The genetic basis of autosomal dominant familial Mediterranean fever

Familial Mediterranean fever (FMF) is classically an autosomal recessive pe riodic inflammatory disease occurring in Mediterranean and Middle Eastern p opulations. lt is caused by mutations affecting both alleles of MEFV, a gen e that encodes pyrin (marenostrin), an uncharacterized neutrophil protein. Occasional reports of autosomal dominant FMF have often been discounted, on the basis that asymptomatic FMF carriers are common in certain populations , and give rise to pseudo-dominant inheritance. We performed comprehensive MEFV genotyping in five families in whom FMF appeared to be inherited domin antly. Transmission proved to be pseudo-dominant in two cases, but true dom inant inheritance of FMF with variable penetrance was supported by the geno typing results in the other three families. The disease in these cases was associated with heterozygosity for either pyrin Delta M694 alone or the com pound pyrin variant E148Q/M6941, the latter occurring in two unrelated fami lies. Complete MEFV sequencing failed to identify any coding region abnorma lity in the other allele in any of these cases, and, in the largest kindred , single-allele disease transmission was further supported by analysis of s ilent single nucleotide polymorphisms, which proved that affected individua ls had at least three different complementary alleles. Studies of two furth er unrelated British patients with FMF associated with simple heterozygosit y for pyrin Delta M694 were also consistent with autosomal dominant inherit ance. The clinical features of dominantly inherited FMF were absolutely typ ical, including AA amyloidosis in a patient with pyrin Delta M694. These fi ndings extend the spectrum of FMF, and suggest that the methionine residue at position 694 makes a crucial contribution to pyrin's function, and that a 50% complement of normal pyrin activity does not prevent susceptibility t o FMF.