title: Familial Mediterranean fever with a single MEFV mutation: where is the second hit?
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland 20892-1820, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Booty
authors.forename: Jae Jin
authors.initials: JJ
authors.lastname: Chae
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: Beverly
authors.initials: B
authors.lastname: Barham
authors.forename: Julie M
authors.initials: JM
authors.lastname: Le
authors.forename: Karyl S
authors.initials: KS
authors.lastname: Barron
authors.forename: Steve M
authors.initials: SM
authors.lastname: Holland
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Ivona
authors.initials: I
authors.lastname: Aksentijevich
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003078:Colchicine / Q000627:therapeutic use; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D010505:Familial Mediterranean Fever / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D000071198:Pyrin; D012189:Retrospective Studies; D050257:Tubulin Modulators / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D003598:Cytoskeletal Proteins; C000604192:MEFV protein, human; D000071198:Pyrin; D050257:Tubulin Modulators; D004247:DNA; D003078:Colchicine