title: Clinical features and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein.
abstract: OBJECTIVE
  Familial Mediterranean fever (FMF) is caused by mutations in MEFV, which encodes pyrin. The nature of substitutions P369S and R408Q in exon 3 remains unclear. Exon 3 encoding pyrin's B-box domain is necessary for interactions with proline serine threonine phosphatase interacting protein 1 (PSTPIP1). The aim was to characterise the phenotype of patients with these substitutions and to determine their functional significance.
  
  
  METHODS
  A database of genetic tests undertaken at the US National Institutes of Health was interrogated. Symptoms and signs were classified according to Tel-Hashomer criteria. Coimmunoprecipitation techniques were employed to determine the variants' effects on pyrin/PSTPIP1 interactions.
  
  
  RESULTS
  A total of 40 symptomatic and 4 asymptomatic family members with these substitutions were identified. P369S and R408Q were found in cis, and cosegregated in all patients sequenced. Clinical details were available on 22 patients. In all, 5 patients had symptoms and signs fulfilling a clinical diagnosis of FMF, and 15 received colchicine. In patients not achieving the criteria, trials of anti-tumour necrosis factor (TNF) agents resulted in partial or no benefit; resolution of symptoms was noted in those receiving anakinra. The carrier frequency was higher in the patient cohort than in controls but was not statistically significant. Coimmunoprecipitation studies demonstrated that these pyrin variants did not affect binding to PSTPIP1.
  
  
  CONCLUSIONS
  P369S/R408Q substitutions are associated with a highly variable phenotype, and are infrequently associated with typical FMF symptoms, however a trial of colchicine is warranted in all. Functional and modelling studies suggest that these substitutions do not significantly affect pyrin's interaction with PSTPIP1. This study highlights the need for caution in interpreting genetic tests in patients with atypical symptoms.
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Building 10, Magnuson Clinical Center, 10C101C, Bethesda, Maryland 20892, USA. johngryan@gmail.com
authors.forename: J G
authors.initials: JG
authors.lastname: Ryan
authors.forename: S L
authors.initials: SL
authors.lastname: Masters
authors.forename: M G
authors.initials: MG
authors.lastname: Booty
authors.forename: N
authors.initials: N
authors.lastname: Habal
authors.forename: J D
authors.initials: JD
authors.lastname: Alexander
authors.forename: B K
authors.initials: BK
authors.lastname: Barham
authors.forename: E F
authors.initials: EF
authors.lastname: Remmers
authors.forename: K S
authors.initials: KS
authors.lastname: Barron
authors.forename: D L
authors.initials: DL
authors.lastname: Kastner
authors.forename: I
authors.initials: I
authors.lastname: Aksentijevich
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D003078:Colchicine / Q000627:therapeutic use; D003598:Cytoskeletal Proteins / Q000235:genetics*; D010505:Familial Mediterranean Fever / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D008875:Middle Aged; D009154:Mutation; D000071198:Pyrin; D012189:Retrospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D003598:Cytoskeletal Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; C000604192:MEFV protein, human; D000071198:Pyrin; D014409:Tumor Necrosis Factor-alpha; D003078:Colchicine