Genes and Immunity (2011) 12, 497–503

& 2011 Macmillan Publishers Limited All rights reserved 1466-4879/11

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REVIEW
The regulation of MEFV expression and its role in health
and familial Mediterranean fever
S Grandemange1, I Aksentijevich2, I Jeru3, A Gul4 and I Touitou1
1
Unité médicale des maladies auto-inflammatoires, CHRU de Montpellier, INSERM U844, UM1, Hopital Arnaud de Villeneuve,
Montpellier, France; 2National Human Genome Research Institute, Bethesda, MD, USA; 3INSERM U933, Université Pierre et Marie
Curie-Paris6 UMR S933, Paris, France and 4Istanbul Faculty of Medicine, Division of Rheumatology, Department of Internal Medicine,
Istanbul University, Istanbul, Turkey

Familial Mediterranean fever (FMF) is a hereditary recurrent fever associated with mutations in the gene MEFV encoding pyrin.
It is expressed mainly in neutrophils and macrophages, and modulates the production of the potent pro-inflammatory cytokine
interleukin-1b through regulation of nuclear factor-kB and caspase-1. The MEFV gene expression depends on multiple levels
of regulation. Sequence variants located in the promoter and at the 30 -untranslated region of the gene modulate this
expression. Two studies demonstrated decreased mRNA levels in FMF patients compared with healthy subjects, whereas two
others found no significant differences. The diverse experimental settings may have resulted in variable quantification of the 15
splice variants that have been identified recently. Some of these isoforms are regulated by nonsense-mediated decay in both
cell- and transcript-specific manner, and may be differentially translated in THP1 cells. In addition, pyrin may be cleaved by
caspase 1. The full-length pyrin was less abundant than the cleaved fragment in mononuclear cells from FMF patients than in
controls, whereas the opposite was observed in granulocytes. Altogether, the regulation of MEFV expression is more complex
than anticipated in both physiological and pathological conditions. Its deregulation is likely to alter the inflammasome function
and subsequently result in uncontrolled inflammation as seen in FMF.
Genes and Immunity (2011) 12, 497–503; doi:10.1038/gene.2011.53; published online 21 July 2011

Keywords: expression; MEFV; FMF

Introduction The gene responsible for FMF, named MEFV, encodes

Familial Mediterranean fever (FMF) is a recessively
inherited systemic auto-inflammatory disease. Auto-
inflammatory diseases are an expanding group of innate
immunity diseases that have been recently revisited as a
continuum, which includes diseases with some features
of adaptive immune deregulation. They include heredi-
tary recurrent fevers, pyogenic disorders such as the
deficiency of interleukin (IL)-1 receptor and pyogenic
sterile arthritis pyoderma gangrenosum and acne (PAPA),
granulomatous diseases such as Crohn’s disease and Blau
syndrome. FMF is considered the prototype among the
hereditary recurrent fevers as the most frequent and the
first whose gene has been identified. FMF patients suffer
from recurrent and seemingly unprovoked attacks of
fever, often associated with peritonitis, pleuritis, arthritis
and localized erysipelas-like erythema. The attacks
usually last 12–72 h.1 The inflammatory reaction is
characterized by a massive influx of polymorphonuclear
leukocytes into the affected tissues.
Correspondence: Professor I Touitou, Unité médicale des maladies
auto-inflammatoires, CHRU de Montpellier, INSERMU844, UM1,
Hopital Arnaud de Villeneuve, Montpellier, 371, Avenue du Doyen
Giraud 34295, Montpellier cedex 5, France.
E-mail: isabelle.touitou@inserm.fr
Received 20 May 2011; accepted 27 June 2011; published online 21
July 2011
pyrin2 (alternatively known as marenostrin,3) a protein of
781 amino-acids (Figure 1). Initial computer analysis of
pyrin/marenostrin sequence revealed that this protein
contains two putative overlapping nuclear binding
motifs and shows high homology with the B30/2 rfp
transcription factor family. This observation led to the
hypothesis that pyrin was a nuclear transcriptional
factor. Later, sequence alignments and secondary struc-
ture prediction highlighted that the first 100 N-terminal
residues of pyrin constituted a novel protein domain
named PYrin Domain (PYD),4–6 and revealed that PYD
was the fourth member of the death domain fold
superfamily. PYD orthologs were also identified in
several species such as mouse, cow and zebrafish.
The PYD is an N-terminal adapter domain that is found
in more than 20 human proteins involved in inflamma-
tion and apoptosis, such as NLRP3 (NLR family, PYD
containing 3), similar to other death domain fold-
containing proteins (for a review see Kohl et al.7) Recent
studies indicate that pyrin modulates the production of
the potent pro-inflammatory cytokine IL-1b probably
through two major pathways: (i) the N-terminal frag-
ment of pyrin may regulate nuclear factor (NF)-kB
activation through interactions with an adapter protein
named apoptosis-associated speck-like protein with a
caspase-recruitment domain (ASC)8–10 and/or with
NFkB-p65,11 and (ii) pyrin regulates caspase-1/IL-1b
activation through its interaction with ASC.12 Addition-
 MEFV expression in FMF
S Grandemange et al
498
MEFV DNA: 14600bp

5’flanking 3’ flanking
1 2 3 4 5 6 7 8 9 10

mRNA: 3499bp 1 2 3 4 5 67 8 9 10

Protein: 781aa
PyD B-Box CC B30.2/SPRY

TRIM20
DDF TRIpartite Motif family
Viral Proteins?
Inflammasome

Figure 1 Schematic representation of the FMF gene (MEFV) and its expression products at the RNA and protein levels. Exons are boxed,
introns are depicted as lines. The protein domains are illustrated along with their putative functions. The death domain fold at the N-terminal
domain is involved in regulating inflammation via homotypic interactions with inflammasomes. Interestingly, residues (680 and 694)
important for the conservation of the pyrin structure are precisely those which, when mutated, are associated with a severe form of the
disease.39 The SPRY domain is present in several proteins of the tripartite motif family. This domain may interact with viral components.
A full colour version of this figure is available at the Genes and Immunity journal online.

ally, the C-terminal B30.2 domain of pyrin, also known as
SPRY, directly interacts with caspase-1 to modulate IL-1b
production.13,14 This domain, together with the B-Box
and coiled-coil domains, constitutes a tripartite motif,
which is contained in proteins involved in viral recogni-
tion. Thus, pyrin is also known as TRIM20.15
The MEFV gene contains 10 exons. Nearly 200
sequence variants, almost all single-nucleotide substitu-
tions, have been recorded in Infevers,16 a database
dedicated to auto-inflammatory mutations (http://
fmf.igh.cnrs.fr/ISSAID/infevers/). Only a small number
of these variants are unambiguously pathogenic, such as
M694V, a severe mutation with a founder effect, and no
more than half of the reported MEFV variations are
associated with the FMF phenotype. The vast majority of
genuine FMF-associated mutations are found in the
SPRY domain of the protein. How mutations in the
MEFV gene can result in so variable an inflammatory
phenotype has been only partially elucidated.17 Most
molecular mechanisms that have been hypothesized
suggest an impaired or dysregulated interaction of
mutant pyrin protein with its partners, resulting in
activation of the NLRP3 inflammasomes.18 Inflamma-
somes are cytoplasmic multiprotein complexes essential
for the maturation of proinflammatory cytokines IL-1b,
IL-18 and IL-33. Several inflammasomes have been
described on the basis of their constituent stress-sensing
components. In NLRP inflammasomes, ASC works as an
adapter molecule that connects the stress-sensing com-
ponent and pro-caspase-1 through its N-terminal PyD
domain and C-terminal CARD domain, respectively (for
reviews see Chae et al.18 and Schroder and Tschopp19).
This brings two molecules of procaspase-1 into close
proximity, leading to proteolytic activation and the
subsequent release of the active catalytic domains, p20
and p10. Active caspase-1, in turn, cleaves the 31-kDa
precursor form of IL-1b into its biologically active 17-kDa
fragment. Given that ASC also interacts with pyrin
through PyD, it is possible that pyrin is somehow
involved in several inflammasomes as a modulator, or
pyrin itself is a component of an inflammasome. Thus,
most studies related to pyrin’s function in the innate
immune system have been focused on the regulation of
the caspase-1 activation and subsequent IL-1b secretion.
A growing body of evidence suggests, however, that
FMF mutations may also lead to dysregulation in the
MEFV expression affecting pyrin level.
The past decade has witnessed the explosion of
reviews on auto-inflammatory diseases written by
scientists and clinicians from a variety of disciplines.
Most of them attempted to correlate clinical features with
genotypes in patients with auto-inflammatory diseases,
or to dissect the underlying inflammatory pathways.
However, there has been no review on the regulation of
MEFV gene expression in physiological or pathological
conditions. In this manuscript, we review the complex
regulation of MEFV expression at the RNA and protein
levels, summarize the data obtained from various cell
lines along with expression data from FMF patients, and
discuss impaired regulation of MEFV expression as a
possible mechanism of the disease.
MEFV expression at the mRNA level
Cellular expression
Initial expression studies using northern blot experi-
ments detected MEFV mRNA only in peripheral blood
leukocytes (PBLs) and in a colorectal adenocarcinoma
cell line, SW480.2 Specific analysis of leukocyte fractions
from bone marrow and PBLs showed that MEFV was
highly expressed in neutrophils, and to some extent in
eosinophils and monocytes, but not in lymphocytes.20,21
MEFV is also expressed in dendritic cells and in
fibroblasts from synovium, peritoneum and to a lesser
extent from skin.22 This highly specific cellular expres-
sion pattern likely accounts for the predilection of FMF
patients to develop inflammation in serosal, synovial and
skin tissues.
Transcriptional regulation
Numerous mediators, such as lipopolysaccarides, pro-
inflammatory or anti-inflammatory cytokines, can mod-
ulate the mRNA expression of the MEFV gene. However,
its expression profile is very much dependent on the
cellular sources and experimental conditions (Table 1).
Most studies have used only semi-quantitative
approaches to measure the MEFV expression. Several
investigators have examined the role of regulatory
regions upstream and downstream of the MEFV coding

Genes and Immunity

 MEFV expression in FMF
S Grandemange et al
499
Table 1 Effect of various soluble mediators on MEFV mRNA levels

Cells Effect Reference

Colchicine Neutrophils None Centolla et al.20

Colchicine Peritoneal fibroblasts Increase Abedat et al.37
Colchicine + IFN-a or + IFN-g Neutrophils Increase Centolla et al.20
PMA Cutaneous and peritoneal fibroblasts None Matzner et al.38
PBLs, PBMCs, monocytes, THP1
LPS Synovial fibroblasts Increase Centolla et al.,20 Papin et al.26 and
Matzner et al.38
IFN-g Neutrophils, peritoneal fibroblasts None Centolla et al.20 and Abedat et al.37
IFN-g Monocytes, neutrophils, peritoneal Increase Centolla et al.20 and Papin et al.26
fibroblasts
TGFb Monocytes Decrease Centolla et al.20
TNFa Monocytes, peritoneal fibroblasts Increase Centolla et al.20 and Abedat et al.37
TNFa Neutrophils None Abedat et al.37
IL1b Cutaneous and peritoneal fibroblasts Increase Centolla et al.20 and Abedat et al.37
IL1b Neutrophils None Abedat et al.37
IL4 Monocytes Decrease Centolla et al.20
IL10 Monocytes Decrease Centolla et al.20

Abbreviations: IFN, interferon; IL, interleukin; LPS, lipopolysaccarides; PBLs, peripheral blood leukocytes; PBMCs, peripheral blood
mononuclear cells; PMA, phorbol myristate acetate; TGF, tumor growth factor; TNF, tumor necrosis factor.

NF!B C/EBP
IFN
c-myb AML IFN PU1
-571 -414 -286 -41
enhancer minimal promoter
c.-614G>C c.-382C>T ATG c.*836_837ins
haplotypes
5’-region Coding region 3’-region

Figure 2 Schematic representation of MEFV regulatory elements. The 1000-bp region upstream of the translation initiation site contains a
putative enhancer and a minimal promoter. The broken arrow stands for the transcription initiation site. Sites common in myeloid-specific
promoters are represented by green boxes (AML, acute myeloid leukemia; cEBP, CCAAT/enhancer binding protein) and those required for
cytokine activation by purple boxes (IFN, interferon). The circle arrow shows the synergistic activation of C/EBP and NF-kB-p65 for
responsiveness to tumor necrosis factor. The functional polymorphisms with possible role in FMF are depicted in red. A full colour version of
this figure is available at the Genes and Immunity journal online.

sequence. The promoter exhibits a number of consensus
binding sites for known transcription factors, for
example, sites common in myeloid specific promoters
and sites required for cytokine activation (Figure 2).
Papin et al.23 reported that the MEFV 50 -flanking region is
necessary for responsiveness to tumor necrosis factor,
and that it is dependent on a synergistic activation of
C/EBPbeta (factor required for cell responsiveness to
tumor necrosis factor) and NFkB-p65 (activating factor
acting in synergy with C/EBPbeta). We have character-
ized the minimal MEFV promoter region between
nucleotide residues c-41 and c-286, and identified a
region with a putative enhancer extending from c-414 to
c-571.24 Further investigation of the 1000-bp sequence
upstream of the initiation codon identified a couple of
nucleotide variants that may have a role in regulation of
the MEFV expression. The novel c-614C4G variant that
was found in a heterozygous state in an FMF patient of
Arab descent resulted in a 70% decrease in promoter
activity as measured by luciferase reporter experiments.
The other promoter variant, c-382C4T found in a non-
Ashkenazi-Jewish asymptomatic individual induced a
100% increased activity. Using electrophoretic mobility
shift assay experiments, we observed specific DNA–
protein complexes at both –382 and –614 wild-type
regions, indicating that nuclear protein(s) were able to
bind to these sequences and perhaps contribute to the
regulation of enhancer activity.24 A separate analysis of
36 Turkish FMF patients without MEFV coding region
mutations did not find any variants in the putative
MEFV promoter region.25 However, sequencing of the
30 -untranslated region revealed several single-nucleotide
polymorphisms within two Alu repeats, which were
expressed in the MEFV mRNA. The respective single-
nucleotide polymorphisms were clustered into two
haplotypes, and the frequency of heterozygote genotypes
was significantly higher in the patients without coding
region mutations compared with healthy controls.25
These data suggest a role of the 50 - and 30 -regulatory
sequences in the expression of MEFV and pathogenesis
of FMF.
Post-transcriptional regulation
MEFV is transcribed into a major full-length transcript of
3.5 kb. The first MEFV splice isoform was described by
Papin et al.26 This variant is generated by in-frame
alternative splicing of exon 2 (2D) and expressed in PBLs.
Seven more transcript isoforms that introduce various
combinations of novel exons 2a and 4a, and a 30
extension of exon 8 (8ext) were identified in synovial
fibroblasts by Diaz et al.22 Recently, our group27 and a
Lebanese group28 detected six more weakly expressed
transcripts, with various deletions in exon 2, 3, 4, 7 and 8,
or a 50 extension of exon 9 (9ext) in PBLs, making the
total number of known MEFV transcript isoforms
hitherto equal to 15. Most of them, if translated, would

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 MEFV expression in FMF
S Grandemange et al
500
conduct to a premature stop codon (Figure 3). The
physiological relevance of these alternatively spliced
isoforms is still unclear.
To determine which of the transcripts could potentially
be expressed at the protein level, we have examined the
effect of nonsense-mediated decay (NMD) inhibition on
the expression of the MEFV transcripts in various cells.27
Alternative splicing and NMD pathways are generally
coupled in the post-transcriptional regulation of gene
expression (for a review see Neu-Yilik and Kulozik29).
Indeed, NMD is a mechanism that controls mRNA
quality, prevents translation of unnecessary and aberrant
transcripts, for example, mutations generating premature
terminal codon, and modulates protein level in a cell-
specific manner. The indirect inhibition of NMD by
cycloheximide in THP1 cells and neutrophils had no
effect on the full-length transcript, but dramatically
increased the expression of exon 4a transcripts. The
expression of exon 8ext and exon 4a transcripts was
increased in monocytes, supporting the role for NMD in
regulation of MEFV expression in these cells. Direct
inhibition of NMD using small interfering RNA against
Upf1, one of the components of the NMD machinery,
showed that in THP1 cells, NMD has a role in the
regulation of a subset of the MEFV isoforms, including
transcripts exon 4a and del234. All together, these results
demonstrated that the expression of MEFV is regulated
by NMD in both a cell- and a transcript-specific manner.
Previous reports suggested that variation in NMD
efficiency is associated with numerous genetic disorders
and responsiveness to treatment.30 We hypothesize that
individual variations in NMD efficiency for alternatively
spliced MEFV transcripts may have a role in FMF
pathophysiology and, thereby, may account for part of
the phenotypic heterogeneity observed in FMF patients.
The MEFV gene expression in FMF patients and
controls has been investigated using both semi-quanti-
tative and quantitative PCR analysis. MEFV mRNA
levels were decreased in PBLs of symptom-free French
FMF patients of Mediterranean origin compared with
controls.31 This effect correlated with the number and the
type of mutations, the lowest mRNA expression being
observed in patients homozygous for the most severe
FMF-associated mutation, M694V. The second study in a
Turkish cohort showed significantly lower mRNA levels
in PBLs of asymptomatic FMF patients compared with
non-FMF controls, and a further decrease in expression
was observed during an acute peritonitis attack. How-
ever, the MEFV gene expression did not correlate with
the patient’s genotypes. Interestingly, MEFV expression
was significantly decreased in non-FMF control patients
with acute appendicitis during the peri-operative period
compared with their asymptomatic states.32 In a recent
study, MEFV gene expression levels were marginally
lower in Greek FMF patients compared with healthy
subjects.33 In contrast, a study performed in the USA
cohort found a tendency for an increased level of the
MEFV expression in 19 asymptomatic FMF patients
compared with controls, but this result was not statisti-
cally significant.34 These apparent discrepancies are

MEFV gene 2a 4a 8ext 9ext

1 2 3 4 5 6 7 8 9 10
317

633

93

350

96

98

231

23

115
33
118

175
33

1667
Splicing variants
kDa
FL 86.4
4a 53.6
8ext 67.7

2" 64.4
2"-4a 31.7
2"-8ext 45.7
2"-9ext 47.4

2a 67.6
2a-4a 34.8
2a-8ext 49

del2.3.4 10.8

del2.3.4 del7 10.8

del2.3.4 del7.8 10.8

del2.3.4.5 11.8

del3.4 del7.8 33.2

coding region

Figure 3 Schematic representation of the 15 currently known MEFV transcripts isoforms. Exons are boxed, introns are depicted as lines.
The open-reading frames of each transcript are greyed and their corresponding untranslated regions are represented by white boxes. Only FL,
2D and 2a transcripts (underlined) retain the full open-reading frame; all other transcripts have a premature stop codon. The sequences
gained are blacked. FL, full-length; del or D, deletion; ext, extension. The expected size of the corresponding protein is on the right in
kilodaltons (kDa).

Genes and Immunity


likely partly accountable to the different experimental
conditions (sample size, cell type used for RNA extrac-
tions, instrument, primer pairs used for quantitative
reverse transcriptase-PCR, methods used for data analy-
sis) that may inconsistently track the different MEFV
transcripts, especially those subjected to NMD regula-
tion. Alternatively, the variable prevalence of putative
regulatory variants in different ethnic cohorts may
account for some variability in gene expression among
these studies.
MEFV expression at the protein level
Cellular localization
Data at the protein level are scarce; however, pyrin
protein expression is also highly variable and dependent
on cell type, experimental conditions and protein iso-
form. In Chinese hamster ovary and HeLa cells stably
transfected with green fluorescent protein-tagged pyrin,
the full-length protein is cytoplasmic, but the form
lacking exon 2 is mainly nuclear.26,35 In synovial
fibroblasts transiently transfected with myc-tagged pyr-
in, the full-length and 2a transcripts are cytoplasmic and
the 2D isoform showed a mixed pattern.22 The native
pyrin is nuclear in synovial fibroblasts, neutrophils and
dendritic cells, but cytoplasmic in monocytes.22 Thus, the
expression of endogenous pyrin is likely related to the
existence of various protein isoforms.
Translational regulation
Reasoning that differential protein expression could be
the result of differential mRNA regulation, we recently
conducted western blot analyses of endogenous proteins
expressed in THP1 cells.27 Parallel overexpression of
various cDNAs in HEK293 cells provided us with the
migration pattern of each isoform. We obtained bands
compatible with the size of the full-length, 2D8ext
and 2a4a products demonstrating that, as expected, at
least some of these alternatively spliced MEFV tran-
scripts are translated into protein variants. Moreover, in
agreement with the results obtained at the mRNA level,
the putative 2D8ext was insensitive to NMD, whereas
expression of the putative 2a4a was increased after
direct inhibition of NMD. Western blots did not
demonstrate a significant difference in pyrin levels
between single and double variant patients. However,
FMF patients of both types showed higher protein
expression, compared with controls and non-FMF
patients with active inflammation.34
Post-translational regulation
Pyrin expression was shown to be dependent to at least
two post-translational modification processes. Pyrin
phosphorylation mediates the binding to 14.3.3 at three
serine residues located in exon 2.36 14.3.3 is thought to
have a role in apoptosis. As a result of this interaction,
full-length pyrin is retained in the cytoplasm. The lack of
interaction with the D2-pyrin isoform results in protein
translocation to the nucleus. These data reconcile some
observations made in vitro about the different subcellular
localization of various isoforms.
Pyrin may also be cleaved by caspase 1 at the residue
Asp330, producing an N-terminal fragment that in-
creases ASC-independent NF-kB activation through
MEFV expression in FMF
S Grandemange et al
501
degradation of I-kappa-B-alpha (IKB-a).11,18 The C-
terminal-cleaved fragment, where most FMF mutations
lie, remains cytoplasmic, whereas the N-terminal-
cleaved fragment translocates along with p65 to the
nucleus. Moreover, the pyrin cleavage is increased in
peripheral blood mononuclear cells from FMF patients,
whereas full-length pyrin seems to be less expressed in
patients. However, the pyrin cleavage appears to be cell-
dependent, and in granulocytes, the full-length pyrin
was shown to be more abundant in FMF patients than in
controls.
Conclusions
This bibliographical work highlighted that MEFV
expression is dependent on cell type and inflammatory
status. This is probably accounted for by the multiple
levels of regulation that the MEFV gene and its products
undergo. At the transcriptional level, MEFV is regulated
by numerous factors such as interferon a and NF-kB.
At the post-transcriptional level, 15 splicing isoforms
have been described so far, some of them being subjected
to NMD regulation. At the post-translational level,
pyrin can be phosphorylated and cleaved. Quantitative
and qualitative differences between controls and FMF
patients have been observed at all levels, although
some of the available data need to be confirmed.
Despite rapidly growing data about the regulation of
MEFV, several questions remain to be addressed. Are
there quantitative and qualitative variations of these
alternative MEFV transcripts in physiological and FMF
conditions? What is the effect of pro- and anti-inflam-
matory cytokines and colchicine, the mainstay treatment
of FMF, on the expression of these transcripts? Could the
possible existence of several MEFV protein variants
explain the controversial results of sub-cellular localiza-
tion studies?
Altogether, the regulation of MEFV expression is much
more complex than initially thought, and it is an
important issue, because its deregulation is likely to be
one of the mechanisms involved in FMF pathogenesis.
Even if the exact role of pyrin in innate immunity is
controversial, it probably has a direct and/or indirect
crucial role in inflammasome regulation, and any
qualitative or quantitative modification of its expression
may have a critical consequence in the balance between
pro- and anti-inflammatory signaling pathways, which
may subsequently result in uncontrolled inflammation.
Conflict of interest
The authors declare no conflict of interest
Acknowledgements
This work was supported by the CHRU of Montpellier
(PHRC2005), the National Human Genome Research
Institute, INSERM and Istanbul Faculty of Medicine. We
thank the clinicians for providing patient samples, J Tazy
for helpful discussion and M Vittal for English editing of
the manuscript.
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 MEFV expression in FMF
S Grandemange et al
502
References
1 Heller H, Kariv J, Sherf L, Sohar E. Familial Mediterranean
fever]. Harefuah 1955; 48 (5): 91–94.
2 The International FMF Consortium. Ancient missense muta-
tions in a new member of the RoRet gene family are likely to
cause familial Mediterranean fever. Cell 1997; 90: 797–807.
3 The French FMF Consortium. A candidate gene for familial
Mediterranean fever. Nat Genet 1997; 17: 25–31.
4 Martinon F, Hofmann K, Tschopp J. The pyrin domain: a
possible member of the death domain-fold family
implicated in apoptosis and inflammation. Curr Biol 2001; 11:
R118–R120.
5 Pawlowski K, Pio F, Chu Z, Reed JC, Godzik A. PAAD - a new
protein domain associated with apoptosis, cancer and auto-
immune diseases. Trends Biochem Sci 2001; 26: 85–87.
6 Staub E, Dahl E, Rosenthal A. The DAPIN family: a novel
domain links apoptotic and interferon response proteins.
Trends Biochem Sci 2001; 26: 83–85.
7 Kohl A, Grutter MG. Fire and death: the pyrin domain
joins the death-domain superfamily. C R Biol 2004; 327:
1077–1086.
8 Stehlik C, Fiorentino L, Dorfleutner A, Bruey JM, Ariza EM,
Sagara J et al. The PAAD/PYRIN-family protein ASC is a dual
regulator of a conserved step in nuclear factor kappaB
activation pathways. J Exp Med 2002; 196: 1605–1615.
9 Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Nunez
G. Regulation of cryopyrin/Pypaf1 signaling by pyrin, the
familial Mediterranean fever gene product. Biochem Biophys
Res Commun 2003; 302: 575–580.
10 Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, Li M
et al. ASC is an activating adaptor for NF-kappaB and caspase-
8-dependent apoptosis. Biochem Biophys Res Commun 2003;
303: 69–73.
11 Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, Masters SL
et al. The familial Mediterranean fever protein, pyrin, is
cleaved by caspase-1 and activates NF-kappaB through its
N-terminal fragment. Blood 2008; 112: 1794–1803.
12 Yu JW, Wu J, Zhang Z, Datta P, Ibrahimi I, Taniguchi S et al.
Cryopyrin and pyrin activate caspase-1, but not
NF-kappaB, via ASC oligomerization. Cell Death Differ 2006;
13: 236–249.
13 Chae JJ, Wood G, Masters SL, Richard K, Park G, Smith BJ et al.
The B30.2 domain of pyrin, the familial Mediterranean
fever protein, interacts directly with caspase-1 to modulate
IL-1beta production. Proc Natl Acad Sci USA 2006; 103:
9982–9987.
14 Papin S, Cuenin S, Agostini L, Martinon F, Werner S, Beer HD
et al. The SPRY domain of Pyrin, mutated in familial
Mediterranean fever patients, interacts with inflammasome
components and inhibits proIL-1beta processing. Cell Death
Differ 2007; 14: 1457–1466.
15 Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L
et al. The tripartite motif family identifies cell compartments.
EMBO J 2001; 20: 2140–2151.
16 Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H,
Aksentijevich I et al. The infevers autoinflammatory mutation
online registry: update with new genes and functions. Hum
Mutat 2008; 29: 803–808.
17 Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet
1998; 351: 659–664.
18 Chae JJ, Aksentijevich I, Kastner DL. Advances in the
understanding of familial Mediterranean fever and possibi-
lities for targeted therapy. Br J Haematol 2009; 146: 467–478.
19 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140:
821–832.
20 Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C
et al. The gene for familial Mediterranean fever, MEFV, is
expressed in early leukocyte development and is regulated
in response to inflammatory mediators. Blood 2000; 95:
3223–3231.
Genes and Immunity
21 Tidow N, Chen X, Muller C, Kawano S, Gombart AF, Fischel-
Ghodsian N et al. Hematopoietic-specific expression of MEFV,
the gene mutated in familial Mediterranean fever, and
subcellular localization of its corresponding protein, pyrin.
Blood 2000; 95: 1451–1455.
22 Diaz A, Hu C, Kastner DL, Schaner P, Reginato AM, Richards
N et al. Lipopolysaccharide-induced expression of multiple
alternatively spliced MEFV transcripts in human synovial
fibroblasts: a prominent splice isoform lacks the C-terminal
domain that is highly mutated in familial Mediterranean fever.
Arthritis Rheum 2004; 50: 3679–3689.
23 Papin S, Cazeneuve C, Duquesnoy P, Jeru I, Sahali D,
Amselem S. The tumor necrosis factor alpha-dependent
activation of the human mediterranean fever (MEFV)
promoter is mediated by a synergistic interaction between
C/EBP beta and NF kappaB p65. J Biol Chem 2003; 278:
48839–48847.
24 Notarnicola C, Boizet-Bonhoure B, de Santa Barbara P, Osta
MA, Cattan D, Touitou I. Characterization of new mutations in
the 50 -flanking region of the familial Mediterranean fever
gene. Genes Immun 2009; 10: 273–279.
25 Ustek D, Ekmekci C, Oku B, Cosan F, Cakiris A, Abaci N et al.
MEFV gene 30 -UTR Alu repeat polymorphisms in patients
with familial Mediterranean fever. Clin Exp Rheumatol 2008;
26(4 Suppl 50): S72–S76.
26 Papin S, Duquesnoy P, Cazeneuve C, Pantel J, Coppey-Moisan
M, Dargemont C et al. Alternative splicing at the MEFV locus
involved in familial Mediterranean fever regulates transloca-
tion of the marenostrin/pyrin protein to the nucleus. Hum Mol
Genet 2000; 9: 3001–3009.
27 Grandemange S, Soler S, Touitou I. Expression of the familial
Mediterranean fever gene is regulated by nonsense-mediated
decay. Hum Mol Genet 2009; 18: 4746–4755.
28 Medlej-Hashim M, Nehme N, Chouery E, Jalkh N,
Megarbane A. Novel MEFV transcripts in familial
Mediterranean fever patients and controls. BMC Med Genet
2010; 11: 87.
29 Neu-Yilik G, Kulozik AE. NMD: multitasking between mRNA
surveillance and modulation of gene expression. Adv Genet
2008; 62: 185–243.
30 Linde L, Boelz S, Nissim-Rafinia M, Oren YS, Wilschanski M,
Yaacov Y et al. Nonsense-mediated mRNA decay
affects nonsense transcript levels and governs response of
cystic fibrosis patients to gentamicin. J Clin Invest 2007; 117:
683–692.
31 Notarnicola C, Didelot MN, Kone-Paut I, Seguret F, Demaille J,
Touitou I. Reduced MEFV messenger RNA expression in
patients with familial Mediterranean fever. Arthritis Rheum
2002; 46: 2785–2793.
32 Ustek D, Ekmekci CG, Selcukbiricik F, Cakiris A, Oku B, Vural
B et al. Association between reduced levels of MEFV
messenger RNA in peripheral blood leukocytes and acute
inflammation. Arthritis Rheum 2007; 56: 345–350.
33 Mitroulis I, Kourtzelis I, Kambas K, Chrysanthopoulou A,
Ritis K. Evidence for the involvement of mTOR inhibition and
basal autophagy in familial Mediterranean fever phenotype.
Hum Immunol 2010; 72: 135–138.
34 Booty MG, Chae JJ, Masters SL, Remmers EF, Barham B, Le JM
et al. Familial Mediterranean fever with a single MEFV
mutation: where is the second hit? Arthritis Rheum 2009; 60:
1851–1861.
35 Cazeneuve C, Papin S, Jeru I, Duquesnoy P, Amselem S.
Subcellular localisation of marenostrin/pyrin isoforms carry-
ing the most common mutations involved in familial
Mediterranean fever in the presence or absence of its binding
partner ASC. J Med Genet 2004; 41: e24.
36 Jeru I, Papin S, L’Hoste S, Duquesnoy P, Cazeneuve C,
Camonis J et al. Interaction of pyrin with 14.3.3 in an isoform-
specific and phosphorylation-dependent manner regulates
its translocation to the nucleus. Arthritis Rheum 2005; 52:
1848–1857.

37 Abedat S, Urieli-Shoval S, Shapira E, Calko S, Ben-Chetrit E,
Matzner Y. Effect of colchicine and cytokines on MEFV
expression and C5a inhibitor activity in human primary
fibroblast cultures. Isr Med Assoc J 2002; 4: 7–12.
38 Matzner Y, Abedat S, Shapiro E, Eisenberg S, Bar-Gil-Shitrit A,
Stepensky P et al. Expression of the familial Mediterranean
MEFV expression in FMF
S Grandemange et al
503
fever gene and activity of the C5a inhibitor in human primary
fibroblast cultures. Blood 2000; 96: 727–731.
39 Masters SL, Yao S, Willson TA, Zhang JG, Palmer KR, Smith BJ
et al. The SPRY domain of SSB-2 adopts a novel fold that
presents conserved Par-4-binding residues. Nat Struct Mol Biol
2006; 13: 77–84.
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