genetica moleculara a febrei mediteraneene familiale

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Molecular Genetics of Familial Mediterranean

Fever Levon Yepiskoposyan, National Academy of Sciences,

Yerevan, Armenia

Ashot Harutyunyan, National Academy of Sciences,

Yerevan, Armenia

Familial Mediterranean fever (FMF), an autoinflammatory disease, is very common in

populations of Mediterranean ancestry. It is an autosomal recessive genetic disorder

caused by mutations in the MEFV gene. The gene encodes a protein called pyrin or

marenostrin which is involved in inflammatory pathways. From more than 150

mutations discovered in the MEFV gene so far, five (M694V, V726A, M680I, M694I and

E148Q) are the most common in classically affected populations (Armenians, Arabs,

Jews and Turks). Specific mutations and genotypes were found to be associated with

severe or mildclinical forms of FMF,while various genetic andenvironmental modifying

factors alter the phenotype. Some evolutionary aspects of the disease are being

intensively studied: the origin of principal MEFV mutations, modification of pyrin’s

structure and function during phylogenesis, possible selective advantage of MEFV

heterozygotes.

Introduction

Familial Mediterranean fever (FMF, MIM 249100) is anautosomal recessive disorder characterized by recurrentattacks of fever and inflammation in the peritoneum,synovium or pleura, accompanied by pain (Livneh et al.,1997). Destructive oligoarthritis and potentially life-

threatening secondary amyloidosis are the majorlong-term complications associated with the disease. Manyuntreated patients develop secondary renal amyloidosiseventually leading to renal failure which is the main causeof FMF-related mortality. So far colchicine is used as theonly medication for controlling FMF symptoms; it reducesthe frequency of inflammatory attacks and effectively pre-vents renal amyloidosis. The disorder is considered asone of the autoinflammatory syndromes, a group of

diseases described by the clinical picture of apparently un-provoked inflammation, lacking high-titre autoantibodies

or self-reactive T-cells that differentiate it from autoim-

mune illnesses. Whereas the latter are caused by distur-bances in adaptive immunity, the autoinflammatorysyndromes seem to originate from abnormalities in innate

immune response.The first mention of diseases with similar symptoms

dates from thebeginning of the nineteenth century, the firstreport describing FMF as a separate nosology (under theterm ‘benign paroxysmal peritonitis’) was published in1945 (Siegal, 1945).

FMF is encountered more frequently in thepeoples fromthe Mediterranean region, particularly in non-AshkenaziJews, Armenians, Turks and Arabs, which are consideredas four classically affected populations. The illness is less

common in other populations of Mediterranean ancestry,with the carrier rate andthe severity of themanifestation of the disease varying considerably both among and withindifferent ethnic groups. Gradually the disorder is beingregistered in other ethnicgroups notonly in Mediterraneanarea, but also from far more distant regions.

The gene responsible for FMF (ME diterranean F eV er – MEFV ) was discovered in 1997 by positional cloning (In-ternational FMF Consortium, 1997; French FMF Con-sortium, 1997). This achievement has enabled genetic

confirmation of the existence of FMF and thorough studyof molecular aspects of the disorder. See also: AutosomalRecessive Traits and Diseases; Familial MediterraneanFever

Advanced article

Article Contents

. Introduction

. MEFV Gene: A Molecular Genetic Basis of FMF

.

Genotype/Phenotype Correlation in FMF Patients. Incidence of MEFV Mutations in Different Populations

. Evolutionary and Population Genetic Aspects

. Conclusions and Perspectives

Online posting date: 15th December 2008

ELS subject area: Genetics and Disease

How to cite:

Yepiskoposyan, Levon; and, Harutyunyan, Ashot (December 2008)Molecular Genetics of Familial Mediterranean Fever. In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester.

DOI: 10.1002/9780470015902.a0021442

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MEFV Gene: A Molecular Genetic Basisof FMF

The gene stretches c. 15kb in length on chromosome16p13.3 andincludes 10 exons; its 3.7kb transcript encodes

a 781-aminoacid protein named pyrin or marenostrin. As aconsequence of alternative splicing two different tran-scripts of MEFV exist in human cells: the full-length tran-script and another one entirely lacking exon 2 (Papin et al.,2000). Interestingly, the level of MEFV mRNA (messengerribonucleic acid) expression is diminished in FMF patientsand healthy carriers, depending on the exact coding se-quence of the gene (Notarnicola et al., 2002).

MEFV has different rates of expression in various typesof cells. Normally, the gene is expressed at high levels inneutrophils, eosinophils, monocytes and dendritic cells,but not in lymphocytes. Pyrin is also present in synovial,peritoneal and skin-derived fibroblasts, but not in chon-

drocytes or endothelial cells. The subcellular localization of the protein is still not completely clear. Full-length pyrinevidently localizes to the cytoplasm, whereas its isoformencoded by an alternative splice variant is also present inthe nucleus (Papin et al., 2000). Moreover, pyrin is cyto-

plasmic in monocytes, but mainly nuclear in granulocytes,dendritic cells and synovial fibroblasts (Diaz et al., 2004).

Different regions of MEFV are responsible for distinctfunctional domains of pyrin. Exon 1 encodes a death do-main-related structure named ‘pyrin domain’ (PYD). Theregion encoded by exons 2– 10 also includes some formerlyknown motifs: a bZIP transcription factor basic domain(corresponding to exon 2); a B-box zinc finger (exon 3); two

nuclear localizationsignals (exons3 and4); an alpha helicalregion (exons 3–8) and a C -terminal domain named theB30.2/SPRY/rfp domain encoded by exon 10 where thebulk of MEFV mutations are identified. This peculiarityimplies that exon 10 encodes an evolutionarily importantpart of the protein (Figure 1).

Pyrin is likely to assist in keeping inflammation undercontrol by deactivating the immune response. Without thiscontrol an inappropriate full-blown inflammatory reaction

occurs. Normally, inflammation is expected to react pow-erfully and systemically to a strong stimulus, while ignoringminor ones. An important role in this process is attributedto pyrin. FMF attacks are now unanimously considered tobe theresult of a shift from normalcontrol of inflammationleading to vigorous responses to minor inflammatory

triggers.Structurally, pyrin is present in cells as a homotrimer in

an autoinhibited state as a consequence of intramolecularinteractions between its N -terminal pyrin domain andB-box. Proline serine threonine phosphatase-interactingprotein 1 (PSTPIP1) homotrimer binds to the pyrin ho-motrimer through direct interaction with the B-box. Thisresults in unveiling the PYD of pyrin, which consequentlyis able to interact with the PYD of ASC (apoptosis-associated speck-like protein containing a caspase-recruit-ment domain, CARD) (Yu et al., 2007).

Two major hypotheses regarding the mechanism of

pyrin’s action currently exist. The first, called ‘sequestra-tion hypothesis’, suggests that the PYD of pyrin interactswith the PYD of ASC and competes with cryopyrin to bindASC, hence decreasing theamount of ASC available forthecryopyrin inflammasome. The aggregate effect is expectedto be a reduction of caspase-1 activation and a reduction ininterleukin-1b (IL-1b) processing (Chae et al., 2003). Thealternative assumption, ‘pyrin inflammasome hypothesis’,suggests that a pathogen-associated molecular pattern

(PAMP) might bind the carboxy (C )-terminal B30.2 do-main of pyrin. This possibly leads to a conformational al-teration in pyrin structure that would permit it toparticipate in a macromolecular complex, similar to the

cryopyrin inflammasome, resulting in caspase-1 activation.Recent data show that pyrin might play an important roleas an antiviral proinflammatory mediator (Centola et al.,2000; Yu et al., 2007).

The way in which the MEFV mutations lead to the pro-inflammatory phenotype of FMF is still unclear. Simula-

tion of the structure of the B30.2/rfp/SPRY domain of pyrin (encoded by exon 10 of MEFV ) has demonstratedthat the frequently encountered mutations are expected notto result in alteration of the structure of pyrin but presum-ably affect binding of this domain to other proteins(Goulielmos et al., 2006).

MEFV mutations

To date, 166 mutations have been identified in the MEFV

gene and flanking regions (INFEVERS database, http://fmf.igh.cnrs.fr/ISSAID/infevers/), most of which are sub-stitutions (89 are missense, 1 nonsense, 40 silent mutations,21 located in introns, 3 in UTS), 2 duplications, 2 insertionsand 2 deletions. Of these mutations, 5 account for morethan 70% of FMF cases – V726A, M694V, M694I, M680Iand E148Q and have different frequencies in classicallyaffected populations. So far 64 MEFV mutations have been

demonstrated to be associated with FMF or FMF-likesymptoms.

5′

Exons 1 2 3 4 5 6 7 89 10

3′

PYD BBbZIP CC B30.2

Pyrin

MEFV

(a)

(b)

Figure 1 The structure of MEFV gene and its product, pyrin. (a) Structure of

MEFV gene; exon 10, where the four most common mutations are located, is

highlighted in red. (b) Domain organization of pyrin protein. PYD, pyrin

domain; bZIP,bZIP transcriptionfactorbasic domain; BB, B-box domain; CC,coiled coil domain and B30.2, C -terminal B30.2/SPRY/rfp domain.

Molecular Genetics of Familial Mediterranean Fever

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The finding that four missense mutations (M680I,M694V, V726A and M694I) located in a small part of MEFV (in exon 10) account for the majority of FMF casesin various ethnic groups has significant implications forunderstanding the biological role of pyrin and designingrelevant molecular diagnostic approaches for FMF.

It turns out that most of MEFV mutations are missensemutations or small deletions and insertions. This may im-

ply that more drastic loss-of-function mutations lead to amuch more severe inflammatory phenotype, possibly evenembryonically lethal, or result in phenotypes very differentfrom FMF (International FMF Consortium, 1997). Con-sequently, the chance of finding such mutations might bevery small in classic FMF patients (Bernot et al., 1998).

Studies in different populations have shown that FMFpatients not only arehomozygousfor one MEFV mutationbut are sometimes compound heterozygotes (i.e. havingtwo different mutations on homologous chromosomes) or

have more than one mutation on a single chromosome(Aksentijevich et al., 1999; Cazeneuve et al., 1999). Thesecases, complex alleles, were likely formed by an intragenicrecombination event, rather thana multiple mutational hit.Specifically, intron 2 of MEFV has been suggested as apossible recombination hotspot (Aldea et al., 2004a).See also: Genetic Disease: Prevalence

Genotype/Phenotype Correlation inFMF Patients

One of the core issues of FMF is the relationship between

MEFV mutations and clinical manifestations of the disease.The majority of patients have two MEFV mutations,thoughthere are patients with the clinical picture of FMF carryingone or no mutations. The latter cases might be regarded asFMF-like disorders caused by mutations in other loci.

In clinical practice, three categories of individuals withtwo MEFV mutations are considered (Kogan et al., 2001):

1. Phenotype I – typical FMF: patients display a widerange of manifestations and mutations with a more se-vere picture of disorder associated with M694V andM694I mutations;

2. Phenotype II – development of amyloidosis in the ab-sence of other symptoms or before their manifestation:these cases are predominantly caused by M694V andM694I mutations and

3. Phenotype III – absence of FMF symptoms: the mostcommon mutations in these patients are E148Q andV726A.

The classification clearly shows that the penetrance of MEFV genotypes varies considerably, being the highest forM694V homozygotes (99%) and the lowest for E148Qhomozygotes (45%) based on pooled data.

Though FMF is considered an autosomal recessive dis-ease, there are some reported cases explained by the

autosomal dominant mode of inheritance. These cases aregenerally due to relatively rare mutations such as M694del,complex E148Q-M694V allele (Booth et al., 2000) andH478Y (Aldea et al., 2004b).

Not only homozygotes or compound heterozygotes forMEFV mutations but alsosome heterozygouscarriers have

proinflammatory phenotypes. The latter in some cases evendevelop classical symptoms of FMF in the presence of rel-

evant modifying factors (Kalyoncu et al., 2006).MEFV mutations might be classified into several groups

according to their phenotypic effects: severe, mild andmoderate mutations. M694V and M694I are consideredsevere mutations because these are found in the most com-plicated cases of FMF. M694V homozygosity is associatedwith a more harsh form of the disease, as judged by anearlier age at onset, higher frequency of pleurisy and ar-thritis, higher incidence of musculoskeletal manifestationsand, most importantly, higher prevalence of renal am-

yloidosis in patients with no access to colchicine therapy(Shohat et al., 1999; Gershoni-Baruch et al., 2003). How-ever, in some studies no clear correlation between am-yloidosis and M694V homozygosity was found (Dewalleet al., 1998; Atagunduz et al., 2004).

The mutation V726A is associated with a mild form of FMF and is commonly encountered in populations with alower incidence of amyloidosis (Centola et al., 1998).M680I is considered a moderatemutation and althoughthehomozygotes have typical FMF symptoms, the rate of clinical manifestations of the disorder is lower than forM694V (Yalcinkaya et al., 2000).

It is not yet clear whether some of MEFV mutations (par-

ticularly E148Q and P369S) are causative of FMF. Thus,E148Q homozygotes have very few FMF symptoms andmany such patients remain completely asymptomatic. Someresearchers even argue that E148Q is just a benign poly-morphism (Tchernitchko et al., 2006), whereas others con-sider it a trueFMF-causingmutation (Topalogluetal., 2005).

MEFV compound heterozygous patients display varia-ble patterns of clinical manifestations depending on thepresence of specific combinations of mutations, for exam-ple the phenotypic effect of M694V/V726A genotype is in-termediate between M694V and V726A homozygotes.

In general, the results witness that genotype/phenotypecorrelation predominantly exists in M694V homozygotes,

whereas for other genotypes it is not strong. A special webresource (MetaFMF database, http://fmf.igh.cnrs.fr/metaFMF/) contains constantly updated information on

genotype/phenotype correlation in FMF. See also: Geno-type-Phenotype Relationships; Genotype–PhenotypeRelationships

Modifying factors

The FMF phenotype is modified by various genetic andenvironmental factors. One of the genetic modifiers is theMICA gene (major histocompatibility complex class I

chain-related gene A); its polymorphisms influence thefrequency of attacks and age of onset of the disease (Touitou




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et al., 2001). Different findings indicate that the environmentmay have a notable impact on FMF clinical manifestation.It is based on the fact that patients of the same ethnicityliving in different geographic regions have different clinicalpictures of the disease. Conversely, descendants of differentpopulations living in the same area display similar patterns

of FMF manifestation even though they have a distinctmutation/genotype distribution (Mimouni et al., 2000).

The occurrence of themost severecomplication of FMF,amyloidosis, in the majority of cases is linked to differentmodifying factors. Among these the most important areSAA1 a/a genotype (Cazeneuve et al., 2000), country of origin, the occurrence of arthritis attacks and male sex,which are significantly and independently associated withrenal amyloidosis. SAA1 encodes the protein serum am-yloid A, the substrate for amyloid fibril formation in sec-ondary (AA) amyloidosis. Therefore this gene significantlyaffects the development of amyloidosis. Recently it was

shown that country of origin is a key modifier in the in-cidence of amyloidosis in FMF, possibly reflecting the in-fluence of both environmental and social factors (Touitouet al., 2007). See also: Amyloidosis

Incidence of MEFV Mutations inDifferent Populations

So far representative data on the frequency of MEFV mu-tations and genotypes mainly refer to classically affectedpopulations. Carrier rates in those populations are very

high, varying in the range 1/4–1/10. There are significantdifferences in frequencies of principal MEFV mutationsbetween ethnic groups while comparing both FMF pa-tients and healthy individuals.

In Jewish patients, one mutation, M694V, is predomi-nant, accounting for approximately 85–90% of all chro-mosomes; other mutations are present in less than 10%each. In healthy individuals of Jewish origin, besides

M694V (4–5%), two other mutations are also found atcomparable frequencies – E148Q (6–7%) and V726A(3–4%) (Stoffman et al., 2000; Dode et al., 2000).

In Arab FMF patients, the frequency of MEFV muta-tions depends on what territorial group of this population

is studied. Two mutations, M694V andM694I, account forthe majority of cases. In healthy individuals the most fre-quent mutations are E148Q and V726A – approximately3% and 6.5%, respectively (Gershoni-Baruch et al., 2001;Mattit et al., 2006).

Armenians affected with FMF have three MEFV muta-tions at high frequencies: M694V, V726A and M680I withrespective values of approximately 40–50%, 22–24% and18–22%. The vast majority (98.65%) of patients have the7 most common MEFV mutations. In the group of healthysubjects, M694V, V726A, E148Q and P369S are found inapproximately 2–2.5% of alleles, whereas M680I has a

frequency of about 1% (Cazeneuve et al., 1999; Sarkisianet al., 2005).

In Turkish FMF patients, M694V is the most frequent(50–55%), while V726A and M680I are observed at ap-proximately 10–15% each. In healthy individuals E148Qprevails (6%); the other three common mutations, M694V,V726A and M680I, are in range 1–3% each (Akar et al.,1999; Yilmaz et al., 2001).

The most frequent MEFV genotype in FMF patients isM694V/M694V in all classically affected populations ex-

cept Arabs, where M694I/M694I exceeds the frequency of M694V/M694V. In Armenian and Turkish patientsM694V/V726A and M694V/M680I are also relativelycommon.

Beyond classically affected populations, E148Q is ob-served at unusually high frequencies not only in the Med-iterranean region, but also in the Chinese and Indianpeoples, where it is present at 15% and 21%, respectively(Booth et al., 2001).

The great diversity in the distribution of MEFV muta-

tions between ethnically different populations may indicatethat this diversity is the result of distinct origins of muta-tions and genetic contacts between populations over a longhistory.

Evolutionary and Population GeneticAspects

The origins of MEFV mutations

The study of the genesis of different MEFV mutations

would contribute to the understanding of their evolution-arysignificance and therole of ancient contactsbetweenthepopulations of theMediterranean and Near East regions inthe spatial spread of FMF.

The estimation of the age of MEFV mutations is based onthe typing of short tandem repeats (STR), or microsatellites,flanking the gene. Each mutation is associated with specificSTR haplotypes which are assumed to derive from one an-

cestral haplotype. The knowledge of the mutation rate of STRs permits estimation of the age of the most recent com-mon ancestor (MRCA) who carried the specific mutation,and thus is considered as the progenitor of all chromosomeswith this mutation. See also: Dating Mutations

Studies based on a limited number of microsatelliteslinked to MEFV have provided rough estimates of the ageof different mutations. For the most frequent mutations,M694V, M694I, V726A, M680I and E148Q, the respectiveestimated values are 7000, 8500, 15 000, 23 000 and 30 000years. In other words, M694V, M694I and V726A are rel-atively recent mutations, approximately within theNeolithic period, whereas E148Q and M680I are more an-cient, preceding the Neolithic (Jalkh et al., 2007).

The majority of common MEFV mutations seem to besingle events, whereas the unique origin of E148Q is ques-tionable: some scholars consider it as a recurrent mutation.

E148Q is evidently older than other MEFV mutations andis associated with a large number of STR haplotypes.









Whether this diversity is the result of recombination, mi-crosatellite mutations or recurrent mutation is difficult todetermine. Haplotype analysis is in favour of E148Q beinga unique and ancient event. However, surprisingly highfrequencies of the mutation in Chinese and Indian peoplemay indicate that E148Q has a recurrent nature and inde-

pendently arose far from the Mediterranean basin.It seems that the main FMF-causing mutations origi-

nated in the Near East and were spread during prehistoricand historic migrations and contacts between populationsof the Mediterranean area. Thus M694V mutation in theArabs of North Africa might have been introduced by theJews that emigrated there from the Middle East after thedestruction of Solomon’s Temple, and also from Spainsince the end of fifteenth century CE. The M694I mutationis present in the Berbers, the indigenous population of theMaghreb, indicating that it was present in North Africabefore Arabization and Islamicization started in the sev-

enth century CE (Belmahi et al., 2006).

Evolution of pyrin

Since the majority of FMF-causing mutations are observedin exon 10 of MEFV , one would expect this region to behighly conserved during evolution. However, the real find-

ings prove the opposite. Thus, in rodents, the domain of pyrin encoded by exon 10 is absent (Chae et al., 2000); inzebrafish, moreover, no separate gene encoding pyrin ex-ists, instead this species possesses a hybrid gene encoding aprotein homologous to both human pyrin and cryopyrinproteins (Yu et al., 2007).

In primates, of the main amino acid positions where amutation results in FMF in humans, only M694 is com-pletely conserved, whereas in other positions human mu-tant residues are observed as wild type in apes, who

nevertheless do not suffer from FMF-like illnesses. Thoughit is plausible that variability at positions of exon 10 mu-tations over evolution is caused by relaxed functional con-straint, it is obvious that the recurrence of ancestral allelesin humans has functional significance. Overall, these find-ings indicate that the function of pyrin has been modifiedand altered over time: it has undergone episodic positiveselection and selective pressure played key role in its func-tional evolution (Schaner et al., 2001).

Possible selective advantage of heterozygotes

Available data on the distribution of MEFV mutations inthe Mediterranean area indicate that the gene is under thepressure of selection within some human populations.Otherwise it would be quite difficult if not impossible toexplain the strikingly high MEFV mutation frequencies inlocalized regions. Therefore the majority of researchersconsider the hypothesis of heterozygote advantage asthe most probable mechanism of selection. This mecha-

nism is responsible for some common inherited disorders,for example sickle cell anaemia, cystic fibrosis,

haemochromatosis, etc. See also: Cystic Fibrosis; SickleCell Anaemia

Several arguments support the hypothesis of selectiveadvantage of MEFV mutation carriers (heterozygotes) andat the same time reject the possible role of founder effectand genetic drift (which in many cases account for high

frequency of deleterious mutations) as the main causes of high incidence of FMF in the region. Firstly, FMF is

mainly confined to the Mediterranean region and is virtu-ally absent in other populations worldwide, thus ruling outhigh mutation rates in the MEFV gene. Secondly, the pres-ence of multiple mutations with high frequencies in thesame population strongly supports a selective advantage inthe carriers of MEFV mutations; in the case of foundereffect usually one predominant mutation is observed. Itshould be added that founder effect and genetic drift areworking in small isolated groups, whereas all classicallyaffected populations have been relatively large. Finally,

compound heterozygotes account for a significant propor-tion of affected individuals, which confirms ancient originof the mutations. See also: Balancing Selection in HumanEvolution; Ethnicity and Disease; Heterozygous Advan-tage; Selection and Common Monogenic Disease

The possibility of heterozygote advantage in FMF inev-itably raises the question about the precise nature of theagent(s) which are opposed by selective advantage. Differentinfectious and noninfectious diseases have been proposed as

agents to which MEFV heterozygotes have increased resis-tance: tuberculosis (Cattan, 2003), brucellosis (Ross, 2006),allergy (Sackesen et al., 2004; Kalyoncu et al., 2006), asthma(Brenner-Ullman et al., 1994; Rabinovitch et al., 2007),

smallpox (Gul, 2006), etc., but none of these has been un-ambiguously proven yet. However, the selective advantageof the carriers of MEFV mutations may originate fromheightened innate immune response to a large class of in-fectious agents rather than to a single pathogen. Anotherobstacle in the way of identifying the exact factor causing

heterozygote advantage is the widespread use of antibiotictherapy and modern public health measures, which likelymask harmful consequences of infectious diseases.

Conclusions and Perspectives

The ‘molecular genetic history’ of FMF goes back just overa decade. During this time different aspects related to the

molecular mechanisms of the disorder have been clarified.Large numbers of mutations in the MEFV gene were iden-tified, though only a few of them are common and aremainly confined to one exon. Consequently, many popu-lations of the Mediterranean area and beyond have beenstudied for the presence of different MEFV mutations.Some progress has been made in studying the function of pyrin, its participation in innate immune response and therole of its altered function (due to mutations) in the patho-genesis of FMF. The relationship between specific MEFV

genotypes and FMF clinical manifestation has been estab-lished. Owing to various genetic and environmental






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modifying factors the genotype/phenotype correlation isstill not completely understood. Rough estimations of theage of MEFV mutations have been performed and differenthypotheses on the possible heterozygote advantage inFMF have been suggested.

However, there is still a lot of work to be done. Firstly,

the precise function of wild-type pyrin and molecularpathogenesis of FMF should be elucidated. The clarifica-

tion of pyrin’s role in inflammatory pathways will providenecessary information in designing new treatment strate-gies. Considering the fact that some FMF patients do nothave any MEFV mutations, further efforts should be tar-geted at revealing ‘the participants’ of inflammation inter-acting with wild-type pyrin. This will help to identify othergenes whose mutations cause FMF symptoms.

So far it is not completely clear whether the mutations inthe MEFV gene resultin loss of function or gain of functionfor pyrin. The vast majority of MEFV mutations are mis-

sense and these possibly alter rather than destroy the func-tion of pyrin. The existence of multiple frequent mutationsand recessive inheritance of FMF favour the loss-of-fun-ction view. However, the presence of an inflammatoryphenotype in carriers could be alternatively explained byan autosomal dominant mode of inheritance with greatlyreduced penetrance in heterozygotes.

The role of modifying factors for FMF is far from beingfully understood. It seems that more factors are involved in

altering the pattern of FMF clinical manifestation than areknown so far. Identification of the distinct ‘risk factors’ of FMF severity may significantly contribute to the manage-ment of patients.

Further steps in clarifying the evolutionary features of FMF related to more precise estimation of the ages andplaces of origin of MEFV mutations will require using moreSTRs and larger samples from different regions. Establish-ing theselective advantageof MEFV heterozygotes is a morecomplicated issue. The proposed hypotheses attempt to

demonstrate the existence of advantage based on morbidityand mortality data of carriers. However this approachproved not to be an efficient way to proceed. It seems that abetter strategy to elucidate the exact nature of heterozygoteadvantage should be based on the knowledge of the precisefunction of pyrin in inflammation. The same method hasbeen successfully applied in case of cystic fibrosis.

Past successes and ongoing developments in the molec-ular genetics of FMF provide hope that it is a matter of timebefore both precise and timely diagnosis and significantly

improved treatment strategies emerge.

References

Akar N, Misiroglu M, Yalcinkaya F et al. (1999) MEFV muta-

tions in Turkish patients suffering from familial Mediterranean

fever. Human Mutation 15: 118–119.

AksentijevichI, Torosyan Y, Samuels J etal. (1999) Mutation and

haplotype studies of familial Mediterranean fever reveal new

ancestral relationships andevidence for a high carrierfrequency

with reduced penetrance in the Ashkenazi Jewish population.

American Journal of Human Genetics 64: 949–962.

Aldea A, Calafell F, Arostegui JI etal. (2004a)The westside story:

MEFV haplotype in Spanish FMF patients and controls, and

evidence of high LD and a recombination ‘‘Hot-Spot’’ at the

MEFV locus. Human Mutation 23: 399.

Aldea A, Campistol JM, Arostegui JI et al. (2004b) A severe au-tosomal-dominant periodic inflammatory disorder with renal

AA amyloidosis and colchicine resistance associated to the

MEFV H478Y variantin a Spanishkindred:an unusual familial

mediterranean fever phenotype or another MEFV -associated

periodic inflammatory disorder? American Journal of Medical

Genetics 124A: 67–73.

Atagunduz MP, Tuglular S, Kantarci G, Akoglu E and

Direskeneli H (2004) Association of FMF-related (MEFV )

point mutations with secondary and FMF amyloidosis. Ne-

phron Clinical Practice 96: 131–135.

Belmahi L, Sefiani A, Fouveau C et al. (2006) Prevalence and

distribution of MEFV mutations among Arabs from the Ma-

ghreb patients suffering from familial Mediterranean fever.Comptes Rendus Biologies 329: 71–74.

Bernot A, daSilva C, Petit J-L et al. (1998) Non-founder muta-

tions in the MEFV gene establish this gene as the cause of

familial Mediterranean fever (FMF). Human Molecular Genet-

ics 7: 1317–1325.

Booth DR, Gillmore JD, Lachmann HJ et al. (2000) The genetic

basis of autosomal dominant familial Mediterranean fever. The

Quarterly Journal of Medicine 93: 217–221.

Booth DR, Lachmann HJ, Gillmore JD, Booth SE and Hawkins

PN (2001) Prevalence and significance of the familial Mediter-

ranean fever gene mutation encoding pyrin Q148. The Quarterly

Journal of Medicine 94: 527–531.

Brenner-Ullman A, Melzer-Ofir H, Daniels M and Shohat M

(1994) Possible protection against asthma in heterozygotes for

familial Mediterranean fever. American Journal of Medical

Genetics 53: 172–175.

Cattan D (2003) Familial Mediterranean fever: is low mortality

from tuberculosis a specific advantage for MEFV mutation

carriers? Mortality from tuberculosis among Muslim, Jewish,

French, Italian and Maltese patients in Tunis (Tunisia) in the

first half of the 20th century. Clinical & Experimental Rheum-

atology 21(Suppl. 30): S53–S54.

Cazeneuve C, AjrapetyanH, Papin S et al. (2000) Identification of

MEFV -independent modifying genetic factors for familial

Mediterranean fever. American Journal of Human Genetics 67:

1136–1143.

Cazeneuve C, Sarkisian T, Pecheux C et al. (1999) MEFV -geneanalysis in Armenian patients with familial Mediterranean fe-

ver: diagnostic value and unfavorable renal prognosis of the

M694V homozygous genotype – genetic and therapeutic im-

plications. American Journal of Human Genetics 65: 88–97.

Centola M, Aksentijevich I and Kastner DL (1998) The hereditary

periodic fever syndromes: molecular analysis of a new family of

inflammatory diseases. HumanMolecular Genetics 7: 1581–1588.

Centola M, Wood G, Frucht DM et al. (2000) The gene for

familial Mediterranean fever, MEFV , is expressed in early

leukocyte development and is regulated in response to inflam-

matory mediators. Blood 95: 3223–3231.

Chae JJ, Centola M, Aksentijevich I et al. (2000) Isolation, ge-

nomic organization, and expression analysis of the mouse and





rat homologs of MEFV , the gene for familial Mediterranean

fever. Mammalian Genome 11: 428–435.

Chae JJ, KomarowHD, Cheng J et al. (2003) Targeted disruption

of pyrin, the FMF protein, causes heightened sensitivity to

endotoxin and a defect in macrophage apoptosis. Molecular

Cell 11: 591–604.

Dewalle M, Domingo C, Rozenbaum M et al. (1998) Phenotype-genotype correlation in Jewish patients suffering from familial

Mediterranean fever (FMF). European Journal of Human Ge-

netics 6: 95–97.

Diaz A, Hu C, Kastner DL et al. (2004) 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 & Rheumatism 50:

3679–3689.

Dode C, Pecheux C, Cazeneuve C et al. (2000) Mutations in the

MEFV gene in a large series of patients with a clinical diagnosis

of familial Mediterranean fever. American Journal of Medical

Genetics92

: 241–246.French FMF Consortium (1997) A candidate gene for familial

Mediterranean fever. Nature Genetics 17: 25–31.

Gershoni-Baruch R, Brik R, Zacks N et al. (2003) The contribu-

tion of genotypes at the MEFV and SAA1 loci to amyloidosis

and disease severity in patients with familial Mediterranean fe-

ver. Arthritis & Rheumatism 48: 1149–1155.

Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K and Brik R

(2001) Familial Mediterranean fever: prevalence, penetrance

and genetic drift. European Journal of Human Genetics

9: 634–637.

Goulielmos GN, Fragouli E, Aksentijevich I et al. (2006)

Mutational analysis of the PRYSPRY domain of pyrin

and implications for familial Mediterranean fever (FMF). Bi-

ochemical and Biophysical Research Communications 345:

1326–1332.

Gul A (2006) Selective pressures for the high prevalence of

MEFV variants induced by smallpox infection in the ‘‘Old

World’’: a hypothesis. Clinical & Experimental Rheumatology

24: 213.

International FMF Consortium (1997) The ancient missense mu-

tations in a new member of the RoRet gene family are likely to

cause familial Mediterranean fever. Cell 90: 797–807.

Jalkh N,Ge ´ nin E,Chouery E etal. (2007) Familial Mediterranean

fever in Lebanon: founder effects for different MEFV muta-

tions. Annals of Human Genetics 72: 41–47.

Kalyoncu M, Acar BC, Cakar N et al. (2006) Are carriers for

MEFV mutations ‘‘healthy’’? Clinical & Experimental Rheuma-tology 24(Suppl. 42): S120–S122.

Kogan A, Shinar Y, Lidar M et al. (2001) Common MEFV mu-

tations among Jewish ethnic groups in Israel: high frequency of

carrier and phenotype III states and absence of a perceptible

biological advantage for the carrier state. American Journal of

Medical Genetics 102: 272–276.

Livneh A, Langevitz P, Zemer D et al. (1997) Criteria for the

diagnosis of familial Mediterranean fever. Arthritis & Rheuma-

tism 40: 1879–1885.

Mattit H, Joma M, Al-Cheikh S et al. (2006) Familial Mediter-

ranean fever in the Syrian population: gene mutation frequen-

cies, carrier rates and phenotype–genotype correlation.

European Journal of Medical Genetics 49: 481–486.

Mimouni A, Magal N, Stoffman N et al. (2000) Familial Med-

iterranean fever: effects of genotype and ethnicity on inflam-

matory attacks and amyloidosis. Pediatrics 105: E70.

Notarnicola C, Didelot M-N, Kone-Paut I et al. (2002) Re-

duced MEFV messenger RNA expression in patients with

familial Mediterranean fever. Arthritis & Rheumatism 46:

2785–2793.Papin S, Duquesnoy P, Cazeneuve C et al. (2000) Alternative

splicing at the MEFV locus involved in familial Mediterranean

fever regulates translocation of the marenostrin/pyrin protein

to the nucleus. Human Molecular Genetics 9: 3001–3009.

Rabinovitch E, Harats D, Yaron P et al. (2007) Familial Med-

iterranean fever gene and protection against asthma. Annals of

Allergy, Asthma & Immunology 99: 517–521.

Ross JJ (2006) Goats, germs, and fever: are the pyrin mutations

responsible for familial Mediterranean fever protective against

Brucellosis? Medical Hypotheses 68: 499–501.

Sackesen C, Bakkaloglu A, Sekerel BE et al. (2004) Decreased

prevalence of atopy in paediatric patients with familial Med-

iterranean fever. Annals of the Rheumatic Diseases63

: 187–190.SarkisianT, AjrapetyanH and Shahsuvaryan G (2005) Molecular

study of FMF patients in Armenia. Current Drug Targets –

Inflammation & Allergy 4: 113–116.

Schaner P, Richards N, Wadhwa A et al. (2001) Episodic evolu-

tion of pyrin in primates: human mutations recapitulate ances-

tral amino acid states. Nature Genetics 27: 318–321.

Shohat M, Magal N, Shohat T et al. (1999) Phenotype–genotype

correlation in familial Mediterranean fever: evidence for an as-

sociation between Met694Val and amyloidosis. European Jour-

nal of Human Genetics 7: 287–292.

Siegal S (1945) Benign paroxysmal peritonitis. Annals of Internal

Medicine 23: 1–22.

Stoffman N, Magal N, ShohatT etal. (2000) Higher than expected

carrier rates for familial Mediterranean fever in various Jewish

ethnic groups. European Journal of Human Genetics 8: 307–310.

Tchernitchko DO, Ge ´ rard-Blanluet M, Legendre M et al. (2006)

Intrafamilial segregation analysis of the p.E148Q MEFV allele

in familial Mediterranean fever. Annals of the Rheumatic Dis-

eases 65: 1154–1157.

Topaloglu R, Ozaltin F, Yilmaz E et al. (2005) E148Qis a disease-

causing MEFV mutation: a phenotypic evaluation in patients

with familial Mediterranean fever. Annals of the Rheumatic

Diseases 64: 750–752.

Touitou I, Picot M-C, Domingo C et al. (2001) The MICA region

determines the first modifier locus in familial Mediterranean

fever. Arthritis & Rheumatism 44: 163–169.

Touitou I, Sarkisian T, Medlej-Hashim M etal. (2007) Country asthe primary risk factor for renal amyloidosis in familial Med-

iterranean fever. Arthritis & Rheumatism 56: 1706–1712.

Yalcinkaya F, C akar N, Misirlio]lu M et al. (2000) Genotype-

phenotype correlation in a large group of Turkish patients with

familial Mediterranean fever: evidence for mutation-indepen-

dent amyloidosis. Rheumatology 39: 67–72.

Yilmaz E, Ozen S, Balci B et al. (2001) Mutation frequency of

familial Mediterraneanfever andevidence fora high carrier rate

in the Turkish population. European Journal of Human Genetics

9: 553–555.

Yu J-W, Fernandes-Alnemri T, Datta P et al. (2007) Pyrin acti-

vates theASC pyroptosome in response to engagement by auto-

inflammatory PSTPIP1 mutants. Molecular Cell 28: 214–227.





Further Reading

Cattan D (2005) MEFV mutation carriers and diseases other than

familial Mediterranean fever: proved and non-proved associ-

ations; putative biological advantage. Current Drug Targets –

Inflammation & Allergy 4: 59–66.

Schaner PE and Gumucio DL (2005) Familial Mediterranean fe-verin the post-genomic era: how an ancient disease is providing

new insights into inflammatory pathways. Current Drug

Targets – Inflammation & Allergy 4: 67–76.

Simon A and van derMeer JWM (2007) Pathogenesis of familial

periodic fever syndromes or hereditary autoinflammatory syn-

dromes. American Journal of Physiology – Regulatory, Integra-

tive and Comparative Physiology 292: 86–98.

Stiehm ER (2006) Disease versus disease: how one disease may

ameliorate another. Pediatrics 117: 184–191.

Ting JP-Y, Kastner DL and Hoffman HM (2006) CATER-

PILLERs, pyrin and hereditary immunological disorders.

Nature Reviews Immunology 6: 183–195.

Touitou I (2001) The spectrum of familial Mediterranean fever

(FMF) mutations. European Journal of Human Genetics

9: 473–483.

Yepiskoposyan L and Harutyunyan A (2007) Population genetics

of familial Mediterranean fever: a review. European Journal of

Human Genetics 15: 911–916.

Zlotogora J (2007) Multiple mutations responsible for frequentgenetic diseases in isolated populations. European Journal of

Human Genetics 15: 272–278.

Web Links

INFEVERS database http://fmf.igh.cnrs.fr/ISSAID/infevers/

MetaFMF database http://fmf.igh.cnrs.fr/metaFMF/

Online Mendelian Inheritance in Man (OMIM) Johns Hopkins

University, Baltimore, Md. MIM numbers: 249100 (familial

Mediterranean fever, FMF), 608107 (familial Mediterranean

fever gene, MEFV ) http://www.ncbi.nlm.nih.gov/omim/



genetica moleculara a febrei mediteraneene familiale

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