Jump to comment:

• E148Q MEFV sequence variation and familial Mediterranean fever
  Serge Amselem
  Published on: 29 November 2004

• Published on: 29 November 2004

  E148Q MEFV sequence variation and familial Mediterranean fever

  • Serge Amselem, Professor of Human Genetics
  • Other Contributors:
    • Dimitri Tchernitchko, Cécile Cazeneuve

  Dear Editor,

  We read with great interest the article by Topaloglu et al (Sep. 30 issue) [1] on the implication of the E148Q sequence variation in familial Mediterranean fever (FMF). In our opinion, the best interpretation of this study is not that E148Q is a disease-causing MEFV mutation, but, rather, that this sequence variation is not involved in FMF, or more precisely that the E148Q allele is not impli...

  Show More

  Dear Editor,

  We read with great interest the article by Topaloglu et al (Sep. 30 issue) [1] on the implication of the E148Q sequence variation in familial Mediterranean fever (FMF). In our opinion, the best interpretation of this study is not that E148Q is a disease-causing MEFV mutation, but, rather, that this sequence variation is not involved in FMF, or more precisely that the E148Q allele is not implicated in the development of FMF.

  Indeed, as no assay exists to date to evaluate the functional consequences of the missense mutations identified in MEFV, it is worth recalling that such sequence variations are considered as disease-causing mutations on the basis of their high incidence in the homozygous or compound heterozygous state in patients only, and not in healthy relatives. This is the case for a few mutations including M694V, but not for E148Q, as recently shown by a study that compared the allele and genotype frequencies in a large group of patients of Sephardic Jewish origin to those found in a control group consisting of healthy relatives [2]. Most importantly, the study by Topaloglu et al. [1] underlines that “the E148Q mutation is the one of the common mutations among the patients with FMF with 3.5% allele frequency, the carrier frequency being found to be 12% in the healthy Turkish population”. This data, therefore, not only does not support the authors’ conclusion (given in the title of this article), but rather strongly argues against the pathogenic role of E148Q in FMF.

  In addition, the inclusion criteria used by the authors are not clear to us, since although the diagnosis of FMF was based on established criteria [3], the authors mention the presence of E148Q in so-called “asymptomatic patients” (4 of the 26 patients homozygous for E148Q) or “quite symptomatic patients”; it seems to us, therefore, particularly difficult to interpret the data presented in tables 1 (e.g. age at onset) and 2 (frequency of phenotypic features). Furthermore, as the authors identified several complex alleles involving E148Q in their population, the patients with a “compound heterozygous genotype” (e.g. E148Q/M694V) may actually carry a complex allele (E148Q-M694V) together with a normal MEFV allele (N), and be, therefore, heterozygous at the MEFV locus (E148Q- M694V/N). In this regard, although the implication of the sole E148Q sequence variation as a disease-causing mutation is so far not demonstrated, it is also worth mentioning a study that suggested the effect of this sequence variation, when combined with V726A (i.e. complex E148Q-V726A allele), in the clinical severity of the FMF disease [4].

  Finally, the authors conclude that the symptomatic individuals homozygous for E148Q should not be ignored. In our opinion, all symptomatic individuals (i.e. patients) should not be ignored, regardless of their MEFV genotype. In particular, all patients with a clinical diagnosis of FMF should benefit from colchicine therapy; and in those patients, the presence of two disease-causing mutations simply allows diagnostic confirmation of MEFV-related FMF. As shown recently by means of population genetics-based studies [5], a FMF-like condition that does not result from mutations in MEFV indeed exists in all populations classically affected by FMF, including patients of Turkish origin; in this latter population, the proportion of patients with a clinical diagnosis of FMF and whose disease phenotype does not result from MEFV mutations is at least of 13% [5]. One cannot, therefore, exclude the possibility that the few symptomatic individuals carrying the E148Q sequence variation identified by Topaloglu et al. [1] have a FMF-like condition unrelated to the MEFV gene.

  References

  (1). Topaloglu, R., Ozaltin, F., Yilmaz, E., Ozen, S., Balci, B., Besbas N., et al. E148Q is a disease causing MEFV mutation: a phenotypic evaluation in patients with familial Mediterranean fever. Ann Rheum Dis 2004; Epub Sep 30.

  (2). Tchernitchko, D., Legendre, M., Cazeneuve, C., Delahaye, A., Niel, F., and Amselem, S. The E148Q MEFV allele is not implicated in the development of familial Mediterranean fever. Hum Mutat 2003; 22:339-340.

  (3). Livneh, A., Langevitz, P., Zemer, D., Zaks, N., Kees, S., Lidar, T., et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40:1879-1885.

  (4). Gershoni-Baruch, R., Brik, R., Shinawi, M., and Livneh, A. The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. Eur J Hum Genet 2002; 10:145-149.

  (5). Cazeneuve, C., Hovannesyan, Z., Genevieve, D., Hayrapetyan, H., Papin, S., Girodon-Boulandet, E., et al. Familial Mediterranean fever among patients from Karabakh and the diagnostic value of MEFV gene analysis in all classically affected populations. Arthritis Rheum 2003; 48:2324-2331.

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top