Unique spectrum of MEFV mutations in Iranian Jewish FMF patients--clinical and demographic significance.

OBJECTIVES To determine the spectrum of mutations in the Mediterranean fever gene (MEFV) of Iranian Jews with familial Mediterranean fever (FMF) and to analyse their clinical manifestations. METHODS FMF patients with both parents of Iranian-Jewish (IJ) extraction or with one IJ parent (IJ-other, 10 of each) were characterized for clinical manifestations, and the B30.2 (PRYSPRY) domain of their MEFV was sequenced for mutations. RESULTS Only one rare mutation, R653H, and one new mutation, G632S were present in the IJ group (in 2/10 patients), whereas the new, and common mutations were present in the IJ-other patients (8/10 patients). The new mutation was traced thrice to an IJ ancestor, and although carried asymptomatically by family members, it was over-represented in the patients (3/28 unrelated IJ alleles) compared non-affected IJ subjects (1/126 alleles, P = 0.03) or with non-Jewish Iranians (0/108 alleles, P = 0.001). The mutation was associated with a distinct phenotype regarding sites involved in the attack (P = 0.001), mild severity, sole expression of febrile episodes (P = 0.01) and a male bias (P = 0.01). In two 3D PRYSPRY models the G632S mutation was localized to a surface loop and close to a putative binding site. CONCLUSIONS Iranian Jews with FMF have a unique spectrum of mutations including a newly described mutation with a non-typical phenotype.