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Comptes Rendus

Genetics / Génétique
Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever
Comptes Rendus. Biologies, Volume 329 (2006) no. 2, pp. 71-74.

Abstracts

Familial Mediterranean fever (FMF) is an autosomal recessive inherited disease caused by mutations in MEFV. This disease is characterized by recurrent episodes of fever accompanied with topical signs of inflammation. Some patients can develop renal amyloidosis. We prospectively investigated MEFV mutations in a cohort of 209 unrelated Arab patients from Maghreb (85 Algerians, 87 Moroccans, and 37 Tunisians) with a clinical suspicion of FMF. FMF is the main cause of periodic fever syndrome in Maghreb. The most frequent MEFV mutations in this cohort were M694V and M694I. These mutations account for different proportions of the MEFV mutations in Algeria (5%, 80%), Morocco (49%, 37%), and Tunisia (50%, 25%) patients. M694I mutation is specific to the Arab population from Maghreb. Other rare mutations were observed: M680L, M680I, A744S, V726A, and E148Q. We estimated the frequency of MEFV mutation carriers among the Arab Maghrebian population at around 1%, which is significantly lower than in non-Ashkenazi Jews, Armenians or Turks.

La fièvre méditerranéenne familiale (FMF) est une maladie génétique autosomique récessive due à des mutations dans MEFV. Cette maladie de l'inflammation est caractérisée, le plus souvent, par des épisodes récurrents de fièvre, accompagnés de douleurs abdominales et articulaires. Nous avons recherché des mutations dans MEFV chez 209 malades Arabes non liés génétiquement et originaires du Maghreb (85 Algériens, 87 Marocains, 37 Tunisiens) ayant un diagnostic clinique de FMF. La FMF est la principale cause de fièvre périodique au Maghreb. Les mutations MEFV les plus fréquentes trouvées dans cette population sont M694V et M694I. Leur fréquence est variable selon les populations en Algérie (5%, 80%), au Maroc (49%, 37%) et en Tunisie (50%, 25%). La mutation M694I est spécifique de la population arabe du Maghreb. D'autres mutations rares ont été trouvées : M680L, M680I, A744S, V726A et E148Q. Nous avons estimé que la fréquence des individus hétérozygotes porteurs de la mutation dans la population normale est de l'ordre de 1%, ce qui est significativement beaucoup plus faible que dans les autres populations à risque pour cette maladie (Juifs non ashkénazes, Arméniens et Turcs).

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DOI: 10.1016/j.crvi.2005.11.005
Keywords: Familial Mediterranean Fever, Pyrin/Marenostrin, Inherited inflammatory disorder
Mot clés : Fièvre méditerranéenne familiale, Pyrine/Marénostrine, Syndrome inflammatoire d'origine génétique

Latifa Belmahi 1; Abdelaziz Sefiani 1; Corinne Fouveau 2; Josué Feingold 2; Marc Delpech 2; Gilles Grateau 3; Catherine Dodé 2

1 Laboratoire de génétique, Institut national d'hygiène, 11400 Rabat, Morocco
2 Laboratoire de génétique et de biochimie moléculaire, université Paris-5, hôpital Cochin, 24, rue du Faubourg-Saint-Jacques, 75014 Paris, France
3 Service de médecine interne, hôpital Tenon, 4, rue de la Chine, 75020 Paris, France
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     title = {Prevalence and distribution of {\protect\emph{MEFV}} mutations among {Arabs} from the {Maghreb} patients suffering from familial {Mediterranean} fever},
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Latifa Belmahi; Abdelaziz Sefiani; Corinne Fouveau; Josué Feingold; Marc Delpech; Gilles Grateau; Catherine Dodé. Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. Comptes Rendus. Biologies, Volume 329 (2006) no. 2, pp. 71-74. doi : 10.1016/j.crvi.2005.11.005. https://comptes-rendus.academie-sciences.fr/biologies/articles/10.1016/j.crvi.2005.11.005/

Version originale du texte intégral

Version française abrégée

La fièvre méditerranéenne familiale (FMF, MIM 249100) est une maladie autosomique récessive due à des mutations dans MEFV. La FMF est caractérisée par des épisodes récurrents de fièvre accompagnés de douleurs abdominales et articulaires. L'amylose rénale est l'une des complications les plus fréquentes et la plus grave. La colchicine prévient les crises inflammatoires ainsi que le développement de l'amylose. La FMF est très fréquente chez les Juifs non ashkénazes, les Arméniens, les Turcs et les Arabes.

Le but de la présente étude est de déterminer les mutations MEFV et leurs fréquences au sein de la population arabe du Maghreb. Pour ceci, nous avons étudié 209 patients suspects de FMF originaires d'Algérie (85), du Maroc (87) et de Tunisie (37). Nous avons confirmé le diagnostic de FMF par la présence de deux mutations à l'état, soit homozygote, soit hétérozygote composite, chez 29 Algériens, 33 Marocains et 7 Tunisiens. Un seul allèle a été trouvé chez 11 Algériens, 9 Marocains et 6 Tunisiens. Les deux mutations les plus fréquentes sont M694I et M694V, mais leur répartition dans les trois pays est très différente, M694I représente 80% des allèles mutés en Algérie, 37% au Maroc et 25% en Tunisie, alors que la mutation M694V représente 5% en Algérie, 49% au Maroc et 50% en Tunisie. La mutation M694I est spécifique des populations arabes du Maghreb et n'est pas retrouvée dans les autres populations à risque citées auparavant, contrairement à la mutation M694V. Ces deux mutations sont très anciennes : elles sont apparues il y a plus de 2000 ans. Des études de polymorphisme du chromosome Y dans la population marocaine ont montré que l'arabisation et l'islamisation de la population berbère est un phénomène culturel et que la population actuelle est génétiquement et principalement d'origine berbère. Il semble donc que la mutation M694I soit d'origine berbère et que la mutation M694V ait été amenée dans cette région au cours des différentes migrations de certaines populations et notamment par les Juifs non ashkénazes par l'est et par l'Espagne.

Nous avons, de plus, estimé que la fréquence des allèles mutés de MEFV dans la population normale n'excède pas 1%, ce qui est beaucoup plus faible que dans les autres populations à risque. La persistance des mutations MEFV chez les Arabes du Maghreb ne semble donc pas s'expliquer par une forte pression de sélection.

1 Introduction

Familial Mediterranean fever (FMF, MIM 249100) is an autosomal recessive disorder of the group of hereditary recurrent inflammatory fevers and are due to mutations in MEFV [1,2]. FMF is characterized by recurrent episodes of fever accompanied with topical signs of inflammation mainly in the peritoneal, pleural and articular cavities. Renal amyloidosis is a frequent complication. Colchicine has been shown to be effective in preventing attacks as well as the development of amyloidosis. FMF is very common in populations of the Mediterranean Basin, mainly Non-Ashkenazi Jews, Armenians and Turks. In these populations, the estimated carrier rates are very high (1/6 in Armenians and Turks, 1/7 in Non-Ashkenazi Jews), suggesting heterozygote advantage against an as yet not defined infectious pathogen [3,4]. FMF also affects Arab populations, but the prevalence among the North-African Arabs is still unknown.

The aim of this study was to describe the MEFV mutation spectrum frequencies among Arab patients from the Maghreb (Algeria, Morocco and Tunisia) and to estimate the carrier rate among the healthy control population.

2 Subjects and methods

We studied 209 unrelated patients in whom FMF was suspected on a clinical basis according to FMF criteria [5]. Main clinical data were registered on a standardized form [6]. Both parents of the patients were North-African Arabs originating from different countries of the Maghreb: Algeria (85) Morocco (87), and Tunisia (37). Informed consent was given by all patients.

3 Mutation search in MEFV

To search for MEFV mutations, exons 5 and 10 were PCR amplified and sequenced. The E148Q mutation in exon 2 was detected by PCR amplification followed by Ava I digestion as previously described [6].

4 Results and discussion

We studied a cohort of 209 Arab patients from the Maghreb, with a high suspicious diagnosis of periodic fever syndrome. We searched for mutations in MEFV and confirmed the FMF diagnosis by the presence of two mutations in 29/85 (34%) Algerians, 33/87 (38%) Moroccans, and 7/37 Tunisians (19%). Only one FMF allele was found in 11/85 (12%) Algerians, 9/87 (10%) Moroccans and 6/37 (16%) Tunisians. The spectrum of MEFV mutations and the patient's genotypes are given in Tables 1 and 2, respectively. The most frequent mutations are M694I and M694V, but their respective frequencies are different in Algeria, Tunisia, and Morocco. Among patients carrying two MEFV mutations, the M694I mutation is the more frequent one in Algeria (80%), but not in Morocco (37%) and Tunisia (25%), whereas the M694V mutation is more frequently observed in Morocco (49%) and Tunisia (50%) than in Algeria (5%). In contrast to the M694V mutation, which is shared by the different at risk ethnic groups affected by FMF, the M694I mutation is characteristic of the Arab population of the Maghreb. In this study, we also detected rare mutations such as M680I, M680L, V726A, A744S, and E148Q. The M680L mutation has previously been described in a Berber consanguineous family living in Morocco [6]. A previous report [7] has established that the M694V, V726A, M680I and M694I mutation frequencies among Arabs from the Middle-East were 15%, 30%, 18%, and 8%, respectively, which is very different from those observed here in North African Arabs.

Table 1

Spectrum of MEFV mutations among Arabs from the Maghreb affected by FMF

Algeria Morocco Tunisia
M694I 55 28 5
M694V 4 37 10
M680I 1 1 1
E148Q 6 5 3
M680L 0 2 0
V726A 1 0 0
A744S 2 0 1
Total of alleles 69 75 20
Table 2

MEFV genotypes responsible for FMF among Arabs from the Maghreb

Algeria Morocco Tunisia Total
M694I/M694I 21 9 0 30
M694V/M694V 1 16 4 21
M680L/M680L 0 2 0 2
M694V/M694I 1 3 1 5
M694I/M680I 1 1 1 3
M694V/V726A 1 0 0 1
M694I/E148Q 4 2 1 7
M694I 7 4 2 13
M694V 0 2 1 3
E148Q 2 3 2 7
A744S 2 0 1 3
? 45 45 24 114
Total 85 87 37 209

M694I is probably as M694V [2] an ancient mutation based on the following arguments: (i) M694I is present in three different countries, (ii) M694I is rarely described in other populations, (iii) M694I is not a recurrent mutation. A study of Y-chromosome variation among Moroccan Arabs demonstrated that Arabization and Islamization of North Africa starting during the 7th century, was a cultural phenomena without extensive genetic replacement [8] and can explain that the M694I mutation is now still present in the same region where the population remains Berber [9]. The M694V mutation in Arabs of Maghreb could have been inherited from the local Jewish population that came from the Middle East after the destruction of Salomon's temple and from Spain from 1492 onwards. During this second flee, which lasted for more than 200 years, the Jewish population from Spain settled mainly in Morocco. These historical data can explain the very different ratios of the M694V and M694I mutations observed in the three countries of the Maghreb.

We estimated the MEFV mutation carrier frequency in the Arab from Maghreb general population by studying 113 healthy and unrelated individuals (50 Moroccans, 32 Tunisians and 31 Algerians). Only one Moroccan carried a heterozygous M694V mutation leading a carrier frequency below 1%, which is much lower than in the other FMF at-risk populations (Armenians, Turks, Non-Ashkenazi Jews). In terms of selection pressure, this result argues against a strong heterozygote advantage in the Arab population from Maghreb.

In our series, the high proportion of patients without detected MEFV mutations suggest that other genes are involved in these periodic fever syndromes, as previously postulated in the Turkish and Armenians from the Karabakh population [10]. This hypothesis agrees with the observation of two unrelated families from Algeria and Tunisia, with several patients affected by renal amyloidosis associated with periodic fever syndrome without MEFV and TNFRSF1A mutation [11].

Acknowledgements

We thank Prof. Cattan and Dr Jean-Pierre Hardelin for fruitful discussions. Our work on hereditary periodic fever syndromes is supported by grants (N A00047KS) from the INSERM–AFM network on rare diseases, a PHRC (No. 990505) and ‘Coopération franco-marocaine’ (INSERM/CNPRST).


References

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[2] International FMF Consortium Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever, Cell, Volume 90 (1997), pp. 797-807

[3] M. Daniels; T. Shohat; A. Brenner-Ullman; M. Shohat Familial Mediterranean fever: high gene frequency among in the Non-Ashkenazi Jewish populations in Israel, Am. J. Med. Genet., Volume 55 (1995), pp. 311-314

[4] D.B. Rogers; M. Shohat; G.M. Petersen et al. Familial Mediterranean fever in Armenians. Autosomal recessive inheritance with high gene frequency, Am. J. Med. Genet., Volume 34 (1989), pp. 168-172

[5] A. Livneh; P. Langevitz; D. Zemer et al. Criteria for the diagnosis of familial Mediterranean fever, Arthritis Rheum., Volume 40 (1997), pp. 1879-1885

[6] C. Dodé; C. Pêcheux; C. Cazeneuve; D. Cattan et al. Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever, Am. J. Med. Genet., Volume 92 (2000), pp. 241-246

[7] R. Gershoni-Baruch; M. Shinawi; K. Leah et al. Familial Mediterranean fever: prevalence, penetrance and genetic drift, Eur. J. Hum. Genet., Volume 9 (2001), pp. 634-637

[8] E. Bosch; F. Calafell; D. Comas et al. High-resolution analysis of human Y-chromosome variation shows a sharp continuity and limited gene flow between northwestern Africa and Iberian Peninsula, Am. J. Hum. Genet., Volume 68 (2001), pp. 1019-1029

[9] D. Labie; M. Benabadji; J. Elion Genetic disorders in North African populations of the Maghreb: Morocco, Algeria and Tunisia (A.S. Teebi; T.I. Farag, eds.), Genetic Disorders among Arab Populations, Oxford Monographs on Medical Genetics No. 30, Oxford University Press, Oxford, 1996, pp. 290-321

[10] C. Cazeneuve; Z. Hovannesyan; D. Geneviève et al. Familial Mediterranean Fever among patients from Karabakh and the diagnostic value of MEFV gene analysis in all classically affected populations, Arthritis Rheum., Volume 48 (2003), pp. 2324-2331

[11] C. Dodé; B. Hazenberg; C. Pêcheux et al. Mutational spectrum in the MEFV and TNFRSF1A genes in patients suffering from AA amyloidosis and recurrent inflammatory attacks, Nephrol. Dial. Transplant., Volume 17 (2002), pp. 1212-1217


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