Familial Mediterranean fever with a single MEFV mutation: where is the second hit?

Arthritis Rheum. 2009 Jun;60(6):1851-61. doi: 10.1002/art.24569.


Objective: Familial Mediterranean fever (FMF) has traditionally been considered an autosomal-recessive disease; however, it has been observed that a substantial number of patients with clinical FMF possess only 1 demonstrable MEFV mutation. The purpose of this study was to perform an extensive search for a second MEFV mutation in 46 patients diagnosed clinically as having FMF and carrying only 1 high-penetrance FMF mutation.

Methods: MEFV and other candidate genes were sequenced by standard capillary electrophoresis. In 10 patients, the entire 15-kb MEFV genomic region was resequenced using hybridization-based chip technology. MEFV gene expression levels were determined by quantitative reverse transcription-polymerase chain reaction. Pyrin protein levels were examined by Western blotting.

Results: A second MEFV mutation was not identified in any of the patients who were screened. Haplotype analysis did not identify a common haplotype that might be associated with the transmission of a second FMF allele. Western blots did not demonstrate a significant difference in pyrin levels between patients with a single mutation and those with a double mutation; however, FMF patients of both types showed higher protein expression as compared with controls and with non-FMF patients with active inflammation. Screening of genes encoding pyrin-interacting proteins identified rare mutations in a small number of patients, suggesting the possibility of digenic inheritance.

Conclusion: Our data underscore the existence of a significant subset of FMF patients who are carriers of only 1 MEFV mutation and demonstrate that complete MEFV sequencing is not likely to yield a second mutation. Screening for the set of the most common mutations and detection of a single mutation appears to be sufficient in the presence of clinical symptoms for the diagnosis of FMF and the initiation of a trial of colchicine.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cohort Studies
  • Colchicine / therapeutic use
  • Cytoskeletal Proteins / genetics*
  • Cytoskeletal Proteins / metabolism
  • DNA / genetics
  • Familial Mediterranean Fever / diagnosis*
  • Familial Mediterranean Fever / drug therapy
  • Familial Mediterranean Fever / genetics*
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genetic Testing
  • Haplotypes / genetics
  • Humans
  • Infant
  • Male
  • Mutation / genetics*
  • Pyrin
  • Retrospective Studies
  • Tubulin Modulators / therapeutic use
  • Young Adult


  • Cytoskeletal Proteins
  • MEFV protein, human
  • Pyrin
  • Tubulin Modulators
  • DNA
  • Colchicine