumu Saito, MD, Akihiro Fujisawa, MD, Ryuta Nishikomori, MD, PhD, Naotomo Kambe, MD, PhD, Mami NakataHizume, MS, Momoko Yoshimoto, MD, PhD, Katsuyuki Ohmori,
PhD, Ikuo Okafuji, MD, Takakazu Yoshioka, MD, Takashi Kusunoki,
MD, PhD, Yoshiki Miyachi, MD, PhD, Toshio Heike, MD, PhD,
Tatsutoshi Nakahata, MD, PhD: Kyoto University, Kyoto, Japan.
Drs. Saito and Fujisawa contributed equally to this work.
Address correspondence and reprint requests to Ryuta Nishikomori, MD, PhD, Department of Pediatrics, Graduate School of
Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku,
Kyoto 606-8507, Japan. E-mail:
Submitted for publication May 10, 2005; accepted in revised
form August 9, 2005.
active IL-1␤ molecule (13,14). Cryopyrin also participates in regulating NF-␬B (14,15).
All CIAS1 mutations found to date in patients
with CINCA syndrome, FCAS, and MWS are located in
exon 3, which encodes the NACHT domain (7,9,16–19).
It is speculated that these CIAS1 mutations may lead to
an aberrantly functioning cryopyrin protein, which then
leads to dysregulated production of inflammatory cytokines such as IL-1␤ (7,13,14,20). However, although
patients with FCAS and MWS tend to show familial
inheritance patterns, CINCA syndrome usually occurs
de novo, and approximately half the patients with
CINCA syndrome lack detectable mutations in the
CIAS1 coding region (7,9,16,17). It has been postulated
that different genes or a modifier gene could be involved
in these latter cases, although these patients do not
differ clinically from those with CIAS1 mutation(s).
Herein we describe a patient with typical symptoms of CINCA syndrome who was found to have
somatic mosaicism of CIAS1. Such somatic mosaicism
could be easily missed with the sequencing method
usually used to identify CIAS1 mutations. This case may
explain why CIAS1 mutations have not been detected in
some patients with CINCA syndrome.
The patient was a 15-year-old boy born by normal
vaginal delivery with no consanguinity. During the neonatal period, he had developed an urticarial rash. At the
age of 22 months, his abnormal gait led to the diagnosis
of arthritis of the knee. At age 10 years, an ophthalmologic evaluation revealed papilledema, and cerebrospinal fluid examination showed chronic meningitis. At the
age of 11 years, he underwent bilateral knee joint
tendonectomy. When he was 12 years old, audiography
showed mild sensorineural deafness. He had been
treated with glucocorticoids since the age of 2 years and
with methotrexate mini-pulse therapy since the age of 4
years. Laboratory examinations revealed persistent elevations of the C-reactive protein level, erythrocyte sedimentation rate, and white blood cell count, although
eosinophilia was not detected. On the basis of these
characteristic signs and symptoms, the clinical course,
and the persistent inflammation, the patient was diagnosed, at the age of 12 years, as having CINCA syndrome.
Physical examination of the patient at the age of
15 years showed marked growth retardation (height –8.5
SD, weight –8.2 SD), joint contracture of the knees
bilaterally, an urticarial rash, and a saddlenose deform-
ity. However, no mental retardation (IQ 82 by Wechsler
Intelligence Scale for Children III) or epilepsy was
detected. Magnetic resonance imaging and computed
tomography of the head also did not show any abnormalities.
The patient’s parents and sister did not have any
of the symptoms noted above.
Genetic analysis. Informed consent was obtained from
the patient and his family according to a protocol approved by
the Institutional Review Board of Kyoto University Hospital.
Peripheral blood mononuclear cells (PBMCs) and neutrophils
were obtained by density-gradient centrifugation over Ficoll
(Amersham Biosciences, Piscataway, NJ) and with monopoly
reagents (Dainippon, Osaka, Japan), respectively, and phytohemagglutinin (PHA) blasts were produced by culturing
PBMCs with PHA (Invitrogen, Carlsbad, CA) as previously
described (21). Genomic DNA from whole blood, PBMCs,
neutrophils, and PHA blasts was then obtained using a Puregene DNA isolation kit according to the protocol of the
manufacturer (Gentra Systems, Minneapolis, MN), and
genomic DNA from a buccal mucosa sample was obtained
using a DNA isolation kit from Qiagen (Valencia, CA). For
each genomic DNA sample, each CIAS1 exon, including the
exon–intron boundaries, was amplified by polymerase chain
reaction (PCR) and sequenced by the dideoxynucleotide termination method with ABI 3100 (Applied Biosystems, Foster
City, CA). To analyze the frequency with which the CIAS1
mutation occurred, the amplified exon 3 was subcloned using a
TOPO TA cloning kit (Invitrogen) and sequenced. Reverse
transcriptase–PCR (RT-PCR) for CIAS1 was performed as
previously described (21).
Enzyme-linked immunosorbent assay for IL-1␤. For
cytokine analysis, PBMCs were cultured with or without lipopolysaccharide (LPS; 10 ng/ml) (Sigma, St. Louis, MO) and
supernatants were collected. Enzyme-linked immunosorbent
assay for IL-1␤ was performed according to the protocol
recommended by the manufacturer (eBioscience, San Diego,
NF-␬B luciferase assay. Wild-type CIAS1 and its
LRRs-lacking mutant (⌬LRRs; amino acids 1–742) in pEFBOS vector (22) were kindly provided by Dr. T. Suda (Kanazawa University, Ishikawa, Japan). Other mutants were
generated using a QuikChange site-directed mutagenesis kit
(Stratagene, La Jolla, CA). ASC complementary DNA was
kindly provided by Dr. J. Sagara (Shinshu University, Nagano,
Japan). HEK293FT cells (105) were transfected using TransIT293 Transfection Reagent (Milus Bio, Madison, WI) with the
NF-␬B reporter construct (pNF-␬B-luc; 20 ng) (BD Biosciences Clontech, Palo Alto, CA), an internal control construct (pRL-TK; 5 ng) (Toyo Ink, Tokyo, Japan), and wild-type
or mutant CIAS1 in the presence or absence of ASC (16 ng).
The total plasmid contents were adjusted by adding empty
pEF-BOS vector. Twenty-four hours later, the transfected cells
were harvested and subjected to dual luciferase assay as
previously described (23).
Figure 1. Top, Pedigree of the patient’s family. The patient (family member 3) is indicated by the arrow. Bottom, Chromatograms of the CIAS1 gene
at positions 587 and 1709, from CIAS1 gene analysis of the patient and his parents (family members 1 and 2).  indicates position 1709 on the
patient’s chromatogram.
Unexpectedly, 2 heterologous point mutations,
587G⬎A (S196N) and 1709A⬎G (Y570C), were detected in exon 3 of CIAS1 in the patient, as shown in
Figure 1. Even though the chromatographic intensities
of G and A at position 587 were almost identical, the
intensity of the mutated G at position 1709 was, reproducibly, considerably lower than that of the A at this
position (Figure 1). This suggests that the 1709A⬎G
(Y570C) mutation may be a case of somatic mosaicism.
To test this hypothesis, exon 3 of CIAS1 from the
patient’s whole blood, amplified by PCR, was subcloned
to measure the frequency of the mutant allele. This
revealed that the 1709A⬎G mutation occurred with a
frequency of 16.7% in whole blood (Figure 2). Thus,
somatic mosaicism is the cause of the less frequent
occurrence of the 1709G variant compared with 1709A
in the direct sequencing analysis.
When we mixed equal amounts of 2 subcloned
plasmids that expressed G or A at position 1709, respectively, we confirmed that the signal for G was stronger
than that for A (Figure 2). This would help to easily
identify this mutation, even when it occurs at a frequency
of ⬃10–20%. We also identified the mosaicism of CIAS1
at the messenger RNA level by RT-PCR (Figure 2). By
sequencing exon 3 in the subcloned plasmid expressing
G at position 1709, we found that both the 587G⬎A
(S196N) and 1709A⬎G (Y570C) mutations were located on the same allele (data not shown).
To further characterize the mosaicism in this
allele; 1%), while no 1709A⬎G (Y570C) mutations were
CIAS1 mutations detected previously in patients
with CINCA syndrome have been reported to activate
caspase 1 via ASC, and as a result, monocytes from the
patients produce IL-1␤ even in the absence of stimuli
such as LPS (7,13,14,20). Consequently, we cultured
PBMCs from the patient, his mother, and normal controls. The patient’s PBMCs produced large amounts of
IL-1␤ in the absence of LPS stimulation, unlike those
from his mother and the controls, whereas the LPS
response of the patient’s PBMCs was comparable with
that of PBMCs from his mother and controls after 24
hours of LPS stimulation (Figure 3). This indicates that
the Y570C mutation, and not the S196N polymorphism
found in the patient’s mother as well, was likely to be the
CIAS1 mutation responsible for the clinical manifestations of CINCA syndrome in this patient.
To address this question more directly, we measured the effect of various mutations in CIAS1 on
ASC-dependent NF-␬B activity in NF-␬B reporter experiments. HEK293FT cells were cotransfected with
wild-type or mutant CIAS1, ASC, and the NF-␬B reporter construct. We confirmed that the mutant lacking
the LRRs (⌬LRRs) or bearing other reported point
mutations, namely, R260W or D303N (14), activated
Figure 2. Analysis of the frequency with which the 1709G⬎A mutation occurred in various cells from the patient. The chromatograms
resulting from direct sequencing of isolated DNA and the results of
frequency analysis performed by cloning and sequencing are shown.
A:G ⫽ 1:1 indicates the chromatogram resulting from sequencing
analysis of a mixture of equal amounts of plasmids containing CIAS1
exon 3 with either 1709A or 1709G.  indicates position 1709.
PBMC ⫽ peripheral blood mononuclear cell.
patient, the frequency with which the 1709A⬎G mutation occurred in PBMCs, neutrophils, PHA blasts, and
buccal mucosa was analyzed. While the frequency varied
depending on the cell type (Figure 2), the mutation was
identified in the various hematopoietic and somatic cells
examined, which indicates that the somatic mosaicism
occurred at a very early time point during embryogenesis.
We next analyzed samples from the patient’s
parents and found that his mother also had the 587G⬎A
(S196N) mutation. However, neither of his parents bore
the 1709A⬎G (Y570C) mutation. We also performed
single-nucleotide polymorphism (SNP) analysis of the
2 mutated sites in 100 normal Japanese controls and
found that 587G⬎A (S196N) is a rare SNP (2/200
Figure 3. Spontaneous production of interleukin-1␤ (IL-1␤) by peripheral blood mononuclear cells (PBMCs) from the patient. PBMCs
from the patient (who had the Y570C and S196N mutations), his
mother (who had the S196N mutation), and 2 normal controls were
cultured with and without lipopolysaccharide (LPS) (10 ng/ml). The
concentrations of IL-1␤ in the harvested supernatants were then
measured by enzyme-linked immunosorbent assay. Representative
results from 1 of 2 independent experiments are shown.
Figure 4. Effect of the CIAS1 mutations in the patient on ASC-dependent NF-␬B activation. A, HEK293FT cells
were cotransfected with 16 ng of CIAS1, wild-type (WT) or its mutants (carboxy-terminal leucine-rich
repeat–lacking mutant [⌬LRR], S196N, Y570C, Y570C with S196N, R260W, D303N), in the presence or absence
of 16 ng ASC. B, HEK293FT cells were cotransfected with the indicated amounts of CIAS1, wild-type or its
mutants (S196N, Y570C, Y570C with S196N) in the presence or absence of ASC. Results are shown as fold
induction compared with vector without ASC (set at 1); values are the mean and SD of triplicate determinations.
Representative results from 1 of 3 independent experiments are shown.
NF-␬B more vigorously than did wild-type CIAS1 (Figure 4A). We also showed that the mutant bearing the
Y570C point mutation, with or without the polymorphism of S196N, activated NF-␬B (in the presence of
ASC) more strongly than did the wild-type gene,
whereas the S196N polymorphism alone did not (Figure
4A). These data indicate that of the CIAS1 mutation and
the polymorphism found in the patient, the Y570C
mutation was critical for NF-␬B activation and is likely
to be the major cause of his CINCA syndrome.
To further confirm the effect of the individual
mutation and polymorphism detected in this patient on
ASC-dependent NF-␬B activation, we transfected
HEK293FT cells with different amounts of wild-type,
S196N single-mutant, Y570C single-mutant, and S196N/
Y570C double-mutant CIAS1 in the presence of ASC.
The Y570C single mutant and the double mutant induced more NF-␬B activation than did the wild-type
CIAS1 at each of the 3 concentrations tested. Moreover,
we found that the double mutant consistently induced
lower levels of NF-␬B activation relative to that generated by the Y570C single mutant with all concentrations
of ASC tested, although the difference was minimal
(Figure 4B).
This is the first report of somatic mosaicism of
CIAS1 in a patient with CINCA syndrome. Initially, we
failed to detect the small 1709G peak and only identified
the S196N polymorphism. Since we did not find the
latter polymorphism in our database search of Japanese
SNPs, we therefore thought that it was responsible for
the clinical manifestations of CINCA syndrome in this
patient. However, our subsequent analysis of the patient’s family and our own SNP analysis of 100 normal
Japanese controls revealed that S196N is simply a rare
SNP and not the disease-causing mutation. This led us to
examine the patient’s sequence chromatography results
more carefully.
The Y570C mutation, which in this patient occurred as somatic mosaicism, is one of the most common
CIAS1 mutations, and all 4 reported CINCA syndrome
patients with this mutation have a very severe phenotype
that includes mental retardation or epilepsy (7,17,18).
However, our patient did not exhibit such central nervous system dysfunctions, although he did have severe
arthropathy and epiphyseal overgrowth. The relatively
mild phenotype in our patient could be explained by the
lower dose of the active mutant due to the somatic
mosaicism of CIAS1. Alternatively, the milder phenotype may be due to occurrence of the mutation with
differing frequencies in various cell types, i.e., fewer cells
in the central nervous system may express the active
mutation compared with those in articular or cutaneous
Yet another possibility relates to the fact that the
patient not only had the Y570C mutation, but also had
the maternally inherited S196N mutation on the same
allele. This latter mutation could lessen the severity of
the phenotype. In support of this are the results of our in
vitro analysis of the ability of wild-type and mutant
CIAS1 to activate NF-␬B: the S196N/Y570C double
mutant activated NF-␬B slightly, but consistently, less
potently than did the Y570C single mutant. Further
analysis of more patients with CINCA syndrome and
how their disease phenotypes relate to their genotypes,
especially in patients with somatic mosaicism or double
mutation, will be needed before we can determine why
our patient has a less severe phenotype than other
CINCA syndrome patients bearing the Y570C mutation.
To date, patients with somatic mosaicism of
CIAS1 have not been reported, even though CINCA
syndrome largely occurs de novo. In the cohort of 233
type 2 neurofibromatosis founders with bilateral vestibular schwannomas reported by Kluwe et al, the rate of
mosaicism was 24.9% (58 of 233) (24). This suggests the
probable existence of other cases of CINCA syndrome
with somatic mosaicism. Identification of these patients
by whole blood gene sequencing analysis is likely to be
problematic. Indeed, we were able to identify only the
1709A⬎G mutation that encodes the Y570C amino acid
change, because the chromatographic intensity of 1709G
in the sequencing analysis was 2-fold stronger than that
of 1709A; this made it easier for us to detect the small
peak representing the extra G. In order for direct
sequencing methods to be useful in detecting cases of
CIAS1 somatic mosaicism, baseline “noise” on chromatography will have to be minimized.
Since somatic mosaicism of CIAS1 may be difficult to detect by the usual direct sequencing method, we
would like to emphasize the importance of functional
studies such as the IL-1␤ secretion assay in diagnosing
the CINCA syndrome. Once the patient is confirmed to
have dysregulated IL-1␤ secretion, the investigation for
CIAS1 mutations can proceed. In cases in which CIAS1
mosaicism is suspected, subcloning-based sequencing of
CIAS1 would be useful. However, this procedure is very
labor-intensive. To overcome this, we are currently
seeking to establish a method to enrich CIAS1-mutated
cells, which would enhance the probability of finding the
relevant mutations.
In the whole blood of the patient described
herein, the frequency of the Y570C mutation was found
to be only 16.7%. This indicates that ⬃33% of the whole
blood cells bore a heterozygous mutation of Y570C.
Thus, the presence of an active CIAS1 mutation in only
a portion of the cells appears to be sufficient to cause the
clinical manifestations of CINCA syndrome. We speculate that one reason our patient developed CINCA
syndrome despite the somatic mosaicism of the CIAS1
mutation is that the Y570C mutation is particularly
potent in inducing ASC-dependent NF-␬B activation. In
this sense, it may be useful to catalog the CIAS1
mutations that cause CINCA syndrome according to
their relative ability to induce ASC-dependent NF-␬B
activation; this may help in focusing on certain regions of
the CIAS1 gene in the search for possible CIAS1 mosaicism. Furthermore, somatic mosaicism mutation analysis will help to identify the most suitable patients in
whom to investigate for new candidate genes whose
mutation(s) can cause CINCA syndrome.
In conclusion, we have identified a patient with
CINCA syndrome who had CIAS1 somatic mosaicism.
This case reveals that CIAS1 somatic mosaicism is one
reason CIAS1 mutations have not been detected in some
cases of CINCA syndrome.
We would like to thank Dr. T. Suda (Cancer Research
Institute, Kanazawa University, Ishikawa, Japan) for providing
the CIAS1 complementary DNA and Dr. J. Sagara (Research
Center on Aging and Adaptation, Shinshu University, Nagano,
Japan) for providing the ASC complementary DNA.
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